Guest Column | November 19, 2024

Should We Explore Suicidality In Animals During Preclinical Drug Development?

By Anke Rosch, Boehringer Ingelheim

Pet Rat-GettyImages-1052049312

These days, it seems fortunate when a new drug demonstrates therapeutic activity alongside its adverse effects. Some of these side effects, such as suicidal ideation and behavior (SIB), can be more harmful than the disease itself. Therefore, they require our attention not only in clinical but also in early drug development.

Investigating SIB in animal studies represents the closest approximation to the intricate nature of human suicide. However, the FDA Modernization Act 3.01 obligates us to reduce unnecessary animal testing.

This article discusses the relevance of preclinical animal studies and alternatives for drug‑related suicidality in humans in context with behavioral and ethical aspects.

Background Of Suicide

Completed suicide (SC) is annually committed by about 703,000 people (1.3 % of all deaths) worldwide2 and claims more lives than breast cancer (700,660),3 HIV/AIDS (690,000),4 or homicide (475,000 people).5 The global lifetime-prevalence of registered suicidal attempts (SA) ranges from 2.7%6 to 3.1%.7 However, suicidal attempts are estimated to be 10 to 20 times more frequent8 than completed suicides. A high number of health conditions bear an increased risk of SIB,9,10 such as major depression (three- to fivefold higher, SA),11,12 epilepsy (threefold higher, SC),13,14 obesity (nearly one and a half times higher, SA),15 fibromyalgia (threefold higher, SC),16 cancer (11 times higher, SC),17 and asthma (fourfold higher, SA).18

Existing Regulatory Guidance For Drug Companies

The worldwide incidence of suicide along with public health warnings by FDA and EMA about an elevated risk for SIB following treatment with antidepressants in children and adolescents (2004)19 and antiepileptic drugs (2008)20 triggered the release of a clinical Draft Guidance on Suicidal Ideation and Behavior in 2010, which was revised in 2012.21 Even non‑psychiatric drugs have been associated with SIB, including antibiotics like fluoroquinolones (e.g., moxifloxacin),22 as well as drugs prescribed for weight loss (semaglutide,23–25 rimonabant)26 and neuropathic pain (e.g., pregabalin).27 Systematic reviews of medical claims for private health insurance28 or articles in PubMed29 uncovered a risk for drugs without a current warning, such as the cytostatic paclitaxel,30 the glucocorticoid prednisone,31 and bronchodilators.32,33

The FDA guidance21 consequently defined clinical testing requirements for drugs treating psychiatric and neurologic conditions, as well as non-psychiatric conditions similar to those currently listed for SIB (e.g., same indication, pharmacological class or chemical similarity). However, there are no requirements for preclinical suicidality investigations yet.

Suicide In Animals?

When we think about suicide in animals, a crowd of lemmings jumping off the cliffs to escape overpopulation34 or dogs starving to death after losing their master pop up in our mind. Suicidal ideation presupposes vocal communication, free will, intentionality, and an awareness of self and death – concepts that are controversially discussed for animals. Several species, such as chimpanzees,35 dolphins36 and magpies,37 show self-awareness in the visual mirror test conducted by Gallop, often absent in children up to the age of 638 across various cultures. Free will in animals, a subject of continuous theological debate, was disenchanted as a simple biological trait that enables multiple choice responses in flies.39,40 Gorillas,41 elephants, and magpies42 engage in burial rituals and display grief when their companions die, indicating their awareness of death.

Although an animal model for suicide may never exist, several physiological and behavioral responses are evolutionarily conserved across species.43 This allows us to investigate personality traits in animals associated with SIB in humans.

Animal Models For Suicidality

Traits with translational value for SIB include impulsivity, anhedonia, irritability, hopelessness/helplessness, and aggression.44,45 For example, aggression shows a moderate association46 with SIB, represents a risk factor in adolescents,47,48 correlates with a higher incidence of lethal suicide attempts,49 and the involved receptors overlap.50

In humans, aggression is defined as behavior that is “directed toward the goal of harming a living being or oneself”.51 In animals, offensive aggression is an adaptive behavior to address resource challenges52 important for survival and reproduction.

For the about 200 types of human aggression per definition,53 correlates in nonhuman behavior rarely exist (e.g., vocal aggression). However, offensive aggression in laboratory rodents and angry human aggression seem to have more in common.54

Several paradigms exist for testing aggression in animals, such as the resident‑intruder test55 or isolation-induced aggression.56 These methods investigate the reaction (number and duration of attacks) of rodents and primates as a response to various external stimuli, including a conspecific (intruder), foot shock,57 isolation, an alcohol dose58 or electrical stimulus.59

In these tests, different outcomes for the same drug are not only influenced by the artificial test scenarios outside the natural behavioral repertoire of the animals and the acquired learning from repeated test performance, but also by the species tested.

Whereas rats60 and hamsters61 show a decrease in aggressive behavior after acute administration of antidepressants, mice exhibit an increase.62 Conversely, after subchronic (repeated) administration of antidepressants, aggressive behavior in rats60 and hamsters63 increases while it decreases in mice.64 According to Mitchell,60 antidepressants might acutely cause anxiety. After repeated administration, the anxiolytic action of the drug associated with a behavioral disinhibition may result in increased aggression.

However, what is different in mice? Mice are more sensitive to anxiolytic drugs than to antidepressants, likely indicating an influence of baseline anxiety levels on aggression. Mice violently defend their territory, whereas rats avoid excessive fighting as it is detrimental to their social group.60 Unfortunately, aggression in female rats and mice is underrepresented in the literature, highlighting a further limitation of aggression testing. While female rats and mice are territorially less aggressive than males, except around the time of birth, both male and female hamsters aggressively defend their territories.66

Are There Alternatives To Animal Testing?

Several biomarkers for the diagnosis and prediction of SIB in clinics appeared in (and disappeared from) literature, including brain imaging,67 gene expression profiling through microarray studies,68 and various potential blood and cerebrospinal fluid biomarkers.

In patients, a combination of serum cortisol, total cholesterol, folate, interleukin-1β, and homocysteine predicted suicidal attempts and their severity during antidepressant treatment.69 Peripheral stathmin 1 (STMN1), protein phosphatase 1 regulatory subunit 9B (PPP1R9B) mRNAs, and two miRNAs (miR-3688 and miR-5695) in whole blood samples, associated with clinical findings, indicated worsening of suicidal ideation after treatment with antidepressants.68,70 Altered expression of SLC4A4 (involved in brain extracellular space pH regulation)71–73 and CLN5 (a lysosomal regulatory protein),70 two blood gene expression biomarkers, predicted suicidality across sexes and psychiatric diseases.

As a standard practice in early drug development, a dedicated receptor panel74 is recommended for both CNS and non-CNS drugs, overlapping with those for off‑target activity75 and abuse potential testing.76 It includes receptors responsible for SIB such as serotoninergic 5HT1A (5-hydroxytryptamine 1A), serotonin transporter 5HTT, cannabinoid CB1 receptors, dopamine D1 receptors, norepinephrine transporter NET, vesicular monoamine transporter VMAT2, CaN (CaN channel) (antagonism), 5HT2A, dopamine D2, and nicotinic a4β2 receptors (agonism).77

Conclusion

The primary population for SIB investigations in clinical studies comprises chronically ill individuals with comorbidities, having a higher prevalence of suicide, who are on multiple medications. These factors complicate the clear attribution of SIB to a drug in development. SIB studies performed in animals before clinical phases could help eliminate confounding factors but uncover new limitations.

Preclinical testing of SIB-associated traits is mostly conducted under conditions that do not facilitate normal animal behavior. The dependence of the preclinical test outcome on individual levels of aggression and fear, the social system of the species, and the status of the individual in the group may lead to equivocal results.78 Therefore, nonclinical testing in more than one behavioral model is required.45 This could cause an increased number of animal studies with inappropriate experimental outcomes. There is doubt that studies involving animals genetically predisposed to certain SIB traits, such as LAB and HAB rats79 or congenital learned helplessness (cLH) rats,80 would improve the situation, as their predictive value is unknown.

Mental pain and complex emotional aspects trigger human suicide, and these neuronal pathways may not be entirely conserved in animal species. In addition, the uniquely human risk factors, stressors, and vulnerabilities for suicide aggravate a predictive modeling in animals. Identification of biomarkers for SIB prediction would be a significant improvement. However, current biomarker research primarily focuses on patients with psychiatric illnesses. Since SIB and psychiatric disorders share overlapping signaling pathways, it is doubtful that these biomarkers, which do not even predict SIB in healthy humans,81 could be applied to animals.

It is the author’s opinion that for routine screening in drug development, valid biomarkers integrated into regulatory studies in animals and in-vitro receptor bindings assays are the only investigations to comply with current animal welfare initiatives. It is not without a certain irony that animals serve for investigation of SIB, although the discussion about animal consciousness has not ended.

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About The Author

Anke Rosch is a board-certified pharmacologist and toxicologist working at Boehringer Ingelheim Pharma GmbH & Co. KG. A doctor of veterinary medicine, she has more than 20 years of experience in the pharmaceutical industry and has special expertise in safety pharmacology. Anke can be reached at ankerosch.PharmacolTox@t-online.de.