Updating our approach to study adverse reactions

Research / 29 May 2024

The traditional “drug-event combination” approach is too simplistic for complex side effects such as behavioural changes. We must adjust our methodology to address this intricacy.

How can medications change our personality? Take pramipexole, for instance, a drug commonly used in Parkinson’s disease treatment. Pramipexole boosts dopaminergic activity, which can lead to heightened motivation and engagement in rewarding activities like crafting and gardening. Initially seen as positive, this increased drive can sometimes spiral into problematic behaviours like gambling, compulsive shopping, overeating, or hypersexuality. Much like Captain Ahab’s obsession with the white whale in “Moby Dick”, what starts as a purposeful pursuit can turn into a harmful obsession, affecting not only the patient but also their caregivers, potentially leading to financial ruin, job loss, divorce, and heightened anxiety.

The lens of the “drug-event combination” approach, where associations between medication use and reported events are analysed to identify potential causal relationships, cannot fully capture the complexity of behavioural side effects to medicines. We need new conceptual frameworks to delve deeper into the complex nature, progression, and management of adverse reactions.

The ”syndrome” approach treats adverse events as occurring together rather than in isolation, much like stars form constellations

The “syndrome” approach acknowledges that adverse events rarely occur in isolation. Just as stars form constellations, events can cluster together to create a syndrome. For example, prolonged use of systemic corticosteroids can lead to a constellation of symptoms known as Cushing syndrome, including mood disorders, immunodeficiency, hyperglycaemia, ulcers, fatty hump, and a characteristic red round face. This syndrome, including adverse events related to the underlying disease and concurrent therapies, profoundly impacts the patient’s life. Tools that identify consistent patterns of adverse events, such as vigiGroup developed by Uppsala Monitoring Centre, reveal how impulsivity often coexists with stress, pain, anxiety, depression, weight gain, financial issues, injuries, sleep disturbances, and suicide attempts, creating complex biopsychosocial syndromes.

The “network” approach takes us beyond viewing adverse events as mere symptoms of an underlying process. Instead, it considers adverse reactions as interconnected networks of adverse events causing and reinforcing each other, influenced by patient characteristics and environmental factors. This way, we can both explore the role of external factors in shaping the expression and the progression of the adverse reaction and identify promising therapeutic targets in pivotal events that potentially trigger causal chains and loops in the network. For instance, in Cushing's syndrome, ulcers, immunodeficiency, and hyperglycaemia can interact with each other. This interaction makes patients more likely to get infections, which can lead to less physical activity. As a result, metabolic disorders can worsen. Treating or preventing an exacerbating event may be our best option when discontinuing the drug is not advisable, e.g., because of the fear of withdrawal and disease aggravation in pramipexole recipients. Network analysis unveils chains of events that exacerbate reactions, loops resulting in chronic conditions, and intricate interactions between adverse events and external factors. It shows how anxiety, stress, and depression could form a feedback loop prolonging the psychological consequences of pramipexole-induced impulsivity, even after discontinuation. Moreover, it highlights potential differences in chains of events induced by different drugs, such as discriminating between pramipexole-induced hyper-sexuality, which can lead to jealousy, psychosis, and marital issues in old patients with Parkinson’s Disease, and aripiprazole-induced hyper-sexuality, which can result in sexually transmitted diseases and unintended pregnancy in younger patients with bipolar disorder.

In summary, by adopting different perspectives – viewing reactions as individual events, constellations of symptoms, or causal networks – we gain deeper insights for understanding, assessing, and managing adverse reactions, especially when it comes to complex side effects such as behavioural changes. While current tools focus on studying reactions as drug-event combinations, the future holds promise for exploring and managing the complexity of adverse reactions through innovative frameworks.

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This work is a spin-off of the Drug Safety Matters Podcast episode 29:

“When medicines change our behaviours – Michele Fusaroli”.

To learn more about the work on the “network approach” to ADRs, read the following publications:

M Fusaroli, et al, “Development of a Network-Based Signal Detection Tool: The COVID-19 Adversome in the FDA Adverse Event Reporting System”, Frontiers in Pharmacology, 2021.

M Fusaroli, et al, "Unveiling the Burden of Drug-Induced Impulsivity: A Network Analysis of the FDA Adverse Event Reporting System”, MedRxiv, 2023.

[Summarised in this Twitter thread]

D Borsboom, “A network theory of mental disorders”, World Psychiatry, 2017.

Finally, the following research by researchers at Uppsala Monitoring Centre reflects its long-standing interest in syndrome detection:

R Orre, et al, “A Bayesian recurrent neural network for unsupervised pattern recognition in large incomplete data sets”. International Journal of Neural Systems, 2005.

L Gattepaille, “Using the WHO database of spontaneous reports to build joint vector representations of drugs and adverse drug reactions, a promising avenue for pharmacovigilance”, IEEE, 2019.

GN Norén, E-L Meldau, RE Chandler, “Consensus clustering for case series identification and adverse event profiles in pharmacovigilance”, Artificial Intelligence in Medicine, 2021.