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The lack of accessible plasma biomarkers to identify target populations limits the promise of precision medicine for Alzheimer’s Disease (AD). Amnestic mild cognitive impairment (aMCI) is an important risk for AD and often occurs years before the onset of AD.
Objectives
Based on an emerging mechanistic model of mitochondrial mechanisms of brain plasticity, we studied the role of acetylcarnitine and free-carnitine levels assayed in plasma as potential markers of cognitive dysfunction in subjects with aMCI or early-AD.
Methods
We used available samples from two independent cohorts well characterized for clinical and neuropsychological characteristics together with ultraperformance liquid chromatography-tandem mass spectrometry and computational approaches. Cerebrospinal fluid (CSF) measures of b-amyloid accumulation and t-Tau levels were also available and used in computational modeling.
Results
Within the primary cohort, our data showed decreased levels of carnitine in relation to cognitive function as assessed by using the Mini Mental Status Exam (MMSE) in women but not men with CI as compared to age- and sex-matched HC. Furthermore, the magnitude of carnitine deficiency reflected the severity of cognitive dysfunction in a sex-specific manner (women: p = 0.015; men: p = 0.441). Our data also replicated the prior finding of decreased LAC levels in both women and men with AD, supporting the robustness of the study samples assayed in our new study. Using computational approaches, we found that the integration of these mitochondrial measures with canonical CSF biomarkers improves diagnostic accuracy. A second cohort provides a validation of the sex-specific relationship between free-carnitine deficiency and the severity of cognitive dysfunction.
Conclusions
Taken together with prior mechanistic studies in rodents, the current findings support future research on the development of individualized treatment models targeting sex-specific changes in mitochondrial metabolism.
New Zealand and Australian governments rely heavily on voluntary industry initiatives to improve population nutrition, such as voluntary front-of-pack nutrition labelling (Health Star Rating [HSR]), industry-led food advertising standards, and optional food reformulation programmes. Research in both countries has shown that food companies vary considerably in their policies and practices on nutrition(1). We aimed to determine if a tailored nutrition support programme for food companies improved their nutrition policies and practices compared with control companies who were not offered the programme. REFORM was a 24-month, two-country, cluster-randomised controlled trial. 132 major packaged food/drink manufacturers (n=96) and fast-food companies (n=36) were randomly assigned (2:1 ratio) to receive a 12-month tailored support programme or to the control group (no intervention). The intervention group was offered a programme designed and delivered by public health academics comprising regular meetings, tailored company reports, and recommendations and resources to improve product composition (e.g., reducing nutrients of concern through reformulation), nutrition labelling (e.g., adoption of HSR labels), marketing to children (reducing the exposure of children to unhealthy products and brands) and improved nutrition policy and corporate sustainability reporting. The primary outcome was the nutrient profile (measured using HSR) of company food and drink products at 24 months. Secondary outcomes were the nutrient content (energy, sodium, total sugar, and saturated fat) of company products, display of HSR labels on packaged products, company nutrition-related policies and commitments, and engagement with the intervention. Eighty-eight eligible intervention companies (9,235 products at baseline) were invited to participate, of whom 21 accepted and were enrolled in the REFORM programme (delivered between September 2021 and December 2022). Forty-four companies (3,551 products at baseline) were randomised to the control arm. At 24 months, the model-adjusted mean HSR of intervention company products was 2.58 compared to 2.68 for control companies, with no significant difference between groups (mean difference -0.10, 95% CI -0.40 to 0.21, p-value 0.53). A per protocol analysis of intervention companies who enrolled in the programme compared to control companies with no major protocol violation also found no significant difference (2.93 vs 2.64, mean difference 0.29, 95% CI -0.13 to 0.72, p-value 0.18). We found no significant differences between the intervention and control groups in any secondary outcome, except in total sugar (g/100g) where the sugar content of intervention company products was higher than that of control companies (12.32 vs 6.98, mean difference 5.34, 95% CI 1.73 to 8.96, p-value 0.004). The per-protocol analysis for sugar did not show a significant difference (10.47 vs 7.44, mean difference 3.03, 95% CI -0.48 to 6.53, p-value 0.09).In conclusion, a 12-month tailored nutrition support for food companies did not improve the nutrient profile of company products.
We investigate the evolution of active galactic nucleus jets on kiloparsec-scales due to their interaction with the clumpy interstellar medium (ISM) of the host galaxy and, subsequently, the surrounding circumgalactic environment. Hydrodynamic simulations of this jet–environment interaction are presented for a range of jet kinetic powers, peak densities of the multiphase ISM, and scale radii of the larger-scale environment – characteristic of either a galaxy cluster or poor group. Synthetic radio images are generated by considering the combination of synchrotron radiation from the jet plasma and free-free absorption from the multiphase ISM. We find that jet propagation is slowed by interactions with a few very dense clouds in the host galaxy ISM, producing asymmetries in lobe length and brightness which persist to scales of tens of kpc for poor group environments. The classification of kiloparsec-scale jets is highly dependent on surface brightness sensitivity and resolution. Our simulations of young active sources can appear as restarted sources, showing double-double lobe morphology, high core prominence (CP $\gt 0.1$), and the expected radio spectra for both the inner- and outer-lobe components. We qualitatively reproduce the observed inverse correlation between peak frequency and source size and find that the peak frequency of the integrated radio spectrum depends on ISM density but not the jet power. Spectral turnover in resolved young radio sources therefore provides a new probe of the ISM.
Recent changes to US research funding are having far-reaching consequences that imperil the integrity of science and the provision of care to vulnerable populations. Resisting these changes, the BJPsych Portfolio reaffirms its commitment to publishing mental science and advancing psychiatric knowledge that improves the mental health of one and all.
Ice shelves affect the stability of ice sheets by supporting the mass balance of ice upstream of the grounding line. Marine ice, formed from supercooled water freezing at the base of ice shelves, contributes to mass gain and affects ice dynamics. Direct measurements of marine ice thickness are rare due to the challenges of borehole drilling. Here we assume hydrostatic equilibrium to estimate marine ice distribution beneath the Amery Ice Shelf (AIS) using meteoric ice-thickness data obtained from radio-echo sounding collected during the Chinese National Antarctic Research Expedition between 2015 and 2019. This is the first mapping of marine ice beneath the AIS in nearly 20 years. Our new estimates of marine ice along two longitudinal bands beneath the northwest AIS are spatially consistent with earlier work but thicker. We also find a marine ice layer exceeding 30 m of thickness in the central ice shelf and patchy refreezing downstream of the grounding line. Thickness differences from prior results may indicate time-variation in basal melting and freezing patterns driven by polynya activity and coastal water intrusions masses under the ice shelf, highlighting that those changes in ice–ocean interaction are impacting ice-shelf stability.
Inflammation and infections such as malaria affect concentrations of many micronutrient biomarkers and hence estimates of nutritional status. We aimed to assess the relationship between malaria infection and micronutrient biomarker concentrations in pre-school children (PSC), school-age children (SAC) and women of reproductive age (WRA) in Malawi and examine the potential role of malarial immunity on the relationship between malaria and micronutrient biomarkers. Data from the 2015/2016 Malawi micronutrient survey were used. The associations between current or recent malaria infection, detected by rapid diagnostic test and concentration of serum ferritin, soluble transferrin receptor (sTfR), zinc, serum folate, red blood cell folate and vitamin B12 were estimated using multivariable linear regression. Factors related to malarial immunity including age, altitude and presence of hemoglobinopathies were examined as effect modifiers. Serum ferritin, sTfR and zinc were adjusted for inflammation using the BRINDA method. Malaria infection was associated with 68 % (95 % CI 51, 86), 28 % (18, 40) and 34 % (13, 45) greater inflammation-adjusted ferritin in PSC, SAC and WRA, respectively (P < 0·001 for each). In PSC, the positive association was stronger in younger children, high altitude and children who were not carriers of the sickle cell trait. In PSC and SAC, sTfR was elevated (+ 25 % (16, 29) and + 15 % (9, 22) respectively, P < 0·001). Serum folate and erythrocyte folate were elevated in WRA with malaria (+ 18 % (3, 35) and + 11 % (1, 23), P = 0·01 and P = 0·003 respectively). Malaria affects the interpretation of micronutrient biomarker concentrations, and examining factors related to malarial immunity may be informative.
Objectives/Goals: We will conduct a 12-week pilot randomized controlled trial (RCT) to test the feasibility, acceptability, and preliminary efficacy of a staged-intensity whole foods intervention on hemoglobin A1c (HbA1c) change in adults, diet quality change (via the 2020 healthy eating index [HEI-2020]) in adults and offspring, and diet adherence and social determinants of health (SDOH) considerations via focus groups. Methods/Study Population: In this two-arm, parallel RCT, 30 adults with prediabetes (25–59 years) and their offspring (6–18 years) will be randomized to receive the 1) 12-week whole foods intervention which includes a 2-week feeding period (all foods/recipies provided), a 6-week customizable feeding period (3 dinners/recipies weekly), and a 4-week maintenance period (no food/recipies). The control group will receive standard of care (i.e., single RD-led diet counseling session). Primary outcomes include feasibility (≥80% retention and completion of study outcome measures) and acceptability (≥75% adult self-reported diet satisfaction). Intervention effects include 1) HbA1c change at 12-weeks in adults and 2) adult/offspring HEI-2020 scores assessed via diet records. Focus groups will assess influences of SDOH on diet adherence. Results/Anticipated Results: We have received Institutional Review Board approval, and recruitment is planned for January 2025. We will enroll 30 families from the greater Nashville, TN area. An intent-to-treat analysis will be conducted to test the preliminary effects of the whole foods diet intervention on the 12-week change in HbA1c (adults only) and 2020-HEI diet quality scores during the intervention period (adults and offspring). Focus groups will be conducted to understand how individual and family needs/preferences and SDOH may be perceived barriers or facilitators of diet adherence. Data generated from this study will be used to guide a fully powered RCT of our whole foods intervention to assess long-term effects on additional diabetes and metabolic outcomes and assessment of SDOH influences to support long-term adherence. Discussion/Significance of Impact: A healthy diet pattern is an effective nonpharmacological solution to prevent T2D, but only if it can be maintained. A family-centered whole foods diet pattern that uses “food as medicine” and considers how individual and family needs/preferences, and SDOHs could be an effective and sustainable multigenerational solution to prevent T2D in families.
Inflammation and infections such as malaria affect micronutrient biomarker concentrations and hence estimates of nutritional status. It is unknown whether correction for C-reactive protein (CRP) and α1-acid glycoprotein (AGP) fully captures the modification in ferritin concentrations during a malaria infection, or whether environmental and sociodemographic factors modify this association. Cross-sectional data from eight surveys in children aged 6–59 months (Cameroon, Cote d’Ivoire, Kenya, Liberia, Malawi, Nigeria and Zambia; n 6653) from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anaemia (BRINDA) project were pooled. Ferritin was adjusted using the BRINDA adjustment method, with values < 12 μg/l indicating iron deficiency. The association between current or recent malaria infection, detected by microscopy or rapid test kit, and inflammation-adjusted ferritin was estimated using pooled multivariable linear regression. Age, sex, malaria endemicity profile (defined by the Plasmodium falciparum infection prevalence) and malaria diagnostic methods were examined as effect modifiers. Unweighted pooled malaria prevalence was 26·0 % (95 % CI 25·0, 27·1) and unweighted pooled iron deficiency was 41·9 % (95 % CI 40·7, 43·1). Current or recent malaria infection was associated with a 44 % (95 % CI 39·0, 52·0; P < 0·001) increase in inflammation-adjusted ferritin after adjusting for age and study identifier. In children, ferritin increased less with malaria infection as age and malaria endemicity increased. Adjustment for malaria increased the prevalence of iron deficiency, but the effect was small. Additional information would help elucidate the underlying mechanisms of the role of endemicity and age in the association between malaria and ferritin.
This editorial considers the value and nature of academic psychiatry by asking what defines the specialty and psychiatrists as academics. We frame academic psychiatry as a way of thinking that benefits clinical services and discuss how to inspire the next generation of academics.
To learn about the perceptions of healthcare personnel (HCP) on the barriers they encounter when performing infection prevention and control (IPC) practices in labor and delivery to help inform future IPC resources tailored to this setting.
Design:
Qualitative focus groups.
Setting:
Labor and delivery units in acute-care settings.
Participants:
A convenience sample of labor and delivery HCP attending the Infectious Diseases Society for Obstetrics and Gynecology 2022 Annual Meeting.
Methods:
Two focus groups, each lasting 45 minutes, were conducted by a team from the Centers for Disease Control and Prevention. A standardized script facilitated discussion around performing IPC practices during labor and delivery. Coding was performed by 3 reviewers using an immersion-crystallization technique.
Results:
In total, 18 conference attendees participated in the focus groups: 67% obstetrician-gynecologists, 17% infectious disease physicians, 11% medical students, and 6% an obstetric anesthesiologist. Participants described the difficulty of consistently performing IPC practices in this setting because they often respond to emergencies, are an entry point to the hospital, and frequently encounter bodily fluids. They also described that IPC training and education is not specific to labor and delivery, and personal protective equipment is difficult to locate when needed. Participants observed a lack of standardization of IPC protocols in their setting and felt that healthcare for women and pregnant people is not prioritized on a larger scale and within their hospitals.
Conclusions:
This study identified barriers to consistently implementing IPC practices in the labor and delivery setting. These barriers should be addressed through targeted interventions and the development of obstetric-specific IPC resources.
The U.S. Department of Agriculture–Agricultural Research Service (USDA-ARS) has been a leader in weed science research covering topics ranging from the development and use of integrated weed management (IWM) tactics to basic mechanistic studies, including biotic resistance of desirable plant communities and herbicide resistance. ARS weed scientists have worked in agricultural and natural ecosystems, including agronomic and horticultural crops, pastures, forests, wild lands, aquatic habitats, wetlands, and riparian areas. Through strong partnerships with academia, state agencies, private industry, and numerous federal programs, ARS weed scientists have made contributions to discoveries in the newest fields of robotics and genetics, as well as the traditional and fundamental subjects of weed–crop competition and physiology and integration of weed control tactics and practices. Weed science at ARS is often overshadowed by other research topics; thus, few are aware of the long history of ARS weed science and its important contributions. This review is the result of a symposium held at the Weed Science Society of America’s 62nd Annual Meeting in 2022 that included 10 separate presentations in a virtual Weed Science Webinar Series. The overarching themes of management tactics (IWM, biological control, and automation), basic mechanisms (competition, invasive plant genetics, and herbicide resistance), and ecosystem impacts (invasive plant spread, climate change, conservation, and restoration) represent core ARS weed science research that is dynamic and efficacious and has been a significant component of the agency’s national and international efforts. This review highlights current studies and future directions that exemplify the science and collaborative relationships both within and outside ARS. Given the constraints of weeds and invasive plants on all aspects of food, feed, and fiber systems, there is an acknowledged need to face new challenges, including agriculture and natural resources sustainability, economic resilience and reliability, and societal health and well-being.
COMP360 is a synthetic, proprietary, purified form of psilocybin in development for treatment-resistant depression (TRD) with FDA Breakthrough Therapy designation. In a recent phase IIb study, COMP360 psilocybin 25mg was superior to 1mg on change from baseline (CFB) to Week 3 on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score (primary efficacy endpoint), when administered alongside psychological support. Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) total score (exploratory efficacy endpoint) showed similar results.
Objectives
To analyse changes in specific depression symptoms after psilocybin treatment in the aforementioned study, as measured by individual item scores on the MADRS and QIDS-SR16 (range 0-6 and 0-3).
Methods
Participants with TRD were randomised to single doses of psilocybin 25mg (n=79), 10mg (n=75), or 1mg (n=79). A remote, blinded rater assessed the MADRS at Baseline, Day 2 (the day post-psilocybin), and Weeks 1, 3, 6, 9, and 12. The QIDS-SR16 was self-rated at Baseline, Day 1, Day 2, and Weeks 1, 2, 3, 6, 9, and 12. At each time point, descriptive statistics were calculated for each MADRS and QIDS-SR16 individual item score.
Results
At Week 3, MADRS items with the largest differences in mean CFB in the 25mg arm were Inability to Feel, Apparent Sadness, Lassitude, and Reported Sadness. Greater improvement in the 25mg arm was apparent from Day 2 and remained to Week 12 (Lassitude remained to Week 6 only). On the QIDS-SR16, the item with the largest difference in mean CFB at Week 3 in the 25mg arm was in Feeling Sad and remained evident to Week 12 (Table 1).Table 1.
Item (mean CFB at Week 3 [standard deviation])
Psilocybin 25mg
Psilocybin 10mg
Psilocybin 1mg
MADRS - Inability to Feel
-1.8 [1.81]
-0.9 [1.54]
-0.8 [1.61]
MADRS - Apparent Sadness
-1.7 [1.94]
-1.1 [1.60]
-0.9 [1.62]
MADRS - Lassitude
-1.6 [1.81]
-1.2 [1.83]
-0.8 [1.58]
MADRS - Reported Sadness
-1.6 [1.95]
-1.0 [1.52]
-0.6 [1.53]
QIDS-SR16- Feeling Sad
-1.1 [1.08]
-0.8 [1.07]
-0.4 [0.91]
Conclusions
A single administration of COMP360 psilocybin therapy rapidly and dose-relatedly improved symptoms of depressed mood and anhedonia – the two key symptoms of depression. As anhedonia is predictive of poorer treatment response, and improvements in anhedonia correlate with improvements in functioning, it is important to understand the impact of treatments on this symptom.
Disclosure of Interest
G. Goodwin Shareolder of: COMPASS Pathways, P1Vital, and P1Vital products , Employee of: COMPASS Pathways, L. Marwood Shareolder of: COMPASS Pathways, Employee of: COMPASS Pathways, S. Mistry Employee of: COMPASS Pathways, A. Nowakowska Employee of: COMPASS Pathways, H. Simmons Employee of: COMPASS Pathways, J. Tsai Employee of: COMPASS Pathways, S. Williams Employee of: COMPASS Pathways, M. Young Shareolder of: COMPASS Pathways, Employee of: COMPASS Pathways, E. Malievskaia Employee of: COMPASS Pathways
To increase inclusivity, diversity, equity and accessibility in Antarctic science, we must build more positive and inclusive Antarctic field work environments. The International Thwaites Glacier Collaboration (ITGC) has engaged in efforts to contribute to that goal through a variety of activities since 2018, including creating an open-access ‘Field and Ship Best Practices’ guide, engaging in pre-field season team dynamics meetings, and surveying post-field season reflections and experiences. We report specific actions taken by ITGC and their outcomes. We found that strong and supported early career researchers brought new and important perspectives regarding strategies for transforming culture. We discovered that engaged and involved senior leadership was also critical for expanding participation and securing funding to support efforts. Pre-field discussions involving all field team members were particularly helpful for setting expectations, improving sense of belonging, describing field work best practices, and co-creating a positive work culture.
Peer support interventions for dietary change may offer cost-effective alternatives to interventions led by health professionals. This process evaluation of a trial to encourage the adoption and maintenance of a Mediterranean diet in a Northern European population at high CVD risk (TEAM-MED) aimed to investigate the feasibility of implementing a group-based peer support intervention for dietary change, positive elements of the intervention and aspects that could be improved. Data on training and support for the peer supporters; intervention fidelity and acceptability; acceptability of data collection processes for the trial and reasons for withdrawal from the trial were considered. Data were collected from observations, questionnaires and interviews, with both peer supporters and trial participants. Peer supporters were recruited and trained to result in successful implementation of the intervention; all intended sessions were run, with the majority of elements included. Peer supporters were complimentary of the training, and positive comments from participants centred around the peer supporters, the intervention materials and the supportive nature of the group sessions. Attendance at the group sessions, however, waned over the intervention, with suggested effects on intervention engagement, enthusiasm and group cohesion. Reduced attendance was reportedly a result of meeting (in)frequency and organisational concerns, but increased social activities and group-based activities may also increase engagement, group cohesion and attendance. The peer support intervention was successfully implemented and tested, but improvements can be suggested and may enhance the successful nature of these types of interventions. Some consideration of personal preferences may also improve outcomes.
The Covid-19 pandemic profoundly affected delivery and accessibility of mental health care services at a time when most needed. The OPTIMA Mood Disorder Service, a specialist bipolar disorder service, adapted group psychoeducation programme for delivery on-line.
Objectives
We report the feasibility of creating a digital psychoeducation programme.
Methods
The OPTIMA ten session group psychoeducation programme was converted into a ‘Digital’ intervention using video-conferencing. Sessions offered a range of key topics, derived from the initial Barcelona Group Psychoeducation Programme. At the time of writing, OPTIMA had fully completed two 10 session digital courses.
Results
A total of 12 people (6 in each group) consented to be part of a service evaluation of the digital groups. Just over half of the participants were women (7/12; 58.3%) and one identified as being non-binary (8.3); remaining participants were men. Age of participants ranged from 25 years to 65 years (Mean=42.3; SD=13.1). Data showed a high level of engagement (77%) All participants reported some improvement with a mean Bipolar Self-Efficacy scale (BPSES) post-group score of 105.6 (SD=14.8). At group level, this change was not statistically significant (F (1, 15) = 0.71, p=0.41). At an individual level, two out of five showed a reliable change index >1.96.
Conclusions
Delivering a ‘digital’ group psychoeducation programme was possible due to careful planning and programme development. There was good uptake from service users suggesting it is a feasible approach with preliminary evidence of clinical benefit.
We present the first unbiased survey of neutral hydrogen absorption in the Small Magellanic Cloud. The survey utilises pilot neutral hydrogen observations with the Australian Square Kilometre Array Pathfinder telescope as part of the Galactic Australian Square Kilometre Array Pathfinder neutral hydrogen project whose dataset has been processed with the Galactic Australian Square Kilometre Array Pathfinder-HI absorption pipeline, also described here. This dataset provides absorption spectra towards 229 continuum sources, a 275% increase in the number of continuum sources previously published in the Small Magellanic Cloud region, as well as an improvement in the quality of absorption spectra over previous surveys of the Small Magellanic Cloud. Our unbiased view, combined with the closely matched beam size between emission and absorption, reveals a lower cold gas faction (11%) than the 2019 ATCA survey of the Small Magellanic Cloud and is more representative of the Small Magellanic Cloud as a whole. We also find that the optical depth varies greatly between the Small Magellanic Cloud’s bar and wing regions. In the bar we find that the optical depth is generally low (correction factor to the optically thin column density assumption of $\mathcal{R}_{\mathrm{HI}} \sim 1.04$) but increases linearly with column density. In the wing however, there is a wide scatter in optical depth despite a tighter range of column densities.
The impact of the coronavirus disease 2019 (COVID-19) pandemic on mental health is still being unravelled. It is important to identify which individuals are at greatest risk of worsening symptoms. This study aimed to examine changes in depression, anxiety and post-traumatic stress disorder (PTSD) symptoms using prospective and retrospective symptom change assessments, and to find and examine the effect of key risk factors.
Method
Online questionnaires were administered to 34 465 individuals (aged 16 years or above) in April/May 2020 in the UK, recruited from existing cohorts or via social media. Around one-third (n = 12 718) of included participants had prior diagnoses of depression or anxiety and had completed pre-pandemic mental health assessments (between September 2018 and February 2020), allowing prospective investigation of symptom change.
Results
Prospective symptom analyses showed small decreases in depression (PHQ-9: −0.43 points) and anxiety [generalised anxiety disorder scale – 7 items (GAD)-7: −0.33 points] and increases in PTSD (PCL-6: 0.22 points). Conversely, retrospective symptom analyses demonstrated significant large increases (PHQ-9: 2.40; GAD-7 = 1.97), with 55% reported worsening mental health since the beginning of the pandemic on a global change rating. Across both prospective and retrospective measures of symptom change, worsening depression, anxiety and PTSD symptoms were associated with prior mental health diagnoses, female gender, young age and unemployed/student status.
Conclusions
We highlight the effect of prior mental health diagnoses on worsening mental health during the pandemic and confirm previously reported sociodemographic risk factors. Discrepancies between prospective and retrospective measures of changes in mental health may be related to recall bias-related underestimation of prior symptom severity.
This article is a clinical guide which discusses the “state-of-the-art” usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion—this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy—while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward “bridging” methods that may be used to transition simply and safely from other antidepressants to MAOIs.