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 covered a wide variety of psychiatric issues and industry updates, from the unique challenges of treating physician-patients to updates on MDMA and psilocybin research and access. Here are some highlights from the week.

Concurrent Treatment With SRIs and Anticoagulants: Minimizing the Hemorrhagic Hazard

Serotonergic antidepressants (SRIs) are among the most commonly prescribed medications and play important roles in treating depression, anxiety, agitation, and other behavioral syndromes. Data from 2015 to 2018 published by the National Center for Health Statistics show that during those years, 13.2% of adults aged 18 years and over reported using an antidepressant medication within the preceding 30 days. Women aged 60 years and older reported a rate of 24.3%.

The SRIs include selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). Although the SRIs’ adverse effect profiles are milder than those of the earlier tricyclic antidepressants and monoamine oxidase inhibitors, SRI treatment is nonetheless associated with several potentially problematic adverse reactions including effects on sexual function, sleep, appetite, and sodium regulation. Another important adverse effect of SRIs is their association with increased bleeding. Their serotonin reuptake blocking effect not only improves depression through its activity in the brain, but also interferes with normal hemostasis by diminishing platelets’ accumulation of serotonin, which cannot be synthesized by a platelet. 

Senators Introduce New Bill to Promote Research and Access to MDMA, Psilocybin

Senators Cory Booker (D-NJ) and Rand Paul (R-KY) introduced a new bill, the Breakthrough Therapies Act, that would allow the Drug Enforcement Administration to make findings to reclassify MDMA and psilocybin as schedule II drugs. MDMA and psilocybin are currently schedule I substances and have “no currently accepted medical use and a high potential for abuse,” according to the Controlled Substances Act.

“Recent studies suggest that some schedule I substances such as MDMA and psilocybin could represent an enormous advancement for the treatment of severe post-traumatic stress disorder, depression and addiction,” Booker said. “Unfortunately, regulatory red tape and a series of bureaucratic hurdles involved in studying schedule I substances impedes critical research on these and other promising schedule I compounds.” 

“Oh No, My Patient is a Physician!” Hurdles When Treating Physician-Patients

Control is a powerful tool and can affect every aspect of daily life. Within the medical field the term control has its own implications, especially when treating patients. There is an unspoken bond that control is relinquished by the patient and given to the physician in hopes of recovering from the illness. What happens when the physician is the one in need of treatment? What happens when the physician perceives themself as ill and weak?

Physician-patients can be very reluctant to give control of their medical health to another person. The general public is taught from a young age that “the illness belongs to the patient” and that physicians are supposed to be invulnerable. When they are sick, they can be in a world of denial and feel forced to bear the torment of their illness alone. Therefore, physicians may delay seeking medical help; when they do, they may also project their own feelings onto the treating physician, or transference. On the other hand, it is very easy for the treating physicians to project their own feelings onto the physician-patient, or countertransference. 

The Benefits and Limitations of Resilience

After the tragic mass shooting in a LGBTQ+ club in Colorado Springs over the weekend, Nietzsche’s well-known statement takes on tragic proportions. Five were killed, and many more wounded. There will be inevitable traumatic ripples into the wider LGBTQ+ communities, and those who love them.

The goal of trauma recovery will include resilience. Resilience is the ability to bounce back stronger after trauma with the supportive help of community and a vision for the future. That vision, which we have discussed in the last 2 columns, must include less violence and hate toward LGBTQ+ individuals. Generally, resilience is thought to be a positive characteristic, even a panacea for getting through trauma stronger. Yet, like most good things in life, too much resilience may be problematic at times. Why? How could increased psychological strength be a problem? 

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Do you have a comment on any of these or other articles? Have a good idea for an article and want to write? Interested in sharing your perspectives? Write to us at 

From the unique challenges of treating physician-patients to updates on MDMA and psilocybin research and access, here are highlights from the week in Psychiatric Times.

The Week in Review: November 21-25

“Mr Hardy,” a 67-year-old man, sought psychiatric evaluation for increased forgetfulness and word-finding trouble. Prior to this evaluation, he had been prescribed escitalopram 10 mg/d for mild anxiety and low mood. Although his MMSE score at initial assessment was in the normal range at 28 out of 30 points, his growing need for reminders and other compensatory supports suggested the presence of mild neurocognitive disorder in this highly educated individual. His medical health was considered good except for mild, untreated obstructive sleep apnea. His laboratory evaluation included normal range results on CBC, CMP, thyroid functions, B12, folate, ESR, and RPR. His MRI showed a chronic right frontal lacunar infarction and white matter changes consistent with small vessel disease.

Although his functional status suggested only mild cognitive compromise, more extensive neuropsychological testing identified significant impairment of contextual and noncontextual memory. Mr Hardy was started on donepezil 5 mg/d with a provisional diagnosis of early 

. He experienced this medication as helpful, prompting a dose increase to 10 mg/d after several months. He felt that his medications reduced his anxiety and improved his 

, though his occasional bouts of diarrhea may have been an adverse medication effect.

Several months after beginning donepezil, his cardiologist diagnosed atrial fibrillation and prescribed apixaban 5 mg/d. Mr Hardy did not discontinue his previously prescribed ASA 81 mg/d. Five months after adding apixaban to his regimen, Mr Hardy complained of new dizziness, 

, and worsening confusion. He reported no head trauma, although his wife recalled that he had fallen from his bicycle the previous week and could have hit his head. On interview, he seemed to have trouble with verbal communication. CT scan showed a large acute right subdural hematoma with mass effect and midline shift. Apixaban was held and vitamin K–dependent coagulation factors plus antithrombotic proteins C and S were administered in the emergency room. After consultation from neurosurgery, craniotomy was performed with evacuation of the subdural hematoma. Postoperatively, apixaban was held. Donepezil and escitalopram were continued.

Four months postoperatively, Mr Hardy demonstrated more significant cognitive impairment. His MoCA-BLIND score was 15 out of 22 points. He was attending speech therapy for help with focus and communication. His cognition improved gradually, and after 4 additional months his MoCA-BLIND score had increased to 18 out of 22. One year after neurosurgery, his MoCA-BLIND score had risen to 20 out of 22, although he still reported impaired memory, complex attention, and executive function. He was at that time taking aspirin 81 mg/d, donepezil 10 mg/d, and escitalopram 10 mg/d. In retrospect, his clinicians appreciated how confluent multiple factors contributed to his hemorrhagic event and wondered which medications or factors were most relevant. They wondered, too, how bleeding risk might be minimized when serotonergic antidepressants and blood thinning agents are coprescribed.

Serotonergic Antidepressants and Bleeding Risk

Serotonergic antidepressants (SRIs) are among the most commonly prescribed medications and play important roles in treating 

, anxiety, agitation, and other behavioral syndromes. Data from 2015 to 2018 published by the National Center for Health Statistics show that during those years, 13.2% of adults aged 18 years and over reported using an antidepressant medication within the preceding 30 days. Women aged 60 years and older reported a rate of 24.3%.

The SRIs include selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). Although the SRIs’ adverse effect profiles are milder than those of the earlier tricyclic antidepressants and monoamine oxidase inhibitors, SRI treatment is nonetheless associated with several potentially problematic adverse reactions including effects on sexual function, 

, appetite, and sodium regulation. Another important adverse effect of SRIs is their association with increased bleeding. Their serotonin reuptake blocking effect not only improves depression through its activity in the brain, but also interferes with normal hemostasis by diminishing platelets’ accumulation of serotonin, which cannot be synthesized by a platelet. Serotonin is released by platelets to promote vasoconstriction when a bleed is detected, hence decreased serotonin uptake decreases platelets’ capacity to decrease bleeding. The resulting anticoagulant effect is warned against in SRIs’ prescribing information (see, for example, the prescribing information for sertraline).

Prescribed alone, SRIs have been reported to increase a variety of hemorrhagic events including gastrointestinal and intracranial bleeding. In anested case-control study looking at the risk of abnormal bleeding in a cohort of more than 64,000 new 

 users, SRI use was associated with an increased risk of hospitalization due to abnormal bleeding. Higher risk was linked with use of the SRIs with intermediate and high degrees of serotonin reuptake inhibition.

 In another large study, spontaneous intracranial hemorrhage (ICH) was linked with SSRIs possessing greater affinity for the serotonin transporter.

Many reports address bleeding associated with the SSRIs. Bleeding associated with SNRIs has been less fully investigated, although their prescribing information contains a similar warning regarding their coprescription with anticoagulants. An important consideration with the SNRIs may be the serotonin-to-norepinephrine (NE) reuptake inhibition ratio. The medications with greater relative norepinephrine reuptake blocking activity produce less marked serotoninergic effects.

 Further research may shed light on whether SNRIs with greater NE reuptake activity and less dominant effect on serotonin reuptake might have less impact on bleeding risk than the selective SSRIs or the SNRIs with lower NE to 5HT reuptake blocking ratios.

Anticoagulants and Adverse Effects Related to Bleeding

Anticoagulant medications, prescribed for prevention of pathological thrombosis in a variety of medical conditions, are another category of frequently prescribed medications associated with potentially harmful bleeding. About 4.2 million Americans aged 18 years or older take anticoagulants, and the rate is higher among older adults.

 Recent advances in anticoagulant pharmacology have provided clinicians with new treatment options. Many prescribers, however, have limited knowledge of the mechanisms of action, risks, and benefits of this varied class of drugs.

Warfarin and other coumarins work by inhibiting vitamin K’s role in the biosynthesis of prothrombin and are collectively known as vitamin K antagonists (VKAs).

 Treatment with most VKAs is typically safe and effective as long as the international normalized ratio (INR), monitored through periodic blood testing, is maintained within a safe therapeutic range. Achieving a safe and stable range, however, can be challenging, especially in the elderly where 

 is common and can result in drug-drug interactions. In addition, the effect of VKAs can be affected by certain foods.

In contrast to VKAs, low-molecular-weight heparins (LMWHs) such as dalteparin and enoxaparin act by inhibiting the final common pathway of the coagulation cascade, thereby impeding the conversion of fibrinogen into fibrin. Patients self-administer these medications by subcutaneous injection. Dosage is adjusted in individuals with chronic kidney disease, which is associated with a risk of accumulation and increased risk for problematic bleeding.

The third and most recently introduced group of anticoagulants, collectively referred to as direct oral anticoagulants (DOACs), works by yet another mechanism: the direct inhibition of specific proteins within the coagulation cascade. Dabigatran works by reversibly binding to the active site on the thrombin molecule, thereby preventing thrombin-mediated activation of coagulation factors, while several others (rivaroxaban, apixaban, edoxaban, and betrixaban) inhibit factor Xa. DOACs have been shown to be as effective as VKAs with a safer adverse effect profile.

 Advantages of DOACs include their more immediate drug onset and offset effects, fewer drug and food interactions, and fewer monitoring requirements.

Antiplatelet medications such as aspirin and clopidogrel, although not formally classified as anticoagulants, are widely used for the prevention of vascular events and are associated with an increased bleeding risk. Antiplatelet medications inhibit platelet cyclooxygenase, thereby blocking the formation of thromboxane A2. This impairs thromboxane-dependent platelet aggregation and consequently prolongs bleeding time. Many guidelines now caution against their use among those who are at increased risk of bleeding because the risks associated with use of these medications can overshadow their benefits.

Enhanced Bleeding Risk With Coprescribed Anticoagulant and SRI

For a variety of reasons, patients prescribed an SRI may receive concurrent medically appropriate treatment with an anticoagulant. In many cases, these medications are prescribed independently by clinicians who are not in communication with each other. Each of these medication classes increases bleeding risk, and their concurrent use can amplify this risk. SRI package inserts warn clinicians of this enhanced risk when SRIs are coprescribed with aspirin, nonsteroidal anti-inflammatory drugs, warfarin, or other anticoagulants.

 Prescribing clinicians may be unaware of the potential risk associated with this medication combination or even unaware that the combination has been coprescribed. Upper gastrointestinal tract bleeding and intracranial hemorrhage can have serious consequences.

 We will selectively summarize evidence for these adverse drug interactions and suggest an approach to optimizing safety when both an SRI and an anticoagulant are medically necessary. When an SRI and anticoagulant are coprescribed, bleeding risk most likely is affected both by the anticoagulant’s mechanism of action and the pharmacokinetic/pharmacodynamic profile of the SRI.

For VKAs, data regarding the risk of coprescription with SRIs are not all consistent. In 1 large cohort of patients treated with warfarin for atrial fibrillation and followed for a median duration of 6 years, for example, the increase in GI and IC bleeding risk conferred by concurrent use of SRIs was explored.

 The SRIs prescribed in this study were paroxetine (51.6% of SRI users), fluoxetine (49.4%), sertraline (13.9%), venlafaxine (4.6%), citalopram (3.8%), and fluvoxamine (0.5%). After adjusting for underlying bleeding risk and time at international normalized ratio range (INR) >3, SRI exposure was associated with an increased rate of hemorrhage compared with warfarin exposure alone (adjusted relative risk 1.41, 95% confidence interval 1.04 to 1.92, p = 0.03). Although not highlighted in this study, the strong CYP450 1A2 inhibiting effect of fluvoxamine, which could impair warfarin’s deactivating metabolism, suggests that the fluvoxamine/warfarin combination should be regarded as one to avoid when possible. Another study, interestingly, followed a cohort of patients on coumarins for the first time and reported that the risk for non-gastrointestinal tract bleeding, including ICH, was increased among concurrent SSRI users (adjusted OR, 1.7; 95% CI, 1.1-2.5). In this study, however, concurrent use of coumarins with SSRIs did not increase the risk for gastrointestinal tract bleeding (adjusted OR, 0.8; 95% CI, 0.4-1.5).

With regard to DOACs, 1 review of studies published between 2014 and 2016 concluded that DOACs were safer in combination with SRIs than warfarin as a result of the DOACs’ more limited pharmacodynamic interactions.

 This result is consistent with outcome data from the ROCKET AF study, which compared the safety and efficacy of combining SSRI treatment with either the factor Xa inhibitor rivaroxaban or warfarin in 737 patients followed for a mean period of 1.6 years. The authors concluded that the apparently small increase in bleeding risk added by an SSRI to rivaroxaban or warfarin treatment was not statistically significant. There was,however, a nonsignificant trend suggesting slightly greater risk for severe bleeding (intracranial and fatal bleeding) with warfarin than with rivaroxaban.

With regard to low molecular weight heparins (LMWH), findings have not supported a synergistic increased risk of bleeding. The authors of a retrospective cohort study of 575 patients with a primary or secondary diagnosis of an acute venous thromboembolism started on full-dose enoxaparin with or without an SSRI examined 5 years of follow-up data. Concurrent use of an SSRI was not associated with an increased bleeding risk in patients on this LMWH. The concurrent use of 

, however, did significantly increase the rate of major bleeding events.

 Alcohol use by itself, incidentally, increases bleeding risk directly by suppressing the bone marrow and therefore hematopoietic stem cells, and indirectly by promoting nutritional deficiencies that impair the production and function of various hematopoietic cells, most importantly platelets, which are essential in the formation of clots.

Nonsteroidal anti-inflammatory drugs (NSAIDs), or aspirin—which produce reversible inhibition of platelet cyclooxygenase with effects on bleeding that vary depending on the NSAID’s dose, serum level, and half-life—are often used by individuals taking an SRI. The clinical risk of bleeding with NSAID use is enhanced by concomitant use of an SRI, or by concurrent use of alcohol or other anticoagulants, as well as by associated medical factors such as advanced age, liver disease, and other coexisting coagulopathies.

 Clopidogrel may be coprescribed with an SRI, but there is limited information about the effect of this combination on bleeding risk. One retrospective cohort study reported an increased risk of bleeding when this combination of drugs was prescribed to patients at high risk for stroke (HR 2.35, 95% CI 1.61–3.42).

Although the SRIs share overlapping pharmacodynamic effects, they differ in their pharmacokinetic interactions with the cytochrome P450 system. The differences between specific SRIs can affect drug-drug interactions with anticoagulants. Warfarin is a racemic mixture of S-warfarin and R- warfarin, for example, and although both isomers are clinically active, the S-isomer is more potent than the R-isomer.

 The S-isomer is metabolized by the 2C9 isoenzyme, whereas the R-isomer is metabolized by the 1A2 isoenzyme as well as the 2C19 and 3A4 isoenzymes. Among SSRIs, fluvoxamine (which also inhibits 1A2) and fluoxetine appear to have the highest potential for inhibiting warfarin metabolism through the 2C9 isoenzyme, thereby decreasing its clearance and enhancing anticoagulation. Paroxetine coadministered with warfarin has been shown to mildly increase bleeding risk. The DOACs are predominantly metabolized in the liver, mainly by cytochrome P450 enzymes 3A4 and 2J2, and other CYP-independent pathways.

 A retrospective study looking at drug-drug-interactions between DOAC and SRIs showed that 80% of individuals in the study who had suspected interactions were taking SRIs that are known CYP3A4 substrates along with the DOAC.

 The SRIs with strongest CYP3A4 inhibition are fluvoxamine and, perhaps to a lesser extent, fluoxetine. Awareness of the possibly greater bleeding risk when these antidepressants are combined with a DOAC should be factored into the clinician’s prescribing decisions.

Many older adults stand to benefit from treatment with an anticoagulant or antiplatelet medication, yet some of these individuals are already taking an SRI or might come to need one. Similarly, many individuals who are receiving acute or long-term SRI treatment might develop the need for short-term or chronic treatment with an anticoagulant or antiplatelet medication. As it currently stands, the warnings about coprescribing members of these medication classes might deter a clinician from treating 1 of 2 comorbid serious conditions. Rather than avoiding use of any SRI in all patients on anticoagulants or antiplatelet medications, a more nuanced and patient-centered approach can be adopted. We propose the following recommendations for addressing this clinical dilemma.

Although several studies have found an association between SRI use and increased bleeding risk, from our review, we show that not all SRI/anticoagulant combinations substantially increase clinical risk; furthermore, risk appears to differ on the basis both of anticoagulant mechanism of action and pharmacokinetic/pharmacodynamic SRI profiles. We recommend that physicians take a complete inventory of each patient’s medications, including nonprescription drugs such as NSAIDs. Meticulous medication reconciliation and communication among prescribing treaters is encouraged so that all prescribers are aware of all medications coadministered. Ongoing assessment of need for coprescribing and elimination of unnecessary medications, especially considering the risk of 

 in older adults, is paramount. A clinician may opt for the safer combinations (

) or in some cases choose a non-SRI antidepressant. The risk must be evaluated with special care for patients with a history of bleeding, cerebral amyloid angiopathy, or greater alcohol consumption. Other factors to be considered are comorbid clotting disorders, such as von Willebrand disease, or genetic polymorphism in the serotonin transporter gene, which is known to be associated with platelet dysfunction.

 With regard to GI bleeding, if an SRI is required in an individual who is already at high risk of an upper GI bleed, the use of a gastro-protective agents should be considered.

Additionally, physicians should do a thorough risk-benefit analysis and involve the patient in shared decision-making. Patients who take multiple drugs should be educated against the regular use of nonprescription drugs which increase bleeding risk such as aspirin or ibuprofen, as well as on how to recognize symptoms of GI bleeding.

With attention to the considerations and choices outlined here, the risk of bleeding can be diminished for patients who need to use an SRI and an anticoagulant concurrently. This combination can be safely managed in order to diminish the “hemorrhagic hazard” of combined treatment while allowing management of comorbid medical needs. There is a need for further studies to supplement and refine current knowledge, as well as to provide more comprehensive and specific clinical guidance.

is an attending psychiatrist at Zucker Hillside Hospital. 

is a geriatric psychiatrist and director of the Swank Center for Memory Care and Geriatric Consultation, ChristianaCare.

Antidepressant use in persons aged 12 and over: United States, 2005-2008.

2. Highlights of prescribing information: Zoloft. FDA. Accessed November 8, 2022. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019839S74S86S87_20990S35S44S45lbl.pdf

3. Meijer WEE, Heerdink ER, Nolen WA, et al. 

Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants.

4. Renoux C, Vahey S, Dell'Aniello S, Boivin JF. 

Association of selective serotonin reuptake inhibitors with the risk for spontaneous intracranial hemorrhage.

5. Raouf M, Glogowski AJ, Bettinger JJ, Fudin J. 

Serotonin-norepinephrine reuptake inhibitors and the influence of binding affinity (Ki) on analgesia.

6. Hylek EM, Evans-Molina C, Shea C, et al. 

Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation.

7. Kasperkiewicz K, Ponczek MB, Owczarek J, et al. 

Antagonists of vitamin K-popular coumarin drugs and new synthetic and natural coumarin derivatives.

The innovative medicines initiative: a European response to the innovation challenge.

9. Solari F, Varacallo M. Low molecular weight heparin (LMWH). StatPearls. September 4, 2022. Accessed November 8, 2022. 

https://www.ncbi.nlm.nih.gov/books/NBK525957/

Safety and efficacy of direct acting oral anticoagulants and vitamin K antagonists in nonvalvular atrial fibrillation - a network meta-analysis of real-world data.

Direct oral anticoagulant use: a practical guide to common clinical challenges.

Aspirin and gastrointestinal bleeding risk in older people.

Potential vascular and bleeding complications of treatment with selective serotonin reuptake inhibitors.

14. Li N, Wallen NH, Ladjevardi M, Hjemdahl P. 

Effects of serotonin on platelet activation in whole blood.

16. Anglin R, Yuan Y, Moayyedi P, et al. 

Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis.

Selective serotonin reuptake inhibitors and brain hemorrhage: a meta-analysis.

18. Quinn GR, Singer DE, Chang Y, et al. 

Effect of selective serotonin reuptake inhibitors on bleeding risk in patients with atrial fibrillation taking warfarin.

19. Schalekamp T, Klungel OH, Souverein PC, de Boer A. 

Increased bleeding risk with concurrent use of selective serotonin reuptake inhibitors and coumarins.

20. Boguta P, Juchnowicz D, Wróbel-Knybel P, et al. 

Safety of concomitant treatment with non-vitamin K oral anticoagulants and SSRI/SNRI antidepressants.

21. Quinn GR, Hellkamp AS, Hankey GJ, et al. 

Selective serotonin reuptake inhibitors and bleeding risk in anticoagulated patients with atrial fibrillation: an analysis from the ROCKET AF Trial.

Risk of bleeding in patients on full-dose enoxaparin with venous thromboembolism and selective serotonin reuptake inhibitors.

23. Gunasekaran K, Rajasurya V, Devasahayam J, et al. 

A review of the incidence diagnosis and treatment of spontaneous hemorrhage in patients treated with direct oral anticoagulants.

24. Labos C, Dasgupta K, Nedjar H, et al. 

Risk of bleeding associated with combined use of selective serotonin reuptake inhibitors and antiplatelet therapy following acute myocardial infarction.

Warfarin and antidepressants: happiness without hemorrhaging.

26. Weinz C, Schwarz T, Kubitza D, et al. 

Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans.

Potential drug-drug interactions with direct oral anticoagulants in elderly hospitalized patients.

28. Abdelmalik N, Ruhe HG, Barwari K, et al. 

Effect of the selective serotonin reuptake inhibitor paroxetine on platelet function is modified by a SLC6A4 serotonin transporter polymorphism.

An important adverse effect of SRIs: their association with increased bleeding. 

The scale and impact of mental illness across society is immense. In 2019, 1 in every 8 individuals, or 970 million individuals worldwide, were living with a mental illness—with anxiety and depressive disorders the most common.

 In 2020, the number of individuals living with anxiety and depressive disorders rose significantly because of the COVID-19 pandemic. Initial estimates show a 26% and 28% increase, respectively, for anxiety and major depressive disorder in just 1 year.

Although we have treatments for some mental health conditions, they do not work for everyone, and adverse effects can be difficult to tolerate. Yet, despite the pressing unmet need, drug discovery in this field has stayed relatively stagnant compared to other therapeutic areas, with no new types of medicines coming forward in the past 30 years.

Psychiatric drug discovery must be a truly collaborative process to drive advances. To enable a more unified approach, we need a better handover between scientific disciplines and a systematic and structured pathway to take academic advances in our understanding of psychiatric disease biology through the drug discovery process.

, launched in 2019, is a strategic collaboration of 2 leading medical research charities and 8 pharmaceutical companies (

) focusing on the challenge of identifying and validating novel drug targets to address the unmet therapeutic needs of individuals living with mental health conditions. 

The Psychiatry Consortium Partners act as a syndicate, collectively sharing the funding of—and therefore the risk associated with—drug discovery. 

We strive to bring all aspects of the global research community together to tackle and address key challenges within drug discovery. We provide opportunities for funding, collaboration, and industry know-how in this area of unmet patient need. This model of working is designed with the patient, manufacturer, and supplier all in mind, and it is unique in its holistic approach and global reach.

Psychiatry Consortium projects aim to build a deep understanding of a disease or condition and its causative molecular mechanisms to identify and validate novel therapeutic targets. One of the early successes of the Consortium is a multi-million-dollar partnership between leading international research institutions and pharmaceutical companies that joined together to investigate a new drug target for the treatment of schizophrenia. This was the first project funded by the international 

The world-leading team of academic researchers are using their newly designed technical approach to assess which proteins are selectively produced by the kalirin gene in the human brain, and how this differs from other human tissues. Once this is understood, it may be possible to identify the proteins that represent the most promising drug targets for the potential treatment of schizophrenia and how they affect the function of cells, and to begin to develop drugs to alter their function.

In February 2022, we launched our second project: an international collaboration to tackle depression. The project will see academic and industry partners combine efforts and expertise to assess the role of 1 of the most significant risk genes for depression (Neuronal Growth Regulator 1, or NEGR1) in the development of the disorder. Researchers will apply a combination of human genomics, cellular physiology, and neurobehavioral genetics investigations aimed at characterizing gene expression in the human brain and the effects of modulation of gene expression at both the cellular and behavioral levels.

The results will help define a pharmacological approach to interfere with the target activity, paving the way for drug development efforts in the search for new therapies for major depression.

Our third project is a unique collaboration between our industry partners and a UK-based small-to-medium enterprise (SME) investigating GALR3 as a novel target for postpartum depression.

It is projects such as these that showcase the ambitions of the Psychiatry Consortium. Discovering novel ways of treating conditions such as schizophrenia, depression and postpartum depression can have a transformative effect on millions of lives across the globe. Through true, international collaboration, we believe we have the infrastructure and expertise to be successful.

The Psychiatry Consortium is accepting applications for project proposals until 

. We are looking to fund projects that focus on the validation of novel molecular drug targets for mental health conditions, including mood disorders, psychosis, cognitive disorders, and psychiatric symptoms of dementia. The funding is open to universities, research institutes, and small companies (micro and medium, SME) worldwide.

At the initial application stage, we ask for a high-level summary of the proposed target and the biological link between the target and disease. Proposals demonstrating evidence of the link between a novel target and neural circuit, pathway, or disease mechanism, and with converging lines of evidence supporting that link, stand the best chance of success. Successful applicants will be invited to meet our industry partners to cocreate a project that builds on the available evidence and further validates the proposed target.

In addition to providing funding to support and translate research, we also offer learning exchanges and bring together charities, patients, clinicians, large pharma, and academics to understand and discuss ways to overcome barriers to effective psychiatric drug discovery.

Collaboration and engagement with the psychiatry research community is vital. To date, the Psychiatry Consortium has presented at 15 international conferences and delivered 10 webinars, 4 interactive workshops for global opinion leaders, and a virtual symposium with more than 1000 registrants. Our most recently published 

"Guiding Principles for Robust Target Validation in Psychiatry"

 document highlights key considerations deemed important by the drug discovery community when building a target validation package for novel therapeutic targets. 

We hope the guidance will support applicants in building projects that address gaps in our knowledge and strengthen the body of evidence to support a target's role in a particular disease or condition and its potential as a therapeutic target.

The Psychiatry Consortium can only be successful if we engage with experts in the field. If you would like to work with us on a project or collaborate on a workshop or event, we would love to hear from you. You can find more information about what we are looking for and access other helpful resources at 

. If you would like to find out more or work with us, contact us at 

is partnership manager for the Psychiatry Consortium at Medicines Discovery Catapult.

1. UK mental health research funding 2014-17. MQ: Transforming Mental Health. Accessed May 14, 2022. 

https://www.mqmentalhealth.org/wp-content/uploads/UKMentalHealthResearchFunding2014-2017digital.pdf

2. Results: cause of death or injury. Institute for Health Metrics and Evaluation, Global Health Data Exchange. 2022. Accessed May 14, 2022. 

https://vizhub.healthdata.org/gbd-results/

Understanding and addressing the unmet therapeutic needs of individuals living with mental health conditions.

Driving Advances in Drug Discovery for Mental Health Conditions

 covered a wide variety of psychiatric issues and industry updates, from the cardiac adverse effects of lithium to the road to over-the-counter naloxone. Here are some highlights from the week.

Harnessing the Power of AI Technology for Drug Discovery Treatments

The buzz about the power of artificial intelligence (AI) to either save or doom humanity is rather deafening. A way to explain what people mean by AI is that it comprises the technologies we employ to have computers comb through large datasets using programs (“algorithms”) to find and extract patterns, help humans understand those patterns, suggest decisions regarding future choices, and predict future events or suggest outcomes not previously conceived.

Although some expect AI to mimic human intelligence, some AI systems show performance superior to that of humans (eg, AlphaGo). On the other hand, unlike humans, most AI systems need considerable data and training to achieve acceptable performance (eg, we only need to taste strawberries once to know if we like them or not). 

The Road to Over-the-Counter Naloxone: FDA Releases Federal Register Notice

To encourage sponsor application for over-the counter naloxone, the US Food and Drug Administration (FDA) today issued a Federal Register notice, “Safety and Effectiveness of Certain Naloxone Hydrochloride Drug Products for Nonprescription Use,” that could help facilitate the development and potential approval of nonprescription naloxone drugs.

“Today’s action supports our efforts to combat the opioid overdose crisis by helping expand access to naloxone,” said FDA Commissioner Robert M. Califf, MD. “The agency will keep overdose prevention and reduction in substance use disorders as a key priority and area of intense strategic focus for action as rapidly as possible.” 

Lithium: Cardiac Adverse Effects and When to Get an ECG

A recent consultation motivated an evaluation of the evidence on when one should monitor electrocardiograms (ECGs) in patients taking lithium. Opinions vary and tend to be vague about when and how often to measure the ECG. Mogens Schou, MD, who was perhaps the world’s foremost expert on lithium and a passionate advocate for its use, observed that lithium occasionally changes the function or electrical activity of the heart, but the presence of heart disease rarely should prevent lithium treatment. 

If heart disease was present, however, he recommended a consultation with a cardiologist and serial ECGs might be considered. Much more recently, The Maudsley Prescribing Guidelines in Psychiatry from the United Kingdom recommended getting an ECG if there are risk factors for, or preexisting, cardiac disease—but offered no further details. 

The Race Is On to Nurture Resilient People for a Resilient Planet

The scale and devastation of climate change is increasingly apparent. As we witness tenuous and inadequate movement toward effective responses, one thing is clear: 

 are also falling apart, in addition to the places where they live. The rapidly growing human emotional suffering from climate change is alarming from more than a humanitarian perspective: Social and emotional bandwidth is vital to tackle climate change itself.

People must adapt, care, endure, transform, and find hope through these challenges if we are to humanely and effectively make it through at all. The emotional and social challenges of these tasks—our psychiatric work—have been a neglected part of climate efforts. 

From the cardiac adverse effects of lithium to the road to over-the-counter naloxone, here are highlights from the week in Psychiatric Times.

The Week in Review: November 14-18

The buzz about the power of artificial intelligence (AI) to either save or doom humanity is rather deafening. A way to explain what people mean by AI is that it comprises the technologies we employ to have computers comb through large datasets using programs (“algorithms”) to find and extract patterns, help humans understand those patterns, suggest decisions regarding future choices, and predict future events or suggest outcomes not previously conceived. 

Although some expect AI to mimic human intelligence, some AI systems show performance superior to that of humans (eg, AlphaGo

). On the other hand, unlike humans, most AI systems need considerable data and training to achieve acceptable performance (eg, we only need to taste strawberries once to know if we like them or not).

One area of research that has attracted a lot of interest and funding is the AI-based design of novel drugs—small molecules, in particular.

 A simple way to classify the work being done in this area is shown in the 

 selection of a receptor or enzyme to be activated, inhibited, or modulated.

 Targets for psychiatry, for example, could be monoamine transporters (eg, SSRIs) or newer targets such as TAAR1 (eg, Ulotaront

). A receptor model implies knowing or hypothesizing its structure based on known crystalline structures.

 A ligand-based model requires a dataset containing the structure of target-selective molecules (“ligands” and “chemical probes”) and the result of their interaction with a target protein (eg, a neurotransmitter receptor) in an appropriate assay (eg, the serotonin 1A receptor

Importantly, both receptor and ligand-based approaches to 

 drug design implicitly assume that the action at this particular target is the most important action driving the therapeutic value of a drug.

The advantage ofthese modeling platforms is that existing data can be leveraged 

 to predict a new molecule’s action at a target, as well as its physical properties, before triggering costly preclinical work

As the establishment of AI expertise also comes at a considerable cost,various partnerships between AI companies and pharma have been initiated to drive development of AI-based models for 

 drug design, avoiding the need to build up internal AI expertise. 

Partnerships such as Genentech/GNS Healthcare, GSK/Insilico Medicine, Takeda/Numerate AI, Atomwise/Abbvie, CrystalGenomics/Standigm, and Cloud Pharmaceuticals/TheraMetrics use novel machine learning techniques to design or identify molecules that act on biological targets of particular interest.

 Most of these partnerships, however, do not focus on psychiatric indications or on CNS disorders in general.

Phenotypic Drug Discovery: A Holistic Approach

Drug discovery for mental health, whether traditional or AI-based, has been lagging, whereas mental health needs have continued to increase and remain a great societal burden. Although single target-based AI drug design may be adequate for some indications, the evidence from psychiatry research points to the need of polypharmacology (Figure). Indeed, action at different targets, aiming at an appropriate equilibrium, may be needed.

However, to quantify compound effects at multiple targets in a manner that encompasses downstream actions and interactions, it is necessary to explore drug activity using an 

 phenotypic drug discovery (iPDD) approach.

 An iPDD platform can be used for polypharmacology against known multi targets or in a target-agnostic manner (Figure), as the organism used for drug screening acts as an amplifier of all compound’s actions, providing a comprehensive drug profile. iPDD platforms include those high-throughput screens based on drosophila, zebrafish, and mice.

Phenotypic screening using an iPDD platform enables characterization of the complete gamut of behavioral effects of reference drugs and a data-driven, target-agnostic comparison with novel compounds. The potential of machine learning-based analysis of behavioral phenotyping data can be leveraged in many drug discovery applications, such as the mining of iPDD screened compounds libraries looking for new hits, or analysis of novel drug candidate analogs, to speed up the lengthy drug discovery process. Furthermore, using animal models of disease in iPDD platforms opens opportunities to explore phenotypic drug screening for psychiatric, neurodegenerative, and rare disorders.

iPDD drug discovery projects can progress in an agnostic manner or turn into a multi- or single-target programs as needed. Although not knowing the mechanism of action makes the road to the clinic harder, target-agnostic programs can be de-risked using “anti-target” panels, such as avoiding D2 antagonism in the development of novel antipsychotics. Biomarkers can also be used to assess target engagement in the clinic when the mechanism of action is unknown.

Perhaps the most convincing evidence will be at hand very soon. Ulotaront, an antipsychotic with a novel mechanism of action now being tested in Phase III, was discovered and developed in partnership between Sunovion and PsychoGenics,

 drug design approaches have promise for indications with validated hypotheses regarding needed therapeutic mechanisms of action. For complex CNS disorders, on the other hand, phenotypic screens and associated AI methods (such as iPDD platforms) are needed. The phenotypic approach in the upcoming era of AI-based drug design promises to bring new insights and accelerate drug discovery for CNS disorders.

is chief innovation officer at PsychoGenics Inc. and adjunct associate professor at Mt. Sinai School of Medicine. She is a member of the Business Advisory Board of CTF and the Scientific Advisory Board of CureVCP.

1. AlphaGo. DeepMind. Accessed October 12, 2022. 

https://www.deepmind.com/research/highlighted-research/alphago

2. Vedantam K. AI is making its way into drug discovery. What does it mean for biotech? 

. October 4, 2022. Accessed October 13, 2022. 

https://news.crunchbase.com/health-wellness-biotech/artificial-intelligence-venture-drug-discovery/

3. Mouchlis VD, Afantitis A, Serra A, et al. 

What is the buzz about the power of artificial intelligence?

Psychopharmacology

The Week in Review: November 21-25

Concurrent Treatment With SRIs and Anticoagulants: Minimizing the Hemorrhagic Hazard

Driving Advances in Drug Discovery for Mental Health Conditions

The Week in Review: November 14-18

Harnessing the Power of AI Technology for Drug Discovery Treatments

Lithium: Cardiac Adverse Effects and When to Get an ECG

Antidepressants, Placebos, and Lithium—Some Parting Thoughts

The Week in Review: October 31-November 4

From the Pages of Psychiatric Times: October 2022

Exploring Meta-Analyses: An Example