Advancing equitable access to digital mental health in the Asia-Pacific region in the context of the COVID-19 pandemic and beyond: A modified Delphi consensus study.

The COVID-19 pandemic had an unprecedented impact on global mental health and well-being, including across the Asia-Pacific. Efforts to mitigate virus spread led to far-reaching disruption in the delivery of health and social services. In response, there was a rapid shift to the use of digital mental health (DMH) approaches. Though these technologies helped to improve access to care for many, there was also substantial risk of access barriers leading to increased inequities in access to mental health care, particularly among at-risk and equity-deserving populations. The objective of this study was to conduct a needs assessment and identify priorities related to equitable DMH access among at-risk and equity-deserving populations in the Asia Pacific region during the first year of the COVID-19 pandemic. The study consisted of a modified Delphi consensus methodology including two rounds of online surveys and online consultations with stakeholders from across the region. Study participants included policy makers, clinicians and service providers, and people with lived experience of mental health conditions. Results demonstrate that vulnerabilities to negative mental health impacts and access barriers were compounded during the pandemic. Access barriers included a lack of linguistically and culturally appropriate DMH options, low mental health literacy and poor access to technological infrastructure and devices, low levels of awareness and trust of DMH options, and lack of policies and guidelines to support effective and equitable delivery of DMH. Recommendations to improve equitable access include ensuring that diverse people with lived experience are engaged in research, co-design and policy development, the development and implementation of evidence-based and equity-informed guidelines and frameworks, clear communication about DMH evidence and availability, and the integration of DMH into broader health systems. Study results can inform the development and implementation of equitable DMH as its use becomes more widespread across health systems.

A Randomized Evaluation of MoodFX, a Patient-Centred e-Health Tool to Support Outcome Measurement for Depression: Une évaluation randomisée de MoodFX, un outil de santé en ligne centré sur le patient pour soutenir la mesure du résultat dans la dépression.

BACKGROUND: e-Health tools using validated questionnaires to assess outcomes may facilitate measurement-based care for psychiatric disorders. MoodFX was created as a free online symptom tracker to support patients for outcome measurement in their depression treatment. We conducted a pilot randomized evaluation to examine its usability, and clinical utility. METHODS: Patients presenting with a major depressive episode (within a major depressive or bipolar disorder) were randomly assigned to receive either MoodFX or a health information website as the intervention and control condition, respectively, with follow-up assessment surveys conducted online at baseline, 8 weeks and 6 months. The primary usability outcomes included the percentage of patients with self-reported use of MoodFX 3 or more times during follow up (indicating minimally adequate usage) and usability measures based on the System Usability Scale (SUS). Secondary clinical outcomes included the Quick Inventory of Depressive Symptomatology, Self-Rated (QIDS-SR) and Patient Health Questionnaire (PHQ-9). RESULTS: Forty-nine participants were randomized (24 to MoodFX and 25 to the control condition). Of the 23 participants randomized to MoodFX who completed the user survey, 18 (78%) used MoodFX 3 or more times over the 6 months of the study. The mean SUS score of 72.7 (65th-69th percentile) represents good usability. Compared to the control group, the MoodFX group had significantly better improvement on QIDS-SR and PHQ-9 scores, with large effect sizes and higher response rates at 6 months. There were no differences between conditions on other secondary outcomes such as functioning and quality of life. CONCLUSION: MoodFX demonstrated good usability and was associated with reduction in depressive symptoms. This pilot study supports the use of digital tools in depression treatment.

E-health tools may be useful for measuring and tracking symptoms and other outcomes during treatment for depression. This study is a randomized evaluation of MoodFX, a free web-based app that helps patients track their symptoms using validated questionnaires, and also offers depression information and self-management tips. A total of 49 participants with clinical depression were randomized to using MoodFX or a health information website, for 6 months. In a survey, the participants that used MoodFX found it easy and useful to use. In addition, the participants that used MoodFX had greater improvement in depressive symptoms after 6 months, compared to those who used the health information website. These results suggest that MoodFX may be a useful tool to monitor outcomes and support depression treatment.

A comparative study into the effects of venous and arterial blood on clot microstructure in critically unwell patients. Assessment of the diagnostic potential of a biomarker of haemostasis.

Blood for coagulation analysis can be sampled from the arterial or venous system in intensive care units (ICU). The determination of clot microstructure and strength by fractal analysis (df) gives valuable information in a range of vascular haemostatic disease and sepsis. We aimed to determine if df could be measured equally and comparatively in arterial or venous blood, and 45 critically ill patients in an ICU were recruited. df was found to be readily measured in arterial blood with results comparable to those in venous blood and that add value of df as a potential marker of haemostasis in these patients.

A COVID-19 Vaccination Program to Promote Uptake and Equity for People Experiencing Homelessness in Los Angeles County.

People experiencing homelessness (PEH) have been disproportionately affected by COVID-19, yet their vaccination coverage is lower than is that of the general population. We implemented a COVID-19 vaccination program that used evidence-based and culturally tailored approaches to promote vaccine uptake and equity for PEH in Los Angeles County, California. From February 2021 through February 2022, 33 977 doses of vaccine were administered at 2658 clinics, and 9275 PEH were fully vaccinated. This program may serve as a model for future service delivery in vulnerable populations. (Am J Public Health. 2023;113(2):170-174. https://doi.org/10.2105/AJPH.2022.307147).

Memory CD4+ T cells that co-express PD1 and CTLA4 have reduced response to activating stimuli facilitating HIV latency.

Programmed cell death 1 (PD1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4) suppress CD4+ T cell activation and may promote latent HIV infection. By performing leukapheresis (n = 21) and lymph node biopsies (n = 8) in people with HIV on antiretroviral therapy (ART) and sorting memory CD4+ T cells into subsets based on PD1/CTLA4 expression, we investigate the role of PD1 and CTLA 4 in HIV persistence. We show that double-positive (PD1+CTLA4+) cells in blood contain more HIV DNA compared with double-negative (PD1-CTLA4-) cells but still have a lower proportion of cells producing multiply spliced HIV RNA after stimulation as well as reduced upregulation of T cell activation and proliferation markers. Transcriptomics analyses identify differential expression of key genes regulating T cell activation and proliferation with MAF, KLRB1, and TIGIT being upregulated in double-positive compared with double-negative cells, whereas FOS is downregulated. We conclude that, in addition to being enriched for HIV DNA, double-positive cells are characterized by negative signaling and a reduced capacity to respond to stimulation, favoring HIV latency.

The effects of apixaban on clot characteristics in atrial fibrillation: A novel pharmacodynamic biomarker.

Atrial fibrillation (AF) is a major risk factor for stroke. We aim to characterize AF patients and the effects of apixaban therapy in terms of clot microstructure using gel point analysis, a novel biomarker. Seventy-eight patients were included in the study, 50 Stroke with AF (AF-S), and 28 AF without stroke (AF). Pre- and post-anticoagulation samples were collected: gel point (GP) analysis was performed to obtain (i) TGP (the time taken to reach the GP or the clot formation time) and (ii) df, the fractal dimension of the clot, a quantification of clot fibrin microstructure at the GP. At baseline, the AF-S group had a df  = 1.70 (±0.05) and TGP = 306 (±73 s). The AF group had a df = 1.70 ± 0.05 and TGP = 346 ± 78 s, showing a significantly shortened TGP in the stroke group (p = .008). For both groups, apixaban significantly prolonged TGP, p = .005, but resulted in no change in df. Apixaban prolonged clotting time while having no significant impact on the blood's ability to form stable clots (no change in df ). This indicates that apixaban provides protection from the formation of thrombi by reducing clotting kinetics.

Multiparameter immunohistochemistry analysis of HIV DNA, RNA and immune checkpoints in lymph node tissue.

The main barrier to a cure for HIV is the persistence of long-lived and proliferating latently infected CD4+ T-cells despite antiretroviral therapy (ART). Latency is well characterized in multiple CD4+ T-cell subsets, however, the contribution of regulatory T-cells (Tregs) expressing FoxP3 as well as immune checkpoints (ICs) PD-1 and CTLA-4 as targets for productive and latent HIV infection in people living with HIV on suppressive ART is less well defined. We used multiplex detection of HIV DNA and RNA with immunohistochemistry (mIHC) on formalin-fixed paraffin embedded (FFPE) cells to simultaneously detect HIV RNA and DNA and cellular markers. HIV DNA and RNA were detected by in situ hybridization (ISH) (RNA/DNAscope) and IHC was used to detect cellular markers (CD4, PD-1, FoxP3, and CTLA-4) by incorporating the tyramide system amplification (TSA) system. We evaluated latently infected cell lines, a primary cell model of HIV latency and excisional lymph node (LN) biopsies collected from people living with HIV (PLWH) on and off ART. We clearly detected infected cells that coexpressed HIV RNA and DNA (active replication) and DNA only (latently infected cells) in combination with IHC markers in the in vitro infection model as well as LN tissue from PLWH both on and off ART. Combining ISH targeting HIV RNA and DNA with IHC provides a platform to detect and quantify HIV persistence within cells identified by multiple markers in tissue samples from PLWH on ART or to study HIV latency.

Combination Immune Checkpoint Blockade Enhances IL-2 and CD107a Production from HIV-Specific T Cells Ex Vivo in People Living with HIV on Antiretroviral Therapy.

In people with HIV (PWH) on antiretroviral therapy (ART), immune dysfunction persists, including elevated expression of immune checkpoint (IC) proteins on total and HIV-specific T cells. Reversing immune exhaustion is one strategy to enhance the elimination of HIV-infected cells that persist in PWH on ART. We aimed to evaluate whether blocking CTL-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), T cell Ig domain and mucin domain 3 (TIM-3), T cell Ig and ITIM domain (TIGIT) and lymphocyte activation gene-3 (LAG-3) alone or in combination would enhance HIV-specific CD4+ and CD8+ T cell function ex vivo. Intracellular cytokine staining was performed using human PBMCs from PWH on ART (n = 11) and expression of CD107a, IFN-γ, TNF-α, and IL-2 was quantified with HIV peptides and Abs to IC. We found the following: 1) IC blockade enhanced the induction of CD107a and IL-2 but not IFN-γ and TNF-α in response to Gag and Nef peptides; 2) the induction of CD107a and IL-2 was greatest with multiple combinations of two Abs; and 3) Abs to LAG-3, CTLA-4, and TIGIT in combinations showed synergistic induction of IL-2 in HIV-specific CD8+ and CD107a and IL-2 production in HIV-specific CD4+ and CD8+ T cells. These results demonstrate that the combination of Abs to LAG-3, CTLA-4, or TIGIT can increase the frequency of cells expressing CD107a and IL-2 that associated with cytotoxicity and survival of HIV-specific CD4+ and CD8+ T cells in PWH on ART. These combinations should be further explored for an HIV cure.

Neurotoxicity with high-dose disulfiram and vorinostat used for HIV latency reversal.

OBJECTIVE: The aim of this study was to examine whether administering both vorinostat and disulfiram to people with HIV (PWH) on antiretroviral therapy (ART) is well tolerated and can enhance HIV latency reversal. DESIGN: Vorinostat and disulfiram can increase HIV transcription in PWH on ART. Together, these agents may lead to significant HIV latency reversal. METHODS: Virologically suppressed PWH on ART received disulfiram 2000 mg daily for 28 days and vorinostat 400 mg daily on days 8-10 and 22-24. The primary endpoint was plasma HIV RNA on day 11 relative to baseline using a single copy assay. Assessments included cell-associated unspliced RNA as a marker of latency reversal, HIV DNA in CD4+ T-cells, plasma HIV RNA, and plasma concentrations of ART, vorinostat, and disulfiram. RESULTS: The first two participants (P1 and P2) experienced grade 3 neurotoxicity leading to trial suspension. After 24 days, P1 presented with confusion, lethargy, and ataxia having stopped disulfiram and ART. Symptoms resolved by day 29. After 11 days, P2 presented with paranoia, emotional lability, lethargy, ataxia, and study drugs were ceased. Symptoms resolved by day 23. CA-US RNA increased by 1.4-fold and 1.3-fold for P1 and P2 respectively. Plasma HIV RNA was detectable from day 8 to 37 (peak 81 copies ml-1) for P2 but was not increased in P1 Antiretroviral levels were therapeutic and neuronal injury markers were elevated in P1. CONCLUSION: The combination of prolonged high-dose disulfiram and vorinostat was not safe in PWH on ART and should not be pursued despite evidence of latency reversal.

Diverse effects of interferon alpha on the establishment and reversal of HIV latency.

HIV latency is the major barrier to a cure for people living with HIV (PLWH) on antiretroviral therapy (ART) because the virus persists in long-lived non-proliferating and proliferating latently infected CD4+ T cells. Latently infected CD4+ T cells do not express viral proteins and are therefore not visible to immune mediated clearance. Therefore, identifying interventions that can reverse latency and also enhance immune mediated clearance is of high interest. Interferons (IFNs) have multiple immune enhancing effects and can inhibit HIV replication in activated CD4+ T cells. However, the effects of IFNs on the establishment and reversal of HIV latency is not understood. Using an in vitro model of latency, we demonstrated that plasmacytoid dendritic cells (pDC) inhibit the establishment of HIV latency through secretion of type I IFNα, IFNß and IFNω but not IFNε or type III IFNλ1 and IFNλ3. However, once latency was established, IFNα but no other IFNs were able to efficiently reverse latency in both an in vitro model of latency and CD4+ T cells collected from PLWH on suppressive ART. Binding of IFNα to its receptor expressed on primary CD4+ T cells did not induce activation of the canonical or non-canonical NFκB pathway but did induce phosphorylation of STAT1, 3 and 5 proteins. STAT5 has been previously demonstrated to bind to the HIV long terminal repeat and activate HIV transcription. We demonstrate diverse effects of interferons on HIV latency with type I IFNα; inhibiting the establishment of latency but also reversing HIV latency once latency is established.

Combination Immune Checkpoint Blockade to Reverse HIV Latency.

In people living with HIV on antiretroviral therapy, HIV latency is the major barrier to a cure. HIV persists preferentially in CD4+ T cells expressing multiple immune checkpoint (IC) molecules, including programmed death (PD)-1, T cell Ig and mucin domain-containing protein 3 (TIM-3), lymphocyte associated gene 3 (LAG-3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT). We aimed to determine whether these and other IC molecules have a functional role in maintaining HIV latency and whether blocking IC molecules with Abs reverses HIV latency. Using an in vitro model that establishes latency in both nonproliferating and proliferating human CD4+ T cells, we show that proliferating cells express multiple IC molecules at high levels. Latent infection was enriched in proliferating cells expressing PD-1. In contrast, nonproliferating cells expressed IC molecules at significantly lower levels, but latent infection was enriched in cells expressing PD-1, TIM-3, CTL-associated protein 4 (CTLA-4), or B and T lymphocyte attenuator (BTLA). In the presence of an additional T cell-activating stimulus, staphylococcal enterotoxin B, Abs to CTLA-4 and PD-1 reversed HIV latency in proliferating and nonproliferating CD4+ T cells, respectively. In the absence of staphylococcal enterotoxin B, only the combination of Abs to PD-1, CTLA-4, TIM-3, and TIGIT reversed latency. The potency of latency reversal was significantly higher following combination IC blockade compared with other latency-reversing agents, including vorinostat and bryostatin. Combination IC blockade should be further explored as a strategy to reverse HIV latency.

Variances of dietary preparation for suppression of physiological 18F-FDG myocardial uptake in the presence of cardiac sarcoidosis: A systematic review.

BACKGROUND: 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is used in the diagnosis and management of patients with cardiac sarcoidosis (CS). Various preparation protocols have been proposed to minimise myocardial 18F-FDG uptake and improve scan readability. The aim of this systematic review was to identify the optimal dietary prescription for suppression of physiological 18F-FDG myocardial uptake to enhance clinical diagnosis of CS. METHODS AND RESULTS: MEDLINE and PubMed databases identified 13 studies meeting inclusion criteria for review. Articles were assessed using the Australian National Health and Medical Research Council levels of evidence and categorised as sarcoidosis (human) or non-sarcoidosis (human, animal). Visual uptake scales (qualitative) and/or standardised uptake values (SUV) (quantitative) were used in all the studies reviewed. Nine of 11 human studies showed statistically significant improvements in PET scan interpretation with carbohydrate-restricted diets compared with fasting only, and when carbohydrates were restricted for a longer period of time. Two animal studies showed statistically significant improvements following very low carbohydrate diet preparation (0.01% and 0.4% carbohydrate diets) compared with higher carbohydrate diets. CONCLUSIONS: Variation in measures used, dietary prescriptions, fasting times, species and study quality makes result comparison and applicability difficult. Definitive dietary recommendations are not possible based on current evidence.

Light Therapy for Patients With Bipolar Depression: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: Bipolar disorder (BD) is challenging to treat, and fewer treatments are available for depressive episodes compared to mania. Light therapy is an evidence-based nonpharmacological treatment for seasonal and nonseasonal major depression, but fewer studies have examined its efficacy for patients with BD. Hence, we reviewed the evidence for adjunctive light therapy as a treatment for bipolar depression. METHODS: We conducted a systematic review of databases from inception to June 30, 2019, for randomized, double-blind, placebo-controlled trials of light therapy in patients with BD (CRD42019128996). The primary outcome was change in clinician-rated depressive symptom score; secondary outcomes included clinical response, remission, acceptability, and treatment-emergent mood switches. We quantitatively pooled outcomes using meta-analysis with random-effects models. RESULTS: We identified seven trials representing 259 patients with BD. Light therapy was associated with a significant improvement in Hamilton Depression Rating Scale score (standardized mean difference = 0.43, 95% confidence interval [CI], 0.04 to 0.82, P = 0.03). There was also a significant difference in favor of light therapy for clinical response (odds ratio [OR] = 2.32; 95% CI, 1.12 to 4.81; P = 0.024) but not for remission. There was no difference in affective switches between active light and control conditions (OR = 1.30; 95% CI, 0.38 to 4.44; P = 0.67). Study limitations included different light treatment parameters, small sample sizes, short treatment durations, and variable quality across trials. CONCLUSION: There is positive but nonconclusive evidence that adjunctive light therapy reduces symptoms of bipolar depression and increases clinical response. Light therapy is well tolerated with no increased risk of affective switch.

Relationship between work functioning and self-reported cognitive complaints in patients with major depressive disorder treated with desvenlafaxine.

Patients with major depressive disorder (MDD) often report that cognitive difficulties, such as memory problems or poor concentration, interfere with their work functioning. We examined the association between self-reported cognitive complaints and work functioning in employed patients with MDD treated with desvenlafaxine. A sample of 36 adult outpatients with MDD completed subjective cognition (British Columbia Cognitive Complaints Inventory [BC-CCI]) and functioning scales (Sheehan Disability Scale [SDS]; Lam Employment Absence and Productivity Scale [LEAPS]; and Health and Work Performance Questionnaire [HPQ]) before and after 8 weeks of open-label treatment with flexibly-dosed desvenlafaxine (50-100 mg/day). Multiple regression analyses were used to assess the relationship between subjective cognitive measures and work functioning scales. Patients showed significant improvements in clinical, cognitive, and work functioning measures following treatment with desvenlafaxine. A predictive association was found between the BC-CCI and both the SDS and LEAPS, but not with the HPQ, when adjusted for depression severity. Self-report cognitive questionnaires can provide useful information to monitor changes in cognitive functioning over time and to predict improvement in work functioning outcomes.

The effect of tyramine infusion and exercise on blood flow, coagulation and clot microstructure in healthy individuals.

BACKGROUND: The long term benefits of exercise on the cardiovascular status of a patient have been proven, however, their benefit/risk relationship with exercise intensity is unclear. Furthermore, many thromboembolic diseases such as myocardial infarction and ischaemic stroke are associated with profound catecholamine release. In this study we explore the relationship between catecholamine release and hemodynamic changes and their effect on coagulation. MATERIALS AND METHODS: Twelve healthy recreationally active males were recruited. Local anesthesia was given and catheters were placed under aseptic conditions, in the femoral artery and vein of the experimental leg. The first experiment involved tyramine infusion into the femoral artery at a dose of 1.0 µmol·min-1·L leg volume-1. The second experiment involved single leg knee-extensor exercise performed at 30 W for 15 min. Venous blood was collected at each time point to assess clot microstructure using the df biomarker. RESULTS AND CONCLUSIONS: Tyramine infusion causes a local noradrenaline release in the leg. The increase in noradrenaline was associated with a significant increase in clot microstructure formation (df increased from 1.692 ±â€¯0.029 to 1.722 ±â€¯0.047, p = 0.016). Additionally moderate intensity single leg knee extensor exercise, which minimally alters sympathetic activity, also induced an increases in df (from 1.688 ±â€¯0.025 to 1.723 ±â€¯0.023, p = 0.001). This suggests that exercise can alter clot microstructure formation both via an increase in catecholeamine levels and by factors related to muscle activity per se, such as increased blood flow and consequent shear. These findings have implications for recommendations of exercise in patients at risk of cardiovascular events.

Myeloid Dendritic Cells Induce HIV Latency in Proliferating CD4+ T Cells.

HIV latency occurs predominantly in long-lived resting CD4+ T cells; however, latent infection also occurs in T cell subsets, including proliferating CD4+ T cells. We compared the establishment and maintenance of latent infection in nonproliferating and proliferating human CD4+ T cells cocultured with syngeneic myeloid dendritic cells (mDC). Resting CD4+ T cells were labeled with the proliferation dye eFluor 670 and cultured alone or with mDC, plasmacytoid dendritic cells, or monocytes in the presence of staphylococcal enterotoxin B (SEB). Cells were cultured for 24 h and infected with CCR5-tropic enhanced GFP (EGFP) reporter HIV. Five days postinfection, nonproductively infected EGFP- CD4+ T cells that were either nonproliferating (eFluor 670hi) or proliferating (eFluor 670lo) were sorted and cultured for an additional 7 d (day 12) with IL-7 and antiretrovirals. At day 5 postinfection, sorted, nonproductively infected T cells were stimulated with anti-CD3/CD28, and induced expression of EGFP was measured to determine the frequency of latent infection. Integrated HIV in these cells was confirmed using quantitative PCR. By these criteria, latent infection was detected at day 5 and 12 in proliferating T cells cocultured with mDC and monocytes but not plasmacytoid dendritic cells, where CD4+ T cells at day 12 were poor. At day 5 postinfection, nonproliferating T cells expressing SEB-specific TCR Vß-17 were enriched in latent infection compared with non-SEB-specific TCR Vß-8.1. Together, these data show that both nonproliferating and proliferating CD4+ T cells can harbor latent infection during SEB-stimulated T cell proliferation and that the establishment of HIV latency in nonproliferating T cells is linked to expression of specific TCR that respond to SEB.

Programmed cell death-1 contributes to the establishment and maintenance of HIV-1 latency.

OBJECTIVE: In HIV-infected individuals on antiretroviral therapy (ART), latent HIV is enriched in CD4 T cells expressing immune checkpoint molecules, in particular programmed cell death-1 (PD-1). We therefore assessed the effect of blocking PD-1 on latency, both in vitro and in vivo. METHODS: HIV latency was established in vitro following coculture of resting CD4+ T cells with myeloid dendritic cells. Expression of PD-1 was quantified by flow cytometry, and latency assessed in sorted PD-1high and PD-1low/-nonproliferating CD4+ memory T cells. The role of PD-1 in the establishment of latency was determined by adding anti-PD-1 (pembrolizumab) to cocultures before and after infection. In addition, a single infusion of anti-PD-1 (nivolumab) was administered to an HIV-infected individual on ART with metastatic melanoma, and cell-associated HIV DNA and RNA, and plasma HIV RNA were quantified. RESULTS: HIV latency was significantly enriched in PD-1high compared with PD-1low/- nonproliferating, CD4 memory T cells. Sorting for an additional immune checkpoint molecule, T-cell immunoglobulin domain and mucin domain-3, in combination with PD-1, further enriched for latency. Blocking PD-1 prior to HIV infection, in vitro, resulted in a modest but significant decrease in latently infected cells in all donors (n = 6). The administration of anti-PD-1 to an HIV-infected individual on ART resulted in a significant increase in cell-associated HIV RNA in CD4 T cells, without significant changes in HIV DNA or plasma HIV RNA, consistent with reversal of HIV latency. CONCLUSION: PD-1 contributes to the establishment and maintenance of HIV latency and should be explored as a target, in combination with other immune checkpoint molecules, to reverse latency.

The impact of fatigue and energy on work functioning and impairment in patients with major depressive disorder treated with desvenlafaxine.

Fatigue and low energy are cardinal symptoms of major depressive disorder (MDD) that have an impact on work functioning. Antidepressants with noradrenergic activity have been hypothesized to improve symptoms of fatigue and low energy. We examined the impact of these symptoms on work functioning in patients with MDD treated with the serotonin and noradrenaline reuptake inhibitor, desvenlafaxine. A secondary analysis was carried out from a study of employed adult outpatients (n=35) with MDD and subjective cognitive complaints treated with desvenlafaxine 50-100 mg/day for 8 weeks. Multiple regression analyses modeled improvement in work functioning measures (Lam Employment Absence and Productivity Scale, Health and Work Performance Questionnaire, Sheehan Disability Scale) with measures of fatigue (Patient-Reported Outcomes Measurement Information System Fatigue scale and 20-item Hopkins Symptom Check List Energy scale). Patients showed a significant improvement in Montgomery-Åsberg Depression Rating Scale scores as well as in fatigue and work functioning measures following treatment. Fatigue measures were significantly associated with improvement in some (Lam Employment Absence and Productivity Scale, Sheehan Disability Scale), but not all (Health and Work Performance Questionnaire) work functioning measures, independent of improvement in overall depressive symptoms. The limitations of this study include the small sample size and the lack of a placebo or a comparison group. Fatigue and low energy are important symptoms that are associated with occupational impairment in MDD. Treatments that improve these symptoms are likely to improve work functioning.