Estimated Prevalence of Depressive Disorders in Children From 2004 to 2019

 Michael J. Spoelma, BPsych^1,2; Gemma L. Sicouri, DCP, PhD^1,3,4; Deanna A. Francis, MClinNeuro, PhD^1,4; et al

 doi:10.1001/jamapediatrics.2023.3221

Key Points

Question  What were the prevalence rates of depressive disorders in childhood (ie, age <13 years) between 2004 and 2019?

Findings  In this systematic review and meta-analyses of 41 studies, pooled prevalence estimates were noted for major depressive disorder (0.71%), dysthymia (0.30%), disruptive mood dysregulation disorder (1.60%), and 1.07% overall. These estimates did not differ significantly between males and females or high-income and low- and-middle-income countries and did not appear to increase over a 15-year period.

Meaning  These findings suggest that depression in childhood between 2004 and 2019 was uncommon and did not increase over time, but the lack of data beyond the COVID-19 pandemic is yet to be accounted for.

Abstract

Importance  Depression during childhood (ie, age <13 years) poses a major health burden. Recent changes in environmental and lifestyle factors may increase children’s risk of mental health problems. This has been reported for anxiety disorders, but it is unclear whether this occurs for depressive disorders.

Objective  To provide prevalence estimates for the depressive disorders (ie, major depressive disorder [MDD], dysthymia, disruptive mood dysregulation disorder [DMDD], and overall) in children, and whether they have changed over time.

Data Sources  The MEDLINE, PsycINFO, Embase, Scopus, and Web of Science databases were searched using terms related to depressive disorders, children, and prevalence. This was supplemented by a systematic gray literature search.

Study Selection  Studies were required to provide population prevalence estimates of depressive disorder diagnoses (according to an established taxonomy and standardized interviews) for children younger than 13 years, information about participants’ year of birth, and be published in English.

Data Extraction and Synthesis  Data extraction was compliant with the Meta-Analysis of Observational Studies in Epidemiology guidelines. A total of 12 985 nonduplicate records were retrieved, and 154 full texts were reviewed. Data were analyzed from 2004 (the upper limit of a previous review) to May 27, 2023. Multiple proportional random-effects meta-analytic and mixed-effects meta-regression models were fit.

Main Outcomes and Measures  Pooled prevalence rates of depressive disorders, prevalence rate differences between males vs females and high-income countries (HICs) vs low-and middle-income countries (LMICs), and moderating effects of time or birth cohort.

Results  A total of 41 studies were found to meet the inclusion criteria. Pooled prevalence estimates were obtained for 1.07% (95% CI, 0.62%-1.63%) for depressive disorders overall, 0.71% (95% CI, 0.48%-0.99%) for MDD, 0.30% (95% CI, 0.08%-0.62%) for dysthymia, and 1.60% (95% CI, 0.28%-3.90%) for DMDD. The meta-regressions found no significant evidence of an association with birth cohort, and prevalence rates did not differ significantly between males and females or between HICs and LMICs. There was a low risk of bias overall, except for DMDD, which was hindered by a lack of studies.

Conclusions and Relevance  In this systematic review and meta-analysis, depression in children was uncommon and did not increase substantially between 2004 and 2019. Future epidemiologic studies using standardized interviews will be necessary to determine whether this trend will continue into and beyond the COVID-19 pandemic.

https://jamanetwork.com/journals/jamapediatrics/fullarticle/2808878

FDA approves multiple generics of ADHD and BED treatment

 

Action 

FDA has approved several first generics of Vyvanse (lisdexamfetamine dimesylate) capsules and chewable tablets for attention-deficit/hyperactivity disorder (ADHD) in patients six years and older and moderate to severe binge-eating disorder (BED) in adults. See Vyvanse’s prescribing information for details on dosing.  

Disease or Condition 

People with ADHD may have trouble paying attention, controlling impulsive behaviors (may act without thinking about what the result will be), or be overly active. ADHD is one of the most common neurodevelopmental disorders of childhood, affecting approximately 10% of children. It is usually first diagnosed in childhood and can last into adulthood. ADHD can be successfully managed with behavioral and pharmacological treatment, and some symptoms may improve as the child ages. 

Patients with BED have recurrent episodes of compulsive overeating during which they consume larger amounts of food than normal and experience the sense that they lack control. Patients with this condition eat when they aren’t hungry and often eat to the point of being uncomfortably full. Patients may feel ashamed and embarrassed by how much they are eating, which can result in social isolation. BED may lead to weight gain and to other health problems. 

Safety  

FDA-approved generic medicines work in the same way and provide the same clinical benefit and risks as their brand-name counterparts.  

The prescribing information for lisdexamfetamine dimesylate capsules and chewable tablets contains a boxed warning to inform health care providers and patients about the potential risk of abuse and dependence. Drugs that increase the levels of certain chemicals in the brain, such as amphetamines and methylphenidate-containing products (including lisdexamfetamine dimesylate), have a high potential for abuse, which can lead to addiction and overdose. Health care providers should assess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy. To address continuing concerns of misuse, addiction and overdose, FDA recently required updates to the labeling of prescription stimulants to standardize prescribing information and clearly inform patients, caregivers, and health care professionals of these risks.  

The prescribing information also includes warnings and precautions regarding serious cardiovascular reactions, blood pressure and heart rate increases, psychiatric adverse reactions, suppression of growth, peripheral vasculopathy (reduced circulation of blood flow to body parts), and serotonin syndrome (a potentially life-threatening overage of serotonin). Please see Vyvanse’s full prescribing information for additional details. 

The most common side effects in children, adolescents and/or adults with ADHD taking lisdexamfetamine dimesylate capsules and chewable tablets were anorexia, anxiety, decreased appetite, decreased weight, diarrhea, dizziness, dry mouth, irritability, insomnia, nausea, upper abdominal pain, and vomiting. The most common side effects in adults with BED were dry mouth, insomnia, decreased appetite, increased heart rate, constipation, feeling jittery, and anxiety.

Designation 

Many abbreviated new drug applications (ANDAs) for lisdexamfetamine dimesylate received priority review. Information on priority review of ANDAs is available in the Manual of Policies and Procedures 5240.3 Rev. 6, Prioritization of the Review of Original ANDAs, Amendments, and Supplements.  

https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-multiple-generics-adhd-and-bed-treatment

Novel Oral Tx Shows Early Promise in Relapsed/Refractory Myeloma

 A novel protein-degrading agent exhibited promising activity in patients with relapsed/refractory multiple myeloma, results of a preliminary clinical trial showed.

Among 101 patients who received the recommended phase II dose of oral mezigdomide in combination with dexamethasone, the objective response rate was 41%. All of the patients had triple class-refractory disease, and 30% had prior exposure to therapy targeting B-cell maturation antigen (BCMA).

Neutropenia and infection occurred in most patients treated with mezigdomide, but the side effects were mild or moderate in most cases, reported Paul G. Richardson, MD, of Dana-Farber Cancer Institute in Boston, and co-authors in the New England Journal of Medicineopens in a new tab or window.

"This study aimed to determine the therapeutic window and achieve rapid, prolonged, and maximal substrate degradation for rapid disease response while mitigating hematologic toxic effects," the authors wrote in conclusion. "Mezigdomide plus dexamethasone showed promising preliminary efficacy in this heavily pretreated population, with myelosuppression and infection as the main toxic effects."

The evolution of mezigdomide represents "the latest chapter of a story that started with clinical infamy more than 60 years ago," wrote Jake Shortt, MBChB, PhD, of Monash University in Clayton, Australia, in an accompanying editorialopens in a new tab or window. Mezigdomide targets cereblon, the long-sought binding partner for thalidomide, which failed notoriously as a sedative for use during pregnancy but found a home as the first highly active treatment for myeloma. As discovered in 2010, cereblon plays a crucial role in protein degradation but also was the culprit in thalidomide-associated teratogenicity.

The response rate for an all-oral regimen was encouraging, but the relatively brief median progression-free survival (PFS) of 4.4 months showed that more work is required, he added.

"Although mezigdomide is active in cells with low levels of cereblon, it cannot work in the complete absence of cereblon or overcome cereblon-independent resistance mechanisms," Shortt continued. "Further studies will determine the safety and efficacy of mezigdomide concomitant with other antimyeloma therapies."

"Concurrently, the myeloma field is being revolutionized by immunotherapies, such as bispecific antibodies and chimeric antigen receptor T cells," he noted. "Because mezigdomide bears the same immunostimulatory hallmarks as its IMiD [immunomodulatory drug] forebears, it may also partner well with these immune effector cell-based approaches."

Despite the plethora of effective new therapies for myeloma, almost all patients eventually relapse, develop refractory disease, or both, Richardson and co-authors noted in their introduction. Each remission becomes briefer than the one before. A need persists for alternative medications with favorable safety and ease of administration.

Mezigdomide is one of two cereblon E3 ligase modulators under development, the other being iberdomide (CC-220). Mezigdomide was designed to target Ikaros and Aiolos, key transcription factors in hematopoietic cell development and differentiation, the authors continued. In vitro studies showed the mezigdomide-induced degradation of the two factors enhanced cytotoxic effects in myeloma cells, including cells resistant to IMiDs lenalidomide (Revlimid) and pomalidomide (Pomalyst) and with cereblon down-regulation.

Following encouraging results with mezigdomide in ex vivo models, investigators conducted a phase I/II multicenter, dose-escalation, dose-expansion clinical study. Phase I included 77 patients and 13 dose levels of mezigdomide, administered with dexamethasone. A fourth of the patients had objective responses, including one complete response.

Eligibility for phase II included disease refractory to an IMiD, a glucocorticoid, a proteasome inhibitor, and an anti-CD38 antibody. A response rate of ≤12% would be considered a negative outcome.

The 101 patients included in data analysis had received a median of six prior lines of therapy, and three-fourths of the patients had undergone stem-cell transplantation. The most common adverse events (AEs, all grades) were neutropenia (77%), infection (65%), anemia (52%), and thrombocytopenia (43%). Febrile neutropenia occurred in 15% of patients. The most common grade 3/4 AEs were neutropenia (22% grade 3 and 54% grade 4), infection (29% and 6%), and anemia (35% and 1%). Grade 3 febrile neutropenia occurred in 13% of patients and grade 4 in 2%.

AEs led to mezigdomide dose reduction in 29% of patients and treatment discontinuation in 6%. Three-fourths of the patients received growth factor support. The 41 objective responses had a median duration of 7.6 months. The overall response rate was 30% for patients with plasmacytomas and 50% for patients with prior exposure to anti-BCMA therapy. A third of patients with high-risk cytogenetics responded to mezigdomide.

"This study represents the culmination of discoveries made over the past decade related to the mechanism of action of immunomodulatory agents in multiple myeloma," the authors wrote in their discussion of the findings. "Lenalidomide and pomalidomide were developed empirically on the basis of clinical observations."

"The understanding that they act as molecular glues to co-opt cereblon to target Ikaros and Aiolos for ubiquitination and proteasomal degradation came after their approval," they continued. "This finding also led to novel insights into mechanisms of resistance, including cereblon dysregulation. Mezigdomide was designed on the basis of these insights to achieve deep and sustained Ikaros and Aiolos degradation and overcome cereblon down-regulation and mutations observed in some patients."

Disclosures

The study was supported by Celgene.

Richardson disclosed relationships with AstraZeneca, Celgene, GSK, Janssen, Karyopharm, Oncopeptides, Sanofi, Secura Bio, and Takeda.

Shortt disclosed relationships with Bristol Myers Squibb, Amgen Australia, Astex Pharmaceuticals, Astellas, Otsuka, Pfizer, Novartis, and Mundipharma.

Primary Source

New England Journal of Medicine

Source Reference: opens in a new tab or windowRichardson PG, et al "Mezigdomide plus dexamethasone in relapsed and refractory multiple myeloma" N Engl J Med 2023; DOI: 10.1056/NEJMoa2303194.

Secondary Source

New England Journal of Medicine

Source Reference: opens in a new tab or windowShortt J "Mezigdomide and multiple myeloma" N Engl J Med 2023; DOI: 10.1056/NEJMe2307370.

https://www.medpagetoday.com/hematologyoncology/myeloma/106130

Concizumab Prophylaxis Reduced Bleeding Rates in Hemophilia

 Compared with on-demand treatment, prophylaxis with concizumab -- designed to achieve hemostasis in all hemophilia types -- reduced annualized bleeding rates among patients who have hemophilia A or B with inhibitors, the phase III explorer7 trial showed.

Patients who received the anti-tissue factor pathway inhibitor monoclonal antibody for at least 32 weeks had an estimated mean annualized bleeding rate of 1.7 episodes compared with 11.8 episodes among those who had no prophylaxis for at least 24 weeks -- representing an 86% reduction in treated bleeds (rate ratio [RR] 0.14, 95% CI 0.07-0.29, P<0.001), reported Tadashi Matsushita, MD, PhD, of Nagoya University Hospital in Japan, and colleagues.

"Concizumab represents a novel, subcutaneous treatment option in patients with hemophilia A or B with inhibitors that can potentially improve long-term outcomes," the authors wrote in the New England Journal of Medicine

opens in a new tab or window.

The annualized rates of other bleeding episodes were also lower in the concizumab prophylaxis group compared with the on-demand group:

• Spontaneous bleeding episodes: 1.3 vs 9.4 (RR 0.14, 95% 0.06-0.30)
• Joint bleeding episodes: 1.4 vs 9.1 (RR 0.15, 95% CI 0.07-0.32)
• Target joint bleeding episodes: 0.1 vs 1.1 (RR 0.12, 95% CI 0.02-0.84)
• All treated and untreated bleeding episodes: 4.4 vs 13.3 (RR 0.33, 95% CI 0.17-0.64)

"It is reassuring that this first-in-class drug is effective in treating hemophilia A or B with inhibitors," commented H. Marijke van den Berg, MD, PhD, of the PedNet Hemophilia Research Foundation in Baarn, the Netherlands, and Alok Srivastava, MD, of the Christian Medical College Vellore in India, in an accompanying "Science Behind the Study" editorialopens in a new tab or window. "Given its reported efficacy in both types of hemophilia without inhibitors, concizumab is evolving as an attractive therapeutic for all patients with hemophilia."

While the results of the study "represent an advance in the management of hemophilia, the ramifications of rebalancing hemostasis, particularly during stress or inflammatory conditions, are not well understood and warrant further investigation," the editorialists wrote. Furthermore, more data are needed on the safety and efficacy of the therapy in early childhood, they added.

Moreover, new treatment options like concizumab must be weighed against the potential of cure offered by gene therapy, they said. However, the durability of gene therapy factor product is still being defined and the "abundance of therapeutic options such as concizumab, other non-factor-replacement products, and a multitude of clotting factor products will play a large role in prevention of bleeding in hemophilia for the foreseeable future," they wrote.

While concizumab was recently approved in Canada (marketed as Alhemo), the FDA recently issued a complete response letteropens in a new tab or window, requesting that developer Novo Nordisk provide additional information about its manufacturing process and more details on dose monitoring to ensure the therapy is administered as intended. The agency in 2020 had forced the drugmaker to pause the trial over clotting events.

The explorer7 study

opens in a new tab or window enrolled 133 patients, 80 with hemophilia A and 53 with hemophilia B, both with inhibitors. Anywhere from one in three to one in five peopleopens in a new tab or window with hemophilia A have inhibitors, while just 1% to 4% of those with hemophilia B have inhibitors.

The patients were randomized 1:2 to receive no prophylaxis for at least 24 weeks (19 patients in group 1) or concizumab prophylaxis for at least 32 weeks (33 in group 2). The remaining 81 patients were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4).

The overall median annualized bleeding rate for patients receiving concizumab (groups 2, 3, and 4) was 0 episodes compared with 9.8 episodes in group 1.

In the study (as well as the explorer8opens in a new tab or window trial), concizumab was paused by the safety committee in March 2020, due to nonfatal thromboembolic events in three patients receiving concizumab, including a patient from the explorer7 trial who had a renal infarct. The FDA subsequently issued a clinical hold.

On-demand treatment in group 1 continued during the pause, while patients in the concizumab prophylaxis groups switched to alternative therapies at the investigator's discretion. The trials were restarted 6 months later with participants given a loading dose of 1.0 mg/kg, followed by 0.2 mg/kg daily (potentially adjusted on the basis of concizumab plasma concentration as measured at week 4).

No thromboembolic events were reported after concizumab therapy was restarted.

The most frequently reported adverse events in patients who received concizumab during the period when patients were considered to be exposed to concizumab included arthralgia (10%), injection-site erythema (7%), and upper respiratory tract infection (6%).

A total of five serious adverse events occurred in three patients who received no prophylaxis in group 1, while 18 serious adverse events occurred in 14 patients who received concizumab in groups 1-4. Three patients had serious adverse events related to bleeding, and four patients had serious adverse events related to infections.

Disclosures

The trial was supported by Novo Nordisk.

Matsushita reported relationships with Novo Nordisk.

Co-authors reported multiple relationships with industry.

Srivastava reported relationships with Roche, Novo Nordisk, Sanofi, Pfizer, Takeda, Bayer, and Biomarin.

van den Berg disclosed no relationships.

Primary Source

New England Journal of Medicine

Source Reference: opens in a new tab or windowMatsushita T, et al "Phase 3 trial of concizumab in hemophilia with inhibitors" N Engl J Med 2023; DOI: 10.1056/NEJMoa2216455.

Secondary Source

New England Journal of Medicine

Source Reference: opens in a new tab or windowvan den Berg HM, Srivastava A "Hemostasis -- A balancing act" N Engl J Med 2023; DOI: 10.1056/NEJMe2304535.

https://www.medpagetoday.com/hematologyoncology/hemophilia/106134

FDA Warns Three Baby-Formula Makers Over Violations in Production

 The U.S. Food and Drug Administration issued warning letters to baby-formula manufacturers Reckitt & Benckiser's Mead Johnson Nutrition, Perrigo Wisconsin and ByHeart over their infant formulas.

The U.S. regulator said the three companies violated infant formula regulations, based on data compiled from a number of inspections of their facilities over the past few months.

Each company will have 15 working days to explain what corrective actions they are taking, the FDA said.

The FDA isn't advising parents and caregivers to discard or avoid purchasing any particular infant formula at this time. However, its aim is to make sure infant formula is being produced "under the safest conditions possible."

"The FDA is issuing these letters...to reinforce to these firms the importance of instituting and maintaining appropriate corrective actions when they detect pathogens to ensure compliance with the FDA's laws and regulations," it said.

In December of last year then again in February and March, the FDA initiated formula recalls to remove product potentially contaminated with the bacteria Cronobacter sakazakii.

https://www.marketscreener.com/quote/stock/PERRIGO-COMPANY-PLC-15809538/news/FDA-Warns-Three-Baby-Formula-Makers-Over-Violations-in-Production-44735811/

Sen. Ron Johnson accuses CDC of ‘censorship’ of own COVID vaccine info

 Sen. Ron Johnson (R-Wis.) has accused the Centers for Disease Control and Prevention of coordinating with social media companies to suppress certain information about COVID-19 vaccines.

Citing one of his own social media posts about vaccines that got labeled misleading, Johnson claimed the agency had abused its authority and demanded it fork over key documents about the efforts in a Monday letter to CDC Director Dr. Mandy Cohen.

“Based on recent information I have received … it is clear that CDC abused its authority by engaging in a censorship campaign to suppress and discredit certain viewpoints it labeled as ‘misinformation,'” Johnson wrote in the letter, obtained by The Post.

As an example, Johnson highlighted a Jan. 3, 2022, post he made on Twitter, now known as X, that highlighted information from the CDC’s Vaccine Adverse Event Reporting System (VAERS).

Ron Johnson has been holding various health agencies’ feet to the fire over their response to the pandemic.

REUTERS

The Wisconsin senator admonished the CDC’s push for social media content moderation regarding the COVID-19 vaccines.

Senator Ron Johnson

The post that got Sen. Ron Johnson slapped with a misleading label on X, the platform formerly known as Twitter.

Senator Ron Johnson

In the post, Johnson claimed that VAERS data showed there had been over 1 million adverse effects from the COVID-19 jab. That post was labeled misleading on the platform with a note explaining that most public health officials had deemed the vaccines safe.

All replies, shares, or likes stemming from that post were then blocked by the platform, according to Johnson. Since then, X has switched to a “Community Notes” system that crowdsources corrections to potentially misleading posts.

The platform’s new leadership later explained to Johnson that executive branch officials, particularly from the CDC, “communicated with social media companies, including Twitter, about ‘COVID Vaccine Misinformation,'” the senator wrote.

Mandy Cohen took the reins as CDC director last month.

TNS

“The information Twitter provided showed a clear and concerted effort by the CDC to censor those who tweeted about VAERS data,” Johnson added.

Johnson, the ranking member on the Senate’s Permanent Subcommittee on Investigations, is demanding records detailing interactions between all CDC employees and employees at X, Facebook, and YouTube regarding 10 individuals who expressed vaccine and lockdown-skeptical views beginning Dec. 1, 2019.

Those 10 include Johnson himself, Brianne Dressen, John Ioannidis, Robert Kennedy, Jr., Pierre Kory, Theresa Long, Robert Malone, Peter McCullough, Harvey Risch, and Aaron Siri.

The Wisconsin senator is also requesting all records pertaining to CDC interactions with both private sector companies and federal agencies about suppression of online speech or COVID-19 misinformation policies.

He is also seeking records about “Be On the Lookout” topics and a list of all social media posts the CDC flagged as “containing misinformation, disinformation, or generally disfavored speech.”

Johnson gave the CDC a Sept. 11 deadline to comply. The agency did not return The Post’s request for comment, but has noted in the past that VAERS relies on reports submitted by individuals rather than health officials.

“VAERS is not designed to determine if a vaccine caused a health problem but is especially useful for detecting unusual or unexpected patterns of adverse event reporting that might indicate a possible safety problem with a vaccine,” read an advisory to the social network included in Johnson’s letter.

The Senator noted a CDC advisory to the platform about misinformation and what to be on the lookout for on social media.

Senator Ron Johnson

In the letter, Johnson also laid out a timeline laying out the sequence of events in the run-up to his tweet about VAERS.

“It appears that CDC’s efforts to coordinate with Twitter to discredit posts about VAERS shortly followed my own public statements about VAERS data and the mainstream media’s condemnation of my remarks,” he wrote.

Content moderation policies on social media platforms have long been a rallying cry for conservatives who complain they have been unfairly censored.

In the House, Republicans led by Subcommittee on Government Weaponization Chairman Jim Jordan (R-Ohio) have been probing social media policies.

Ron Johnson won reelection in the battleground state of Wisconsin in the 2022 midterm elections.

AP
Johnson has also been scrutinizing other actions by government health agencies surrounding the pandemic.

Earlier this month, he asked the Department of Health and Human Services’ inspector general whether government scientists concealed critical information about COVID-19 from the public.

https://nypost.com/2023/08/30/sen-johnson-lambasts-cdc-demands-docs-on-censorship-of-vaccine-data/