Most antidepressants used for chronic pain are being prescribed with “insufficient” evidence of their effectiveness, scientists have warned. A major investigation into medications used to manage long-term pain found that harms of many of the commonly recommended drugs have not been well studied.
In a Cochrane review, scientists examined 176 trials consisting of nearly 30 000 patients involved in assessments which prescribed antidepressants for chronic pain.
Among the drugs studied were amitriptyline, fluoxetine, citalopram, paroxetine, sertraline, and duloxetine – with only the latter showing reliable evidence for pain relief. One third of people globally are living with chronic pain, World Health Organization data shows, with many prescribed antidepressants for relieving symptoms.
Lead author Professor Tamar Pincus from the University of Southampton said: “This is a global public health concern. Chronic pain is a problem for millions who are prescribed antidepressants without sufficient scientific proof they help, nor an understanding of the long-term impact on health.
“Our review found no reliable evidence for the long-term efficacy of any antidepressant, and no reliable evidence for their safety for chronic pain at any point. Though we did find that duloxetine provided short-term pain relief for patients we studied, we remain concerned about its possible long-term harm due to the gaps in current evidence.”
The two-year Cochrane study was the largest ever assessment of antidepressants recommended by leading bodies including the UK’s National Institute for Health and Care Excellence (NICE) and the Food and Drug Administration (FDA) in the USA.
Statistician Gavin Stewart, review co-author from Newcastle University, said: “We are calling on governing health bodies NICE and the FDA to update their guidelines to reflect the new scientific evidence, and on funders to stop supporting small and flawed trials. Evidence synthesis is often complex and nuanced but the evidence underpinning the use of these treatments is not equivalent, so current treatment modalities are hard to justify.”
The review revealed that duloxetine was consistently the highest-rated medication and was equally as effective for fibromyalgia, musculoskeletal, and neuropathic pain conditions.
Other results showed:
Standard doses of duloxetine are as successful for reducing pain as higher quantities,
Milnacipran was also effective at reducing pain, but scientists are not as confident as duloxetine due to fewer studies with fewer people.
Prof Tamar Pincus added: “We simply cannot tell about other antidepressants because sufficiently good studies are not available – but it does not mean that people should stop taking prescribed medication without consulting their GP.”
Scientists responsible for the review, funded by the NIHR’s Health Technology Assessment programme, were from the universities of Southampton, Newcastle, Bristol, UCL, Bath, and Keele, alongside Oxford University Hospital.
The team assessed the trials using a statistical method that enables researchers to combine data from relevant studies to estimate the effects of different drugs, which have not been compared directly in individual trials.
University of Southampton researcher Dr Hollie Birkinshaw said: “Though previous investigations show that some antidepressants might relieve pain, there has never been a comprehensive study examining all medications across all chronic conditions – until now.
“The only reliable evidence is for duloxetine. Adopting a person-centred approach is critical to treatment, and when patients and clinicians decide together to try antidepressants they should start from the drug for which there is good evidence.”
Ccancer-associated fibroplasts surrounding a prostate tumour. Credit: Moscat and Diaz Meco lab.
Transgender women keep their prostates after gender-affirming surgery, and as a result are still at risk for prostate cancer, though to what extent remained unclear. A first-of-its-kind study estimates the risk at about 14 cases per 10 000, a little less than half the risk for cisgender males.
The UC San Francisco-led study drew on 22 years of data from the Veterans Affairs Health System. Despite the small sample size due to the size of the transgender population, it is still the largest of its kind.
“What we know about prostate cancer to date is almost exclusively based on cisgender men,” said the study’s lead author, Farnoosh Nik-Ahd, MD, a urology resident at UCSF. “This is an important first step in reshaping how clinicians think about prostate cancer in transgender women.”
Transgender people often face discrimination and disparities, and there has been a growing acknowledgment of the complexities involved in their health care.
The study found 155 confirmed transgender women with prostate cancer and stratified them according to whether they had used oestrogen: 116 had never used oestrogen, 17 had once used oestrogen but stopped before they were diagnosed with prostate cancer and 22 were actively on oestrogen.
The median age of diagnosis was 61 years, and 88% of the patients were white. Just 8% were Black, suggesting possible disparities affecting this group. Black cisgender men are at higher risk of being diagnosed with and dying from prostate cancer.
Though reduced compared to cisgender males, risk remains
The authors found that prostate cancer occurs in transgender women more frequently than published accounts suggest, with about 14 prostate cancer cases annually per 10 000 transgender women. Still, that rate was lower than what could be expected based on cisgender males, with 33 cases annually per 10 000.
While the numbers were small in the new study, the data suggests that transgender women who take estrogen may have delayed diagnoses. The authors also said that lower rates of prostate cancer may have been due to less PSA screening, misinterpretation of PSA levels in patients on gender-affirming hormone therapies, stigma, lack of awareness of prostate cancer risk and the effects of estrogen.
“We still have a lot of work to do to determine optimal prostate cancer screening for transgender women on oestrogen and related treatments,” said co-senior author Matthew R. Cooperberg, MD, MPH, of the UCSF Department of Urology. “This study should be a reminder to clinicians and patients alike that, regardless of gender, people with prostates are at risk for prostate cancer.”
Photo by Anna Shvets: https://www.pexels.com/photo/person-holding-white-printer-paper-4226124/
A recent phase III clinical trial showed that the drug combination of cemiplimab plus platinum chemotherapy can prolong survival in patients with advanced lung cancer when compared with placebo plus platinum chemotherapy. Now, an analysis published in CANCER indicates that cemiplimab plus platinum chemotherapy also improves quality of life (QoL) compared to chemotherapy alone.
In the multinational phase III EMPOWER-Lung 3 trial, the addition of cemiplimab to platinum-based chemotherapy was associated with improved survival in patients with advanced stage non–small cell lung cancer compared to chemotherapy alone. Because QoL is also an important parameter for treatment benefit, investigators examined how cemiplimab plus platinum affected symptoms in comparison to chemotherapy alone for patients enrolled into this trial using the EORTC QLQ-C30 and QLQ-LC13 questionnaires.
Patients who received cemiplimab plus chemotherapy experienced significant improvements in pain, dyspnoea, constipation, nausea, and vomiting compared to those who received placebo plus chemotherapy. Patients enrolled in the cemiplimab arm also had a significant delay in the clinically meaningful deterioration of symptoms including cough, haemoptysis, and dysphagia.
“The findings support the concept that the superior efficacy and favourable safety profile of cemiplimab plus chemotherapy translate to better patient-reported outcomes compared with chemotherapy alone in patients with advanced non–small cell lung cancer,” said corresponding author Tamta Makharadze, MD, of LTD High Technology Hospital Med Center in Batumi, Georgia.
The cooler months bring with them a surge in cases of influenza or ‘flu’. Flu infection causes up to 650 000 deaths globally each year, and the highest numbers occur in sub-Saharan Africa.1
Seasonal flu is characterised by a sudden onset of fever, cough (usually dry), headache, muscle and joint pain, severe malaise, sore throat and a runny nose. The cough can be severe and can last two or more weeks.2
South Africa’s seasonal flu usually has its highest number of recorded cases between May and September each year, with over 11 000 flu-related deaths occurring in the country annually.1 It is therefore important that healthcare professionals (HCPs) and high-risk population groups such as those living with chronic illnesses do not delay getting their flu shot this winter season.
Who is at risk of contracting severe flu, and of experiencing complications?
According to the National Institute for Communicable Diseases (NICD), the people most at risk for severe/complicated influenza include:1
Pregnant women and women up to 2 weeks postpartum
Young children (particularly those under 2 years of age)
Persons over the age of 65 years
Individuals who are morbidly obese (body mass index ≥40)
immunosuppression (e.g. those on immunosuppressive medication, or who have cancer)
heart disease (e.g. congestive cardiac failure), except for hypertension
metabolic disorders (e.g. diabetes mellitus)
kidney or liver disease
neurological and neurodevelopmental conditions
abnormal production or structure of haemoglobin (e.g. sickle cell disease)
Those under 18 years receiving chronic aspirin therapy
HCPs are particularly vulnerable for contracting flu: a systematic review comparing the incidence of flu in healthy adults and HCPs found a significantly higher incidence in HCPs, since they are exposed to the virus via their patients.3 The World Health Organization (WHO) adds that “Because healthcare workers are dedicated individuals, they often come to work when they are sick, increasing the risk of transmission,” and therefore recommends that all HCPs are vaccinated against seasonal flu every autumn.3
The NICD indicates that it is particularly important to protect HCPs and ensure that they are able to continue to work and to reduce any additional burden on the health system.1
Most people recover from fever and other symptoms within a week of contracting the flu, without requiring medical attention. However, among high-risk groups, and those with serious medical conditions, flu can cause severe illness or death.2
Complicated influenza includes cases requiring hospital admission and/or with symptoms and signs of lower respiratory tract infection (hypoxaemia, dyspnoea, tachypnoea, lower chest wall indrawing and inability to feed), central nervous system involvement and/or a significant exacerbation of an underlying medical condition.1
When is the best time to get vaccinated?
Dr Lourens Terblanche, Medical Head: South Africa, Sanofi Vaccines, says: “People should ideally get vaccinated against flu before the flu season begins for the most effective coverage, although vaccination at any time during the flu season can still help protect against flu infections.”
“Influenza viruses evolve constantly, so twice a year the WHO makes recommendations to update vaccine compositions. HCPs and patients who are known to be at high risk for developing severe or complicated illness as a result of contracting the flu, should prioritise immunisation against flu every year, as recommended by the NICD,” says Dr Terblanche. “The vaccine is however available to any individual from the age of 6 months to help prevent influenza infection.”
How vaccination could protect beyond flu
Flu can impact many systems in the body, so flu vaccination can provide protection where these systems would have been affected. For example, complications of flu include a 10x higher risk of having a heart attack,4 an 8x higher risk of stroke,4 and an 8x greater risk of pneumonia in children under the age of 14,5 while persons with diabetes experience a 75% increase in glycaemic events.6
According to the US Centers for Disease Control (CDC), during the 2019-2020 season, flu vaccination averted 7.5 million cases of flu, 3.7 million medical visits, 105 000 flu-associated hospitalisations, and 6 300 deaths.7
A 2021 study by the CDC also showed that among adults hospitalised with flu, vaccinated patients had a 26% lower risk of having to go into the ICU and a 31% lower risk of death from flu, compared with those who were unvaccinated.7
“Flu vaccination is also essential considering the possible co-circulation of both the flu and SARS-Cov-2 or other respiratory pathogens. However, it is important to remember that the flu vaccine will not prevent COVID-19 and vice versa; therefore, it is important to ensure that HCPs and their patients are vaccinated against both. Simultaneous infection with flu and COVID-19 canresult in severe disease,8” says Dr Terblanche.
Current guidance from the Department of Health regarding administering flu and COVID-19 vaccinations at the same time is that this may be done, if they are given in different arms.9
The WHO reports that there are still a number of myths about the flu vaccine10 – myths to which HCPs are not immune – including that ‘Flu is not serious, so I don’t need the vaccine’. The WHO responds as follows: “As many as 650 000 people a year can die of the flu. This only represents respiratory deaths, so the likely impact is even higher. Even healthy people can get the flu, but especially people whose immune systems are vulnerable. Most people will recover within a few weeks, but some can develop complications including sinus and ear infections, pneumonia, heart or brain inflammation.”
“It is good to be aware of the myths surrounding flu vaccination in order to encourage high-risk individuals to have their flu vaccine timeously,” says Dr Terblanche.
The quadrivalent Vaxigrip Tetra vaccine produced by Sanofi Pasteur complies with the WHO’s Southern Hemisphere recommendations for the 2023 season11 and protects against the following strains:
∙ an A/Sydney/5/2021 (H1N1)pdm09-like virus;
∙ an A/Darwin/9/2021 (H3N2)-like virus;
∙ a B/Austria/1359417/2021 (B/Victoria lineage)-like virus; and
∙ a B/Phuket/3073/2013 (B/Yamagata lineage)-like virus.
4. Warren-Gash C, et al. Laboratory-confirmed respiratory infections as triggers for acute myocardial infarction and stroke: a self-controlled case series analysis of national linked datasets from Scotland. Eur Respir J. 2018; DOI: 10.1183/13993003.01794-2017
5. Kubale J, et al. Individual-level Association of Influenza Infection With Subsequent Pneumonia: A Case-control and Prospective Cohort Study. Clin Inf Dis. 2021; 73(11): e4288–e4295.
6. Samson SI, et al. Quantifying the Impact of Influenza Among Persons With Type 2 Diabetes Mellitus: A New Approach to Determine Medical and Physical Activity Impact. J Diabetes Sci Technol. 2019; 15(1):44-52.
8. Stowe J, et al. Interactions between SARS-CoV-2 and influenza, and the impact of coinfection on disease severity: a test-negative design. International Journal of Epidemiology 2021;1-10. doi: 10.1093/ije/dyab081.
In a move bringing it closer in line with other organisations’ breast cancer screening guidelines, The United States Preventative Task Force (USPSTF) has released a draft statement recommending mammography every other year (biennially) from ages 40 to 74.
These recommendations are not applicable to women with a genetic marker or syndrome linked to increased breast cancer risk, a history of high-dose chest radiotherapy at a young age, or previous breast cancer or a high-risk breast lesion on previous biopsies.
According to the USPSTF, “new and more inclusive science about breast cancer in people younger than 50 has enabled us to expand our prior recommendation and encourage all women to get screened in their 40s. We have long known that screening for breast cancer saves lives, and the science now supports all women getting screened, every other year, starting at age 40.”
South African cancer screening guidelines typically closely follow American ones, according to an article by Lipschitz in the South African Journal of Radiology. Many countries had not recommended screening at the ages of 40–50 due to fears of overdiagnosis.
The UPSTF made particular attention the fact that black women are 40% more likely to die of breast cancer than white women, and have a high rate of aggressive cancers at young ages.
The recommendations are not without criticism. Biennial screenings are not seen as worth it by Desountis et al., as it leaving two years between tests leaves too much time for a tumour to grow.
Debra Monticciolo, MD, of Massachusetts General Hospital in Boston, and a member of the Society of Breast Imaging’s board of directors, told MedPage Today that she was “disappointed” with the decision to recommend biennial scans.
“Even if you look at their own data,” Monticciolo said, “annual screening results in more deaths averted, no matter what type of screening program you put in those models.”
Regarding the ongoing debated about continued screening in women ages 75 and older, and supplemental screening for those with dense breasts, the UPSTF found there was not enough evidence for a recommendation.
Sons of women with polycystic ovary syndrome (PCOS) have a twofold increased risk to develop obesity, according to a study published in Cell Reports Medicine. The findings highlight a previously unknown risk of passing PCOS-related health problems across generations through the male side of a family, say the the researchers from Karolinska Institutet.
PCOS is caused by overproduction of testosterone by the ovaries and affects around 15% of women of childbearing age worldwide, impacting fertility. In addition, the disease is associated with various health problems such as diabetes, obesity, and mental illness.
Daughters of women with PCOS have a fivefold risk of developing the same disease. Although it is not yet clear how sons of women with PCOS are affected, research suggests that they are more likely to have weight and hormone problems
The researchers used both registry data and mouse models in the newly published study to determine if and how PCOS-like traits are passed from mothers to their sons. Just over 460 000 sons born in Sweden between July 2006 and December 2015 were included in the registry study. Of these, roughly 9000 had mothers with PCOS. The researchers then identified which of the children were obese.
“We discovered that sons of women with PCOS have a twofold increased risk of obesity and of having high levels of “bad” cholesterol, which increases the risk of developing insulin resistance and type 2 diabetes later in life”, says study leader Elisabet Stener-Victorin, professor at Karolinska Institutet.
These findings were confirmed in the mouse study, where the researchers examined male offspring of female mice that before and during pregnancy were fed either a standard diet or a diet rich in fat and sugar, and were exposed to high levels of the male sex hormone dihydrotestosterone during pregnancy to mimic the pregnancy of normal weight individuals and obese women with PCOS.
The male mice were then fed a standard diet until adulthood when their fat distribution and metabolism were examined.
“We could see that these male mice had more fat tissue, larger fat cells, and a disordered basal metabolism, despite eating a healthy diet”, says Elisabet Stener-Victorin.
To investigate the reproductive function of the offspring and whether physiological characteristics can be passed on from generation to generation, the first-generation male mice were mated with healthy female mice that were not exposed to male sex hormones or a diet rich in fat and sugar. The whole process was repeated in the second generation to reach the third generation which is the first generation that was not affected by the mother condition.
“Through these experiments, we can show that obesity and high levels of male hormones in the woman during pregnancy can cause long-term health problems in the male offspring. Their fat tissue function, metabolism, and reproductive function deteriorate, which in turn affects future generations”, says Qiaolin Deng, associate professor at the same department and one of the researchers behind the study.
“These findings are important because they highlight the risk of passing health problems down through the male side of a family, highlight the risk of passing this kind of health problem, and they may help us in the future to find ways to identify, treat and prevent reproductive and metabolic diseases at an early stage,” says Elisabet Stener-Victorin.
A University of Gothenburg study shows that after a stroke, physical activity can be pivotal to successful recovery. People who spend four hours a week exercising after their stroke achieve better functional recovery within six months than those who do not.
The study, published in JAMA Network Open, analysed data from 1500 stroke patients who were grouped according to their post-stroke patterns of physical activity.
The results show that increased or maintained physical activity, with four hours’ exercise weekly, doubled the patients’ chances of recovering well by six months after a stroke. Men and people with normal cognition kept up an active life relatively more often, with better recovery as a result.
Positive programming from exercise
The researchers have previously succeeded in demonstrating a clear inverse association between physical activity and the severity of stroke symptoms at the actual onset of the condition. These new findings highlight the importance of maintaining a healthy, active lifestyle after a stroke.
The first and corresponding author of the study, Dongni Buvarp, is a researcher in clinical neuroscience at Sahlgrenska Academy, University of Gothenburg. Besides her research internship, she is a resident doctor at an initial stage of specialist training at Sahlgrenska University Hospital.
“Physical activity reprograms both the brain and the body favourably after a stroke. Exercise improves the body’s recovery at the cellular level, boosts muscle strength and well-being, and reduces the risk of falls, depression, and cardiovascular disease. Regardless of how severe the stroke has been, those affected can derive benefits from exercising more,” she says.
Knowledge and support vital
“Being physically active is hugely important, especially after a stroke. That’s a message that health professionals, stroke victims and their loved ones should all know. Women and people with impaired cognition seem to become less active after stroke. The study results indicate that these groups need more support to get going with physical activity,” Buvarp says.
One weakness of the study is that, with a few exceptions, the researchers were unable to study the participants’ degree of activity before the stroke. The patients included were treated in Sweden in the period from 2014 to 2019.
An innovative three-step ablation approach including ethanol infusion of the vein of Marshall improves freedom from arrhythmias in patients with persistent atrial fibrillation compared to pulmonary vein isolation (PVI) alone, according to late breaking science presented at EHRA 2023, a scientific congress of the European Society of Cardiology (ESC). Preliminary results at 10 months are presented, with follow up ongoing until 12 months. The results are discussed in an accompanying editorial.
The cornerstone of catheter ablation of atrial fibrillation is complete isolation of the pulmonary veins. However, only 50–60% of patients remain in sinus rhythm at two years. Numerous trials of different ablation strategies have failed to demonstrate superiority over PVI.
The Marshall-Plan ablation strategy consists of 1) PVI; 2) ethanol infusion of the vein of Marshall; and 3) a linear ablation set to block the three main anatomical isthmuses to the pulmonary veins (dome, mitral and cavotricuspid isthmus lines). The technique focuses on anatomical targets that have been individually recognised as important for the initiation or maintenance of atrial fibrillation but have not been collectively targeted in a systematic manner. The current investigators previously reported encouraging results using this strategy in non-randomised studies.
The present study compared 12-month arrhythmia-free survival with the Marshall-Plan ablation strategy versus PVI only. This was a prospective, randomised, parallel group trial of superiority. The trial included 120 patients with symptomatic persistent atrial fibrillation for more than one month. The average age of participants was 67 years and 21 (18%) were women.
Participants were randomised to receive the Marshall-Plan or PVI alone. Follow up occurred at 3, 6, 9 and 12 months during which patients underwent a number of tests including an electrocardiogram (ECG), echocardiography, stress test and 24-hour Holter monitoring. Recurrence of arrhythmias was identified using ECG teletransmission, with findings sent to the hospital once a week plus any time the patient had symptoms. The primary endpoint was recurrence of atrial fibrillation or atrial tachycardia lasting more than 30 seconds at 12 months (including a 3-month blanking period) after a single ablation procedure.
The total radiofrequency time was significantly longer in the PVI group (29 minutes) compared with the Marshall-Plan group (23 minutes; p<0.001). The full lesion set was successfully completed in 53 patients (88%) receiving the Marshall-Plan strategy and 59 patients (98%) receiving PVI only. In an intention-to-treat analysis, the recurrence of arrhythmias after an average follow up of 10 months was significantly higher in the PVI group compared with the Marshall-Plan group (18 vs. 8 patients; p=0.026). Follow up will continue until 12 months.
Principal investigator Dr Nicolas Derval said: “After 10 months of follow up, the success rate in the Marshall-Plan group was significantly better (87%) compared to the PVI only group (70%). However, the results are still preliminary as follow up is not completed for all patients. While the findings indicate that the Marshall-Plan strategy holds promise for patients with persistent atrial fibrillation, they need to be confirmed in a multicentre trial.”
Electrical problems in the heart such as left ventricular conduction disease can often lead to serious and fatal complications. Treatment to lessen its effects involves implanting a permanent pacemaker, but there are no proven preventive strategies at present.
In a study published in JAMA Cardiology, researchers took advantage of a prospective trial in which individuals with hypertension were randomly assigned to standard and aggressive blood pressure (BP) control. They found that intensive BP control is associated with lower risk of left ventricular conduction disease, indicating left ventricular conduction disease may be preventable.
“This research was motivated by patients who came in with complete heart block where I put in a pacemaker and they asked, ‘Why did this happen to me?’” said senior author Gregory Marcus, cardiologist and UCSF professor of medicine. “The answer to this question has not been clear, so we wanted to look at the impact that blood pressure might have on the development of their conduction disease.”
The authors performed a statistical analysis of the previously completed Systolic Blood Pressure Intervention Trial (SPRINT) to determine the association between targeting intensive BP control and the risk of developing left ventricular conduction disease. Participants included in the five year long SPRINT trial were adults 50 years and older with hypertension and at least one other cardiovascular risk factor. Participants with early signs of left ventricular conduction disease, ventricular pacing or ventricular pre-excitation were excluded from the analysis.
Participants were randomly assigned to either normal blood pressure control (targeting a systolic blood pressure less than 140) or a more aggressive BP control (targeting a BP less than 120). As part of the analysis, the authors reviewed the serial ECGs that the participants received over the course of the trial and found that those randomly assigned to the more aggressive BP control experienced significantly less conduction disease on the left side of the heart.
“This analysis suggests that more aggressive BP control might be a way to prevent this sort of common disease,” said Marcus. “More broadly, the use of randomised controlled trial data provided compelling evidence that this common disease is not an immutable fate, but that the risk can be modified.”
By contrast, the researchers saw no differences in right-sided conduction disease (manifested by right bundle branch blocks). The authors considered right bundle branch blocks as a “negative control” since the right side of the heart is not directly affected by BP control and as such bundle branch blocks are not generally associated with the same severe outcomes as left bundle branch blocks.
The authors note that SPRINT did not examine the role of anti-hypertensive drugs, suggesting further research into associations between specific medications and conduction disease rates may be warranted.
Scientists have developed two new drug candidates for potentially treating addiction and depression, modelled on the pharmacology of a traditional African psychedelic plant medicine called ibogaine. At very low doses, these new compounds were able to blunt symptoms of both conditions in mice.
The study, published in Cell, took inspiration from ibogaine’s impact on the serotonin transporter (SERT), which is also the target of selective serotonin reuptake inhibitor (SSRI) drugs, such as fluoxetine. A team of scientists from UC San Francisco and Yale and Duke universities virtually screened 200 million molecular structures to find ones that blocked SERT in the same way as ibogaine.
“Some people swear by ibogaine for treating addiction, but it isn’t a very good drug. It has bad side effects, and it’s not approved for use in the US,” said Brian Shoichet, PhD, co-senior author and professor in the UCSF School of Pharmacy. “Our compounds mimic just one of ibogaine’s many pharmacological effects, and still replicate its most desirable effects on behaviour, at least in mice.”
Dozens of scientists from the laboratories of Shoichet, Allan Basbaum, PhD, and Aashish Manglik, MD, PhD, (UCSF); Gary Rudnick, PhD, (Yale); and Bill Wetsel, PhD, (Duke) helped demonstrate the real-world promise of these novel molecules, which were initially identified using Shoichet’s computational docking methods.
Docking involves systematically testing virtual chemical structures for binding with a protein, enabling scientists to identify new drug leads without having to synthesise them in the lab. “This kind of project begins with visualizing what kinds of molecules will fit into a protein, docking the library, optimising and then relying on a team to show the molecules work,” said Isha Singh, PhD, a co-first author of the paper who did the work as a postdoc in Shoichet’s lab. “Now we know there’s a lot of untapped therapeutic potential in targeting SERT.”
Optimising a shaman’s cure
Ibogaine is found in the roots of the iboga plant, which is native to central Africa, and has been used for millennia during shamanistic rituals. In the 19th and 20th centuries, doctors in Europe and the US experimented with its use in treating a variety of ailments, but the drug never gained widespread acceptance and was ultimately made illegal in many countries.
Part of the problem, Shoichet explained, is that ibogaine interferes with many aspects of human biology.
“Ibogaine binds to hERG, which can cause heart arrhythmias, and from a scientific standpoint, it’s a ‘dirty’ drug, binding to lots of targets beyond SERT,” Shoichet said. “Before this experiment, we didn’t even know if the benefits of ibogaine came from its binding to SERT.”
Shoichet, who has used docking on brain receptors to identify drugs to treat depression and pain, became interested in SERT and ibogaine after Rudnick, an expert on SERT at Yale, spent a sabbatical in his lab. Singh picked up the project in 2018, hoping to turn the buzz around ibogaine into a better understanding of SERT.
It was the Shoichet lab’s first docking experiment on a transporter – a protein that moves molecules into and out of cells – rather than a receptor. One round of docking whittled the virtual library from 200 million to just 49 molecules, 36 of which could be synthesised. Rudnick’s lab tested them and found that 13 inhibited SERT.
The team then held virtual-reality-guided “docking parties,” to help Singh prioritise five molecules for optimization. The two most potent SERT inhibitors were shared with Basbaum and Wetsel’s teams for rigorous testing on animal models of addiction, depression and anxiety.
“All of a sudden, they popped – that’s when these drugs looked a lot more potent than even paroxetine [Paxil],” Shoichet said.
Manglik, an expert with cryo-electron microscopy (cryo-EM), confirmed that one of the two drugs, dubbed ‘8090,’ fit into SERT at the atomic level in a way that closely resembled Singh and Shoichet’s computational predictions. The drugs inhibited SERT in a similar way to ibogaine, but unlike the psychedelic, their effect was potent and selective, with no spillover impacts on a panel of hundreds of other receptors and transporters.
“With this sort of potency, we hope to have a better therapeutic window without side effects,” Basbaum said. “Dropping the dose almost 200-fold could make a big difference for patients.”
Most antidepressants used for chronic pain are being prescribed with “insufficient” evidence of their effectiveness, scientists have warned. A major investigation into medications used to manage long-term pain found that harms of many of the commonly recommended drugs have not been well studied.
