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Introduction

Alopecia represents a prevalent and challenging condition with multifaceted physical and mental implications, such as anxiety, depression, and emotional disorders,^1–3 which directly impact self-image, personal identity, and quality of life.^4,5 Androgenetic alopecia (AGA) and alopecia areata (AA) account for the majority of non-scarring alopecia.⁶ The most common form of AGA involves representative receding of the forehead hairline in men and thinning the hair between the forehead and the apex of the scalp. The forehead hairline remains unchanged in women.^1,7,8 AA is a chronic follic-specific autoimmune disease characterized by patchy alopecia that can progress to diffuse or complete loss of scalp and body hair.⁹ The prevalence of alopecia was also raised with age, and the impact of non-scarring alopecia on patients’ lives was often underestimated.¹ Alopecia is associated with an increased risk of metabolic syndrome, cardiovascular disease, diabetes, and hypertension.^10–14

Numerous factors interact to promote the development of non-scarring alopecia, including genetic predisposition, endocrine factors, and mental implications.^15,16 Previous studies have suggested that mental disorders are linked with alopecia. A meta-analysis of 4 cross-sectional studies and 4 case–control studies including 6,010 patients with AA and 20,961 control individuals showed that AA has a positive association with anxiety and depression.¹⁷ Moreover, existing Mendelian randomization (MR) has unveiled that AA can exert a risk effect on major depression disorder and anxiety.¹⁸ Although AGA is primarily driven by genetic and androgen sensitivity, psychological stress might modulate disease severity through neuroendocrine and inflammatory pathways.^19–22 Testosterone and dihydrotestosterone modulate the neuroendocrine response to stress and are inversely related to depression rates.²³ A meta-analysis of 41 studies with 7995 patients found a significant association of AGA with moderate impairment of both health-related quality of life and emotions, but no association was found with depressive symptoms.⁵ Besides, the latest MR study provided some clues that AGA may precipitate the development of depression.²⁴ However, evidence for causal associations between AA and other mental health states is insufficient, and it is unclear whether mental disorders have a causal impact on AGA. It is difficult to design studies on whether mental disorders play an etiologic role in the onset and progression of non-scarring alopecia at this stage, and some studies to explain the pathophysiological mechanisms remain speculative. To address the issues, we hypothesize that certain mental disorders may causally influence AA and AGA.

MR, leveraging the genetic variants as instrumental variables (IVs), has been widely used to address causal inference of exposure on outcomes. Genetic variants are randomly allocated at fertilization and not affected by factors later in life, thus the MR design can notably mitigate the residual confounding and preclude reverse causality. Compared with randomized controlled trials, MR design can reduce resource intensity and avoid long-term follow-up.²⁵ Therefore, to examine whether mental diseases (depression, anxiety, panic, distress, and bipolar disorder) are causally related to the pathogenesis of non-scarring alopecia as well as the causal effect of non-scarring alopecia on mental diseases, we executed a two-sample bidirectional MR using publicly available summary statistics from several large-scale genome-wide association studies (GWASs).

Materials and Methods

Study Design

We obtained all data and materials from public databases. Summary statistics from several large-scale GWASs regarding 5 mental disorders and 2 non-scarring alopecia were all obtained from European descent. The bidirectional two-sample MR design was utilized to examine the bidirectional association of mental diseases (depression, anxiety, panic, distress, and bipolar disorder) on non-scarring alopecia (AGA and AA). The forward MR analyses investigated the causal relationship between mental disorders and non-scarring alopecia. In contrast, the reverse MR analyses explored the causality with non-scarring alopecia and mental diseases (Figure 1). We reported this study according to the Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization (STROBE-MR).²⁶ All the original studies were approved by their respective institutional review boards, and informed consent was provided by all participants. Due to the publicly available summary statistics used, no additional ethical approval was required.

Data Sources

The sources of summary statistics for mental disorders and non-scarring alopecia included in our work were placed in Supplementary Table S1. The definitions of all traits and corresponding details, such as recruitment criteria of population and quality control of genetic data, were directly referenced from the original reports without any changes. The datasets of major depression disorder (ieu-b-102), anxiety disorder (ukb-d-20544_15), panic attack (ukb-d-20544_6), distress (ukb-d-20499), and bipolar disorder (ieu-b-5110) were all accessed through the IEU OpenGWAS project (https://gwas.mrcieu.ac.uk/).

GWAS summary statistics for AGA and AA were sourced from the FinnGen Biobank study (Release 10), including 219,469 (220 AGA cases and 219,249 controls) and 394,872 (767 AA cases and 394,105 controls) participants, respectively (https://www.finngen.fi/en). The International Classification of Diseases (ICD) codes for AGA were L64 and 7040A; ICD codes for AA were L63, 7040B, 7040C, and 70400. Crucially, for both forward and reverse MR, to avoid bias and ensure a low type 1 error rate, we chose datasets of mental disorder and non-scarring alopecia with no overlap samples.

Genetic IVs Selection

The genetic variant used in the MR design must fulfill three essential assumptions: (1) The genetic variant is robustly linked with the exposure (relevance); (2) The genetic variant is independent of any confounders (independence); (3) The genetic variant does not affect the outcome, except possibly via the exposure-outcome pathway (exclusion restriction).²⁵

Single nucleotide polymorphisms (SNPs) were utilized as IVs. In the forward MR study, due to the limited number of SNPs of mental disorders, a more lenient significance level (P < 1×10⁻⁵) was set.¹⁸ In the reverse MR study, considering the limited GWAS dataset of AGA and AA, SNPs with the threshold of P < 5×10⁻⁵ were obtained. SNPs were clumped at a stringent linkage disequilibrium (LD) threshold (window=10 Mb; r² = 0.001).¹⁸ F statistics were calculated using the formula of β²/se² for all SNPs involved; SNPs with F statistics <10 were removed to lessen weak instrument bias.^18,27,28 We screened the GWAS Catalog database (https://www.ebi.ac.uk/gwas/downloads/summary-statistics) to exclude SNPs (P < 1×10⁻⁵) associated with confounders (such as, autoimmune diseases and atopic diseases) that could potentially affect the AA.²⁹ When certain SNPs were not included in the outcome datasets, appropriate proxies in strong LD with r² ≥ 0.8 were utilized.

Two-Sample Bidirectional MR

We utilized five MR methods to explore the causal associations between mental disorders and non-scarring alopecia, including inverse variance weighted (IVW),³⁰ weighted median,³¹ MR-Egger,³² weighted mode,³³ and penalised weighted median.³⁴ Results are presented as the odds ratio (OR) with 95% confidence interval (CI). The fixed-effects IVW method was the predominant analysis, which is a robust MR method under the assumption of valid IVs and balanced pleiotropy.³⁵ If heterogeneity exists, IVW with the outliers correction was used as the primary result.³⁵

Sensitivity analyses were performed with the MR pleiotropy residual sum and outlier method (MR-PRESSO),³⁶ RadialMR method,³⁷ MR-Egger intercept, Cochran’s Q statistic, and leave-one-out analysis. MR-PRESSO was employed to detect potential horizontal pleiotropy and heterogeneity and to correct the estimated causal effect by identifying and removing outlier SNPs.³⁶ RadialMR was also utilized to identify and remove outliers. We generally look for estimates that do not indicate bias from horizontal pleiotropy (MR-PRESSO global P > 0.05, also MR-Egger intercept P > 0.05). We utilized Cochran’s Q test to assess IV heterogeneity, with a P-value >0.05 indicating no heterogeneity. Leave-one-out analyses were conducted to evaluate the potential impact of each variant on the estimates.³⁶ Moreover, the visualization of scatter, forest, and funnel plots was also depicted.

Statistical Analysis

When we included the vast number of risk factors and outcomes, the significance would be penalized.³⁸ Notably, the findings should be interpreted cautiously, not based solely on a P-value threshold. To achieve more potentially important findings, we consider the expansive range of risk factors and outcomes a study strength, rather than constructing a “suggestive significance threshold”. Therefore, associations with P <0.05 were considered as significant. The statistical power of the MR estimates was calculated using the online tool (https://sb452.shinyapps.io/power/).³⁹ All analyses were conducted using R software, version 4.3.1 (R Foundation for Statistical Computing, Vienna, Austria). TwoSampleMR, MRPRESSO, and RadialMR R packages were adopted for the MR analyses.

Results

Genetic Instruments

After the removal of ambiguous, palindromic, unavailable SNPs and potential confounding, each outcome finally had different IVs for inclusion. None of the SNP had F-statistics <10, and the minimum F-statistic for all SNPs included in two-sample bidirectional MR was 16.52, indicating that the possibility for weak IV bias is minimal (Supplementary Table S2-S6).

In the forward MR analysis, for the AGA and AA outcome, 204, 30, 28, 51, and 197 SNPs were extracted from GWAS data for major depression disorder, anxiety disorder, panic attacks, distress, and bipolar disorder, respectively. Reversely, to explore the causal association of AGA with mental disorders, 27 to 30 SNPs were chosen as the IVs from the corresponding GWAS datasets. For AA exposure, 9 to 15 SNPs were extracted (Supplementary Table S2).

Causal Effects of Mental Disorders on Non-Scarring Alopecia

In the forward MR analysis, no association between any genetically predicted mental disorders and AGA was found (Supplementary Figure S1). The weighted median, MR Egger, weighted mode, penalised weighted median, and MR-PRESSO method did not alter the findings from IVW. Outliers identified by the IVW Radial MR method were depicted in the Radial plot (Supplementary Figure S2). After the outlier correction, we still observed no associations between mental disorders and AGA (Supplementary Figure S3).

Besides, genetically predicted major depression disorder was positively associated with the risk of AA (OR: 1.59; 95% CI: 1.16–2.17; P=0.0042). In contrast, we uncovered no evidence that a higher genetic predisposition to panic attacks (OR: 1.74; 95% CI: 0.02–123.76; P=0.800), anxiety disorder (OR: 0.47; 95% CI: 0.03–7.80; P=0.596), distress (OR: 0.83; 95% CI: 0.17–4.03; P=0.814), and bipolar disorder (OR: 0.99; 95% CI: 0.85–1.15; P=0.906) was associated with AA. Additionally, other multiple analyses yielded similar estimates to IVW, indicating the robustness of our results (Figure 2). After eliminating additional outliers and potential confounders, genetically predicted major depression disorder was still associated with the risk of AA (OR: 1.55; 95% CI: 1.12–2.14; P=0.0083) (Supplementary Figure S4–S5).

Figure 2 Association between genetically predicted mental disorders and alopecia areata.

No horizontal pleiotropy was shown in the MR-PRESSO method in all non-scarring alopecia analyses (all Global P value >0.05) (Supplementary Table S7). Except for the effect of bipolar disorder on AGA (P for intercept = 0.044), none of the MR-Egger intercepts deviated from 0 for other mental disorders included, indicating no horizontal pleiotropy (P for intercept >0.05). No heterogeneity among the IVs was detected by the Cochran’s Q test (Supplementary Table S8). Additional visualizations of scatter plots, funnel plots, forest plots, and leave-one-out plots can be found in supplementary materials (Supplementary Figure S6–S21).

Causal Effects of Non-Scarring Alopecia on Mental Disorders

For the reverse MR analysis, we found no significant association between AGA and the risk of mental disorders (Supplementary Figure S22). Besides, genetically predicted AA was positively associated with the risk of major depression disorder (OR: 1.02; 95% CI: 1.00–1.03; P=0.0078). For the association of AA with major depression disorder, little evidence of directional pleiotropy and heterogeneity among the individual SNP effects was found (Supplementary Table S7–S9). However, no evidence showed that a higher genetic predisposition to AA was linked to other mental disorders (Figure 3). After removing outliers, genetically predicted AA was still associated with the risk of major depression disorder (OR: 1.01; 95% CI: 1.00–1.02; P=0.0351) (Supplementary Figure S23).

Figure 3 Forest plots for the associations of genetic susceptibility to alopecia areata with different Mendelian randomizations of mental disorders.

Furthermore, the sensitivity analysis also substantiated the robustness and reliability of our findings. More detailed information on additional analyses can be found in the supplementary materials (Supplementary Figure S24–S32). In summary, bidirectional causality was observed between major depression disorder and AA. Notably, the statistical power of MR estimates may be insufficient (Supplementary Table S10).

Discussion

We performed comprehensive bidirectional MR analyses to dissect the causal influence of mental disorders on the risk of non-scarring alopecia using summary statistics from large-scale GWASs. A bidirectional causal association of major depression disorder but not any other mental disorders with AA might exist. No association between any genetically predicted mental disorders and AGA was observed. These findings provide additional insights into non-scarring alopecia development, fostering the development of innovative strategies for non-scarring alopecia prevention and treatment.

Previous meta-analyses have shown a robust association of depression and anxiety with AA, though the causal effect and its direction are vague. A meta-analysis including 37 articles (29 on depression and 26 on anxiety) showed that 7% to 17% of patients with AA had depressive or anxiety disorders.⁴⁰ Another meta-analysis has consistently demonstrated a positive association of AA with anxiety (pooled OR, 2.50) and depression (pooled OR, 2.71).¹⁷ Our findings untangled an increase in AA risk by approximately 59% for each doubling odds increase in major depression disorder; while in the reverse direction, there was an increase in major depression disorder risk by approximately 2% for each doubling odds increase in AA, which is marginal and possibly clinically insignificant. Besides, no association was found between anxiety and AA in the current study. Nevertheless, an earlier MR study using datasets from FinnGen release 9 databases, genome-wide meta-analysis, and Anxiety Neuro Genetics Study Consortium unveiled the association of AA with major depression disorder and anxiety.¹⁸ Compared with the current study, a similar effect magnitude but a different significance (P-value) in the association of AA with depression was found, while an inconsistent estimate in the association of AA with anxiety was observed. The discrepancies in results across MR studies may be due to the limited number of IVs and weak statistical power (<80%) (Supplementary Table S10). More GWAS datasets of mental disorders and non-scarring alopecia would be needed in the future to conduct two-sample MR studies, and the estimates from these analyses were then meta-analyzed further to increase the statistical power and reliability of the results. For individuals, those negative mental states may also be worsened in diverse social interactions. Accordingly, providing timely and suitable mental counseling is important. By identifying the potential mental burdens faced by AA patients and even general populations, clinicians can propose much-needed aid and interventions to handle their emotional well-being.

No evidence of a causal association between any genetically predicted mental disorders and AGA was found, which was inconsistent with a recent MR study. The reported MR has indicated that AGA may precipitate the development of depression, with a marginal increase in risk (IVW OR = 1.015).²⁴ Notably, in the above-mentioned MR study, the AGA (ukb-a-301) and depression (ebi-a-GCST90038650)⁴¹ dataset were both derived from the UK Biobank study, which may introduce a false-positive rate, leading to unreliable conclusions. As the threshold for SNP selection (P < 1×10⁻⁵) is relatively loose, the possibility of weak instrument bias might also be caused. On the other hand, due to the missing report of statistical power in the MR study, interpretations should be made cautiously.

Potential physiologic mechanisms linking depression to AA may involve shared genetic factors and immune pathways. One significant genetic factor is the GRM8 gene, which encodes a protein involved in glutamatergic synapses. This gene shows significant associations with both conditions, as dysregulation of glutamatergic synapses can affect neuronal communication and has been linked to psychiatric disorders as well as hair loss.¹⁸ On the other hand, depression exhibits dual features of immunosuppression and activation (eg, elevated IL-6, TNFα, CRP),⁴² while AA is characterized by Th1/IFN-γ-dominated autoimmunity.⁴³ The etiology of AA is thought to involve immune events that lead to exposure of hair follicle autoantigens, with both Th1 and Th2 pathways implicated in the pathogenesis of AA.^43,44 Shared genetic and inflammatory pathways thus likely underlie their comorbidity.

Admittedly, some likely limitations are inevitable: First, study datasets are derived from European populations, and the generalization of results may be restricted. Future studies will incorporate diverse ancestral populations to validate these findings and disentangle genetic/environmental contributions to the depression–alopecia relationship. Second, to obtain more IVs of mental disorders and non-scarring alopecia and to increase the statistical power, a looser significant threshold was set, which may introduce some concerns. However, pleiotropy and heterogeneity among the individual SNP effects were not detected by the MR-PRESSO and MR-Egger regression intercepts method. In addition, a more liberal P-value threshold would likely bias the results toward the null.⁴⁵ Third, the association of mental disorders with non-scarring alopecia was not corrected by the Bonferroni method, so the findings should be interpreted with caution. Clinical research is also required to validate this finding further.

Conclusion

Our finding provided hints for a bidirectional causal association between major depression disorder and AA instead of AGA, which may partly explain the underlying mechanism of hair loss and offer clues in future prevention and intervention strategies. Mechanistic studies and prospective studies with individual-level data will be warranted to improve understanding of this link.

Abbreviations

AGA, androgenetic alopecia; AA, alopecia areata; MR, Mendelian randomization; IV, instrumental variable; GWAS, genome-wide association study; SNP, single nucleotide polymorphism; LD, linkage disequilibrium; IVW, inverse variance weighted; MR-PRESSO, MR pleiotropy residual sum and outlier method.

Data Sharing Statement

All the original GWAS files are available for download from the IEU OpenGWAS project (https://gwas.mrcieu.ac.uk/) and the FinnGen project (https://risteys.finngen.fi/).

Ethics Statement

According to Article 32 of the Measures for Ethical Review of Life Science and Medical Research Involving Human Beings adopted by the National Science and Technology Ethics Committee of the People’s Republic of China, ethical review can be exempted because the data used in this study do not cause any harm to human beings, do not involve any sensitive personal information or commercial interests, and the databases selected are open and legal.

Acknowledgments

This study was conducted by using GWAS data from the UK Biobank database, FinnGen database, published articles, and other large international consortiums and labs, including Psychiatric Genomics Consortium and Neale lab. We thank all participants and the abovementioned consortiums for their contribution.

Funding

This study was not sponsored by any organization.

Disclosure

The authors declare that they have no competing interests.

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The majority of symptoms reported by patients after stopping antidepressants are mild and do not meet the criteria for discontinuation syndrome — a set of more severe withdrawal-like symptoms that some patients and guidelines describe, new research suggests.

The new findings raise questions about the necessity of routinely using long-term tapering strategies and suggest that current deprescribing guidelines may need to be revised, the investigators, with first author Michail Kalfas, MSc, King’s College London, London, England, noted.

“I would hope that the guidelines from various authorities such as the Royal College… should be considered to be changed to reflect this most recent update in terms of the evidence,” the study investigator Allan H. Young, MD, PhD, told reporters attending a virtual press briefing.

Young emphasized the importance of weighing the benefits and risks when considering antidepressant treatment, noting that some patients hesitate to start medication due to fears of difficult discontinuation symptoms.

He said the new findings should help reassure both clinicians and patients, as commonly used antidepressants for depression and anxiety offer clear benefits, and any discontinuation effects are typically mild, limited in number, and tend to lessen over time.

The study was published online on July 9 in JAMA Psychiatry.

Inconsistent Clinical Guidance

Antidepressant discontinuation symptoms have been recognized since the 1950s, but clinical guidance on how to manage them remains inconsistent. While most international guidelines recommend tapering, there is little consensus on how long tapering should last or what symptoms to expect.

Previous studies have reported wide-ranging rates of discontinuation symptoms, but many lacked details on the type or severity and often did not include comparisons with placebo.

Current Royal College guidelines appear to rely on survey studies with self-selected samples, including users of tapering strips. These are “methodologically weak, with unclear response rates and probable selection bias,” senior author Sameer Jauhar, PhD, told Medscape Medical News.

“I am slightly perturbed that the authors of this guidance did not consider our critiques of clear methodological fallacies in this literature — which they were aware of,” he added.

To determine the incidence and nature of symptoms following discontinuation of antidepressants the researchers conducted a systematic review and analysis of 49 randomized clinical trials of patients who discontinued or continued antidepressants or discontinued placebo. Additional unpublished data from 11 randomized trials were also included.

The primary aim of the research was to assess antidepressant discontinuation symptoms using the Discontinuation Emergent Signs and Symptoms (DESS) scale, by directly comparing symptom scores between individuals who stopped taking an antidepressant and those who either continued treatment or discontinued a placebo.

A secondary goal was to evaluate the incidence of specific discontinuation symptoms in patients who stopped antidepressants compared with those who stopped placebo.

In all, the analysis included 17,828 participants. They had a mean age of 44 years and 66.9% were women. The follow-up was between 1 day and 52 weeks after cessation, with discontinuation symptoms measured using the DESS scale, or as reported adverse events.

Most participants had major depressive disorder, but there were a wide range of conditions including generalized anxiety disorder, panic disorder, fibromyalgia, premenstrual dysphoric disorder, posttraumatic stress disorder, and compulsive-shopping disorder.

Kalfas noted during the briefing that the analysis included a broad range of antidepressants, primarily selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors such as paroxetine, duloxetine, sertraline, escitalopram, venlafaxine, fluoxetine, and vortioxetine.

Discontinuation Effects

The investigators found that participants who discontinued antidepressants experienced significantly more withdrawal symptoms at 1 week than those who either continued treatment or stopped placebo.

Using the DESS scale, the standardized mean difference was 0.31 (95% CI, 0.23-0.39; k = 11 studies; n = 3915), which corresponds to approximately one additional symptom.

Investigators also reported increased odds of specific symptoms following antidepressant discontinuation, including dizziness (odds ratio [OR], 5.52; 95% CI, 3.81-8.01), nausea (OR, 3.16; 95% CI, 2.01-4.96), vertigo (OR, 6.40; 95% CI, 1.20-34.19), and nervousness (OR, 3.15; 95% CI, 1.29-7.64) compared with placebo. Dizziness was the most common symptom, with a risk difference of 6.24%.

Despite including participants with major depressive disorder (k = 5 studies), the analysis showed no association between discontinuation and a re-emergence of depressive symptoms.

Kalfas explained that the primary analysis compared symptom levels in individuals who stopped taking antidepressants with those who either continued the medication or stopped placebo.

On average, those who discontinued antidepressants experienced about one additional symptom — 1.09 to be exact — within a week. The range of additional symptoms (0.8-1.36) remained below the threshold for clinically significant discontinuation syndrome, which is defined as four or more symptoms, Kalfas noted.

There were slightly more symptoms in those discontinuing duloxetine (1.61) and desvenlafaxine (1.37) than those discontinuing vortioxetine (0.56), whereas those who discontinued agomelatine did not experience any symptoms.

“This is a very important and interesting finding, those who discontinued antidepressants did not experience worsening moods in the first 2 weeks, although this outcome was measured in people with major depressive disorder,” said Kalfas.

The authors emphasized the importance of recognizing that antidepressant discontinuation can cause real, and sometimes distressing symptoms. However, they cautioned that both clinical practice and media coverage should present these effects in a balanced way.

Overstating the risks, they warned, could unintentionally contribute to or prolong symptoms through psychological factors such as the nocebo effect — where negative expectations lead to real physical symptoms.

Criticism, Kudos

Commenting on the research for Medscape Medical News, Allen Frances, MD, professor emeritus of psychiatry at Duke University School of Medicine, Durham, North Carolina, and former chair of the DSM-IV Task Force, said the authors have “over-interpreted” their findings.

He added that the study does not change his clinical view that gradual deprescribing remains the best approach for patients who are not benefiting from a psychiatric medication.

Frances described the analysis as questionable and highlighted what he believes are three major weaknesses. These include the inclusion of underpowered studies, short durations of antidepressant therapy, and averaging symptoms across the entire study population. He explained that if only 1 in 5 patients experience clinically significant withdrawal with five symptoms, whereas the other four have none, averaging symptoms for the whole group can mask the true extent of withdrawal harms.

Mark Horowitz, MD, a vocal advocate for gradual antidepressant tapering and Visiting Lecturer in Psychopharmacology at King’s College London, also noted a risk for bias in many of the included studies.

He pointed out that many of the authors have close ties to drug manufacturers and argued that focusing on short-term, industry-funded research may underestimate the potential long-term harms faced by antidepressant users. Horowitz discussed these concerns in an article for The Conversation.

Horowitz, who leads the Psychotropic Deprescribing Clinic at the North East London NHS Foundation Trust, pointed out that the study’s average antidepressant exposure was only 8-12 weeks.

He warned this short duration likely underestimates the risk for withdrawal for the millions of patients taking these medications for years. A recent survey by his group found significantly higher rates and greater severity of withdrawal symptoms among individuals with longer-term antidepressant use.

However, Jauhar denied that his group focused on short-term, industry-funded studies.

“We included all eligible randomized controlled trials irrespective of length and funding source, one of which was the ANTLER trial, the most comprehensive primary study on antidepressant discontinuation, that had a follow up of 12 months and 70% of the sample was treated with antidepressants for at least 3 years,” he noted.

Evidence also shows that industry-funded studies do not report lower rates of discontinuation symptoms than studies not funded by industry, he added, and cited a study published last year showing no association.

“The vernacular in regard to funding is misleading and ignores the fact that almost all antidepressants in the UK are generic — i.e. there is no financial gain,” he added.

In a statement from the UK nonprofit Science Media Centre (SMC), additional experts welcomed the study for its clearer, more comprehensive analysis of antidepressant discontinuation symptoms, but also noted key limitations and the need for further research.

Katharina Domschke, MD, PhD, praised the study’s stronger methodology compared with earlier, smaller studies with significant biases. Susannah Murphy, DPhil, highlighted the large dataset of over 17,000 patients and the inclusion of placebo comparisons but pointed out that the analysis only covered symptoms within the first 2 weeks after stopping medication and did not assess symptom severity.

Christiaan Vinkers, MD, PhD, said the findings help temper alarmist claims about widespread, severe withdrawal but acknowledged remaining gaps — particularly concerning long-term users and real-world tapering strategies.

A spokesperson for the Royal College of Psychiatrists noted that the study reinforces current understanding that most patients benefit from antidepressants, though some individuals experience side effects, and that this new evidence will inform future patient resources.

Overall, the consensus presented by SMC experts underscores the study’s valuable contribution while calling for further research on long-term discontinuation effects and individualized tapering approaches.

Kalfas reported receiving personal fees from Neurocentrx Pharma outside the submitted work; employment by King’s College London; and funding by the UK National Institute for Health Research (NIHR) Biomedical Research Centre. Jauhar reported receiving speaker fees from Boehringer Ingelheim, the Dubai Masterclass conference, Janssen, Lundbeck, and Recordati; serving as a nonpaid member of the UK National Institute for Health and Care Excellence Health Technology Appraisal committee; serving as a committee member and on the funding panel for the Wellcome Trust; and receiving advisory board fees from Boehringer Ingelheim and LB Pharmaceuticals outside the submitted work. Horowitz reported he is an investigator on the RELEASE and RELEASE+ trials in Australia, funded by the Medical Research Future Fund and the National Health and Medical Research Council, evaluating hyperbolic tapering of antidepressants against care as usual. He also reported being a co-founder and consultant to Outro Health, a digital clinic which provides support for patients in the US to help stop no longer needed antidepressant treatment using gradual, hyperbolic tapering. He also reported receiving royalties for the Maudsley Deprescribing Guidelines.Frances reported no relevant financial disclosures. Murphy reported receiving consultancy fees from Zogenix, Sumitomo Dainippon Pharma, UCB Pharma, and Janssen Pharmaceuticals and held grant income from Zogenix, UCB Pharma, Janssen Pharmaceuticals and ADM. Domschke reported receiving speaker’s fees from Janssen and is a member of the Neurotorium editorial board, Lundbeck Foundation. Vinkers reported being involved publicly in ZonMW-funded research on antidepressant discontinuation, including the TEMPO and HARMONIE studies, affiliation with the antidepressant discontinuation outpatient clinic in Amsterdam, and membership of the Dutch multidisciplinary guideline committee on psychotropic drug discontinuation. He had also received a speaker’s fee from Tiofarma but no financial ties to pharmaceutical companies relevant to this work.

Kate Johnson is a Montreal-based freelance medical journalist who has been writing for more than 30 years about all areas of medicine.

Scientists reveal that just a 10% cricket flour blend can turn everyday pasta into a nutrient-rich, eco-friendly superfood, without compromising safety or flavor.

Study: Cricket Flour for a Sustainable Pasta: Increasing the Nutritional Profile with a Safe Supplement. Image credit: Sophie Sparks Photography/Shutterstock.com

Integrating cricket flour into classic foods, such as pasta, could increase the protein and mineral content and may help alleviate malnutrition. A recent study in Foods evaluates the nutritional profile of cricket flour and its potential as a sustainable food source.

Perception and reality of Insect-based foods

Insects are rich in high-quality proteins, beneficial fatty acids, vitamins, fiber, and essential minerals (e.g., zinc, iron, and selenium), making them a favorable nutrient source that could be exploited to alleviate the effects of malnutrition. Besides a high nutritional profile, insect farming has a lower risk of zoonotic disease transmission, emits fewer greenhouse gases, and requires significantly less water and space than traditional livestock farming.

In many parts of the world, including Asia, Africa, and Latin America, insects are traditionally consumed as food. Insect-based products are highly regulated under European legislation and require prior authorization before commercialization. Although many studies have documented multiple benefits of insect-based food products, they still experience cultural resistance, mainly due to unfamiliarity and neophobia.

A previous study indicated the nutritional benefits and safety profiles of cricket (Acheta domesticus) flour. This study revealed that adding cricket flour to baked goods improves the flavor and aroma of the product, thereby enhancing consumer acceptance. Scientists believe that incorporating insect-based ingredients into traditional foods could enable the gradual integration of these products into the Western diet.  

About the study

The current study investigates the key nutrient components of cricket flour and a commercially available durum wheat and cricket flour mixture (containing 10% w/w Acheta domesticus flour). Wheat flour was used as a reference, and wheat pasta as a control (CTR). An expert chef prepared a fettuccine-shaped pasta. Protein, fatty acid, and mineral contents, such as iron (Fe), copper (Cu), zinc (Zn), sodium (Na), potassium (K), calcium (Ca), and magnesium (Mg), were analyzed using a standard procedure. The study also assessed the presence of environmental contaminants such as polycyclic aromatic hydrocarbons (PAHs) and total petroleum hydrocarbons (TPH) to determine the chemical safety of cricket flour.

Study findings

Gravimetric analysis indicated that cricket flour’s ash content constituted 4.2% of the dry sample weight. After 48 hours of drying, the moisture content of CTR and wheat cricket pasta was 14.04% and 11.07%, respectively.

The water activity (Aw) measures for control and wheat–cricket pasta were 0.83 and 0.64, respectively. These Aw values are typical of dried pasta and cereal-based products, although they are slightly above the recommended threshold of <0.6 for dry raw materials. Nonetheless, they indicate favorable stability and functionality during storage and processing.

In line with previous findings, the current study indicated an Fe content of 10.8 mg/100 g in cricket flour, which is higher than the Fe content of other common insect-based novel foods containing Tenebrio molitor and Ruspolia differens. Compared to wheat flour, the Fe content in cricket flour is nearly ten times higher. A similar trend was also observed for Zn (0.84 mg/100 gram) and Cu (1.6 mg/100 gram).

High K (886 mg/100 gram), Na (389 mg/100 gram), and Ca (973 mg/kg) concentrations were measured in cricket flour. In contrast, wheat flour only contained 133 mg/100 grams of K, 20 mg/kg of Na, and 200 mg/kg of Ca. As per the total fat content, cricket flour contained 11% of total fat, and pasta prepared using mixed wheat-cricket flour contained about 2%. The fat content in insects typically varies among species and even within the same species due to physiological adaptations associated with diet, environmental conditions, and temperature.

On consumption of 100 g of cricket flour, 23% of the energy was produced by metabolizing fats. Saturated fatty acids (SFA) accounted for 42% of total fatty acids, polyunsaturated fatty acids (PUFA) for 41%, and monounsaturated fatty acids (MUFA) for 17%. Previous studies have shown that a diet rich in SFAs increases serum low-density lipoprotein levels, increasing the risk of coronary heart disease.

Short-chain SFAs were found to be absent in cricket flour, but medium-chain SFAs, such as palmitic and myristic acids, were present and are known to influence cholesterol levels.

Palmitic and myristic acids were detected in the cricket flour samples. The current study indicated that consumption of cricket flour contributes to 9.8% of total energy from saturated fats, while pasta with wheat-cricket flour provides 1.9% of total energy from SFAs.

Cricket flour contained 17% oleic acid, a nutritionally significant MUFA, and these levels are comparable to traditional wheat pasta (15%) and pasta prepared with wheat-cricket flour. Previous studies have demonstrated that oleic acid reduces low-density lipoprotein (LDL) cholesterol, which protects against cardiovascular diseases, neurodegenerative disorders, and certain types of cancer.

Linoleic acid, a polyunsaturated fatty acid, was found at a high concentration in cricket flour, which accounted for 39% of total fatty acids. An increased intake of linoleic acid has been associated with a reduced risk of coronary heart disease.

The current study estimated cricket flour’s total amino acid content to be 60%, significantly higher than most consumed foods. Both cricket flour and mixed flour samples indicated higher levels of nearly all measured amino acids, including alanine, valine, and lysine, compared to the wheat-based ones. However, while pure cricket samples had a significantly higher concentration of amino acids, the 10% cricket-wheat mix only modestly improved amino acid levels over wheat alone.

Cricket flour samples contained a higher concentration of total petroleum hydrocarbon (TPH) than other flour and pasta samples. Despite this, the levels were well below those in different foods like fish or meat and were within safe consumption thresholds. All samples indicated a Carbon Preference Index (CPI) above 1, indicating a biogenic origin of the hydrocarbons.

The study also tested for polycyclic aromatic hydrocarbons (PAHs) found at low concentrations in all samples. Cricket flour showed no detectable levels of the most concerning PAHs like benzo[a]pyrene, and total PAH levels remained well below EU safety thresholds for foods, further supporting its safety for human consumption.

Researchers confirmed the presence of chitin in the cricket flour, a component with potential prebiotic effects that could benefit gut health and microbial diversity.

Conclusions

In comparison to commercially available wheat flour, cricket flour contained a higher concentration of protein and essential minerals, such as Na, Ca, Fe, and K. Notably, adding 10% cricket flour to wheat flour to make pasta substantially reduces the recommended daily intake (DI) for almost all nutrients considered in this study.

However, the study notes that a 10% substitution only modestly improves amino acid content, suggesting that higher inclusion rates or complementary dietary sources may be necessary to achieve full nutritional benefits.

Notably, the study found that environmental contaminants such as PAHs and hydrocarbons were present at levels far below regulatory limits, reinforcing the safety of cricket flour as a food ingredient.

With its strong nutritional profile, minimal safety concerns, and compatibility with familiar foods like pasta, cricket flour may offer a promising strategy to improve diet quality and sustainability, especially if introduced in small, culturally acceptable amounts.

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