Intro

Federica Santoro 0:15

Aside from our body , medicines can affect our mind, too . That's how drugs like antidepressants or sedatives work , after all . But what happens when those effects on our behaviour are unwanted ? When the medicines we take to keep our health in check alter our personality in odd or dangerous ways ?

Federica Santoro 0:40

My name is Federica Santoro , and this is Drug Safety Matters , a podcast by Uppsala Monitoring Centre , where we explore current issues in pharmacovigilance and patient safety . Joining me today is Michele Fusaroli , medical doctor and pharmacovigilance scientist from the University of Bologna in Italy . Michele is fascinated by the area of research where medicine and behavioural science overlap , so it's no surprise that he chose to focus his PhD studies on behavioural effects of drugs and specifically on impulsivity . He is currently visiting UMC for a research collaboration and as he's also a big fan of this podcast , I just had to invite him to the studio for a chat . He explained how impulsivity manifests , which drugs cause it , how to cope with it, and much more . I hope you enjoy listening .

Welcome, Michele!

Federica Santoro 1:53

Hi , Michele , and welcome to Drug Safety Matters . I'm really glad you could make time for this interview and come here to talk about your research and behavioural side effects of drugs . How are you feeling today ?

Michele Fusaroli 2:08

I'm really good , I'm really excited because of the opportunity to talk with you and with the listeners of Drug Safety Matters about my research . This podcast has been always invaluable to me because of how it allows you to access other workers' perspective , and I believe experiences like Drug Safety Matters are vital for fostering collaboration and allow us to advance pharmacovigilance together .

Federica Santoro 2:34

What an endorsement . Well , I'm really glad to hear that you found the podcast useful and I hope listeners will find that these episodes spark ideas for collaboration

Body versus mind

Federica Santoro 2:47

. So, let's get right into it . I'm really looking forward to learning more about behavioural side effects , because I have the feeling it's a topic that's not discussed nearly enough . Even in everyday life, right, as patients taking medicines , we tend to think more about how medicines affect our body , and not so much our mind and behaviour . So, why is that ? Why is there so little talk about such side effects ?

Michele Fusaroli 3:18

I believe we are still entrenched into Descartes' body-mind dualism . Descartes was a 17th century French philosopher and scientist that theorised that the body and the mind are two separate entities . This way of thinking has two effects that make behavioural side effects some sort of invisible: under-reporting and under-acknowledgement . First , we , as patients , under-report behavioural side effects due to our reluctance to acknowledge that organic conditions and exposure to substances may influence our behaviours , our thoughts , our choices – those components of what we define as our identity .

Michele Fusaroli 4:01

Imagine , after taking a medication for Parkinson's disease , for example , we perform an action that we would normally not perform , that even feels strange to us .

Michele Fusaroli 4:11

For example , we enter into a car shop and we spend all our money in buying an extremely expensive car .

Michele Fusaroli 4:18

Well , in this situation , we may not report these strange things that happen to us just because we fear judgment , because we feel responsible . Second , we , as healthcare practitioners , under-acknowledge behavioural side effects because medical education taught us to diagnose and treat only organic conditions , up to the point that psychosocial conditions are of interest to us only if they have a tangible and measurable substrate . Even mild physiological drug effects , like a small increase in blood pressure , are more readily acknowledged than severe behavioural changes . For example , our patient may take a drug for schizophrenia and just after that, they may develop aggressivity . In this situation, just because we were taught to do that, we may hurriedly think that schizophrenia may be enough to explain this anger , to explain this episode , and maybe we are not even thinking about a potential role of the medication . To sum up , the reason for so little talk of behavioural side effects is that there are both under-reporting and under-acknowledgement .

Federica Santoro 5:30

And we'll try to dissect those elements a little more in the rest of the interview .

Tamoxifen and brain fog

Federica Santoro 5:38

We advertised , as usual , the interview on our social media channels , and one of our listeners cited an example of how drugs can affect cognition . She cited tamoxifen , which is a drug normally used to treat breast cancer , and how it can , on occasion , induce brain fog . Have you heard about that reaction ?

Michele Fusaroli 6:00

Indeed , there is evidence that tamoxifen may be toxic for neural cells and therefore may result in a loss of focus and even in memory impairment . Another well-established effect of drugs on cognition and behaviour is that of irritability and aggressivity associated with chronic use of corticosteroids . Well , all drugs have adverse drug reactions , and still we need their beneficial effect , at least as long as the underlying disease is worse than the side effects themselves .

Federica Santoro 6:32

Absolutely . It's always about weighing the benefits against the risks .

Drug-induced impulse control disorders

Federica Santoro 6:36

But you're more of an expert on behaviour rather than cognition , as far as I understand , and you specialise in a particular kind of behavioural side effects known as drug-induced impulse control disorders . Now , I know that may sound like a mouthful for our listeners , but don't worry , we will explain what they are . Let's start with the basics , then . How do these disorders manifest ?

Michele Fusaroli 7:01

If you have a drug-induced impulse control disorder , it means that you have a difficulty in resisting the urges or temptation to behave in a certain way , and this in turn affects your well-being and may even harm people around you .

Michele Fusaroli 7:16

Four main manifestations , termed as the 'four knights' of impulsivity , have an apocalyptic effect on the quality of life of patients and their families . They are drug-induced pathological gambling , hypersexuality , compulsive shopping, and overeating . However , impulse control disorders vary widely and they can take any form in the spectrum of human behaviours , and they usually align with the cultural roles , social roles, and even life experiences of the patient . For instance , historically , hypersexuality has been more prevalent among men and compulsive shopping among women, and these conditions are distributed nowadays a bit more equally , and this also reflects a change in our society and in our culture . In some Islamic countries , impulsivity may affect some otherwise completely normal religious behaviours , such as resulting in excessive charity or compulsive reading of the Quran , even many hours per day . Another example is that of individuals with administrative jobs , who may compulsively organise documents , for example , and there are also case reports in the literature that describe some patients writing poems or love letters up to 12 hours per day .

Federica Santoro 8:37

So I guess the manifestation varies depending on who you are and what you normally like to do or what kind of activities you're drawn to .

Michele Fusaroli 8:45

Exactly

Drugs and mechanisms

Michele Fusaroli 8:46

.

Federica Santoro 8:46

What drugs are more likely to cause these types of disorders , and is it known why ?

Michele Fusaroli 8:53

There are two drug classes with an established role in increasing impulsivity: dopamine agonists , which are used in Parkinson's disease , restless leg syndrome, and prolactinoma; and third- generation antipsychotics, used in psychosis and mood disorder . The exact mechanism , in fact , is still underdefined . We know that these drugs can directly enhance dopaminergic activity in the nucleus accumbens , that is , a region of the brain involved in both physiological motivation and pathologic addiction . We also know that they may switch off a serotonergic pathway that normally modulates dopamine levels in the nucleus accumbens . Given these mechanisms' speculations , we may also imagine that antidepressants and psychostimulants in other situations , in other conditions , may have an effect on impulsivity . Anyways , as always in science , there are plausibly multiple mechanisms at work , and we still have much research to do in front of us to really understand them .

Frequency of impulse control disorders

Federica Santoro 9:58

What about frequency ? So, how often do these side effects manifest with these drugs ?

Michele Fusaroli 10:07

Exact frequencies are unknown . This is also because of lack of a clear definition of when impulsivity becomes a disorder and also because there is an extremely heterogeneous time to onset . We can have impulsivity days or months or even years after the first administration of the medication . For this reason , estimates range from 2 to 60% in different study designs with different impulsivity definitions . A plausible estimate is that around 50% of patients taking dopamine agonists develop impulse control disorders within five years . For third-generation antipsychotics instead , the frequency is even less clear . There is some idea , some evidence that supports an even higher risk relative to dopamine agonists , but these may also be distorted by the fact that it seems that third-generation antipsychotics may cause impulsivity in just days or weeks .

Risk factors

Federica Santoro 11:07

Are there any risk factors that can predispose a patient to such disorders ?

Michele Fusaroli 11:13

Yes , there are . The main risk factors are pre-existing depression and impulsivity traits, for example, if someone has novelty-seeking personality , or it is more common for males , for young people, or for people that had a history of alcoholism , of smoking, or even excessive coffee consumption . Other possible risk factors for impulsivity are higher doses of dopamine agonists and also certain genetic factors may play a role

Impact on quality of life

Michele Fusaroli 11:45

.

Federica Santoro 11:45

From everything you've said, it can't be easy to live with an impulse control disorder , and you've mentioned a few examples , but can you help us understand exactly how patients are impacted . Like, to what extent do these disorders affect quality of life ?

Michele Fusaroli 12:02

The impact of impulse control disorders varies greatly depending on their expression and severity . Mind that the impact of impulsivity may not always be negative , it may also be positive . In fact , individuals with Parkinson's disease usually have lower levels of dopamine in the nucleus accumbens and therefore also lower motivation . And when they start getting dopamine agonists we sort of normalise their dopamine levels in the nucleus accumbens , we boost motivation and creativity . And what the patients experience in the first months of dopamine agonist treatment is an actual honeymoon period in which they start again getting involved in activities , in which they even develop new hobbies .

Michele Fusaroli 12:49

However , problems arise when impulsivity gets out of control . In this situation , the pathologic behaviours consume the entire life of the individual and it can have a serious impact on the financial stability , on the social relationships , on the employment of the individual . It can even cause legal issues . Moreover , there are also expressions that are more specific to the behaviour . Pathological gambling and compulsive shopping , for example , result more often in higher loss of money and therefore can have more problem in financial stability and in the social relationships . Hypersexuality, instead , is usually associated with marital problems , with sexually transmitted diseases , depending on the age also in unintended pregnancy and sexual dysfunction . Overeating instead can lead to obesity , metabolic syndrome , sleep apnoea . And we don't have to think that other behaviours that are not among these four have no impact on the quality of life . For example , even a seemingly harmless compulsive gardening may cause excessive expenditure of money and may result in the patient staying outside in the garden and doing work , even during a storm , for example , with serious danger for their life .

Federica Santoro 14:07

Exactly . So, quite serious consequences , even though they may sound as harmless behaviours to begin with . Something to keep in mind .

First identification

Federica Santoro 14:17

Let's move on to the diagnosis now , which I imagine must be really challenging , not least because of what you said earlier , that it can be really difficult to distinguish compulsive actions from normal ones . I mean, behaviour , even in a normal situation, occurs on a spectrum , so how do you tell what's normal from pathological ? So, if we go back in time , can you tell me how these disorders were identified in the first place ?

Michele Fusaroli 14:46

I think the first time was in 2003 , when Driver- Dunckley and colleagues from the Barrow Neurological Institute in Phoenix published a study , a case series , with nine cases of pathological gambling that developed after taking dopamine agonists . What raised a concern and a suspicion of adverse drug reaction was not the time to onset , because the average was around 20 months . It wasn't even the frequency , because it wasn't really significantly higher than what expected based on the entire population . What raised a concern was the seriousness of the event . These patients started gambling without any control . They started losing more and more money and even one patient committed suicide after an extremely severe episode of gambling . Interestingly , reducing the dose or switching to alternative medication showed promise in mitigating this condition and also , as we said before , subsequent research highlighted that there is an extreme difference between the low motivational drive that is implicit in Parkinson's disease and the extreme motivational drive that we observe when patients take dopamine agonists .

Third-generation antipsychotics

Federica Santoro 16:03

And what about the other class of drugs you mentioned at the beginning , so these third- generation antipsychotics ? Was it even trickier to associate abnormal behaviours to those types of drugs , since they are used in conditions like psychosis or bipolar disorder that are already marked by impulsivity ? How did it work out for those drugs ?

Michele Fusaroli 16:29

Yeah , it was more challenging . In fact , third-generation antipsychotics- induced impulsivity may be considered that sort of 'black swan' that François Montastruc spoke about in the last episode: therefore , an event , a reaction that is completely unexpected and also particularly serious . Healthcare providers initially blamed the disease and not the drug . For example , they attributed the impulsivity episode to schizophrenia or to a bipolar disease . Consequently , when in 2014 a disproportionality analysis on the FDA adverse event reporting system found a signal of potential adverse drug reaction between aripiprazole and impulse control disorders , most of the reports were from patients , not from doctors . Doctors , in fact , started to report only after 2016 , when an FDA warning came out .

Michele Fusaroli 17:27

The key factor aiding in the detection of this signal was the patient's experience , just a few days after taking the first dose of aripiprazole , of an extreme loss of control . Also , behaviours that they may have shown before the first administration of the drug, for example , they are patients that may be more susceptible to gambling and to compulsive shopping and hypersexuality because of the underlying disease, started spiralling down and they completely resolved after the discontinuation of the drug . I think that the journey of discovery of impulse control disorders induced by third- generation antipsychotics has an important message for us . That is to listen to the patients . Patients should be acknowledged as the main expert of their disease , of their experience of disease , and they should be actively involved as primary stakeholders in clinical practice , but also in signal detection and signal refinement .

Federica Santoro 18:35

And that message truly resonates with us . We have at least two episodes in the archives on patient engagement and patient voices in pharmacovigilance , but you raise so many important points . It's also so fascinating to hear what sparks that initial suspicion . I think that's what makes the job of pharmacovigilance professionals so interesting .

Diagnosis

Federica Santoro 19:00

So, we've looked at the past and how these conditions were first identified . Back to present day: so, how are drug-induced impulse control disorders diagnosed nowadays ?

Michele Fusaroli 19:15

If you listen to the recent episode on drug-induced liver injury by Rita Baião , you know that diagnosis in medicine is usually based on well-defined diagnostic criteria , and the problem here is that we really don't have those diagnostic criteria . There are some scales that can be used to diagnose and stage impulsivity in Parkinson's disease , like QUIP and Ardouin , but they have extremely well-recognised limitations . For example , they consider only a few possible behaviours as manifestation . They don't include , for example , kleptomania that may be one of the manifestations of drug-induced impulsivity . Timely diagnosis should therefore rely on two main factors . The first is education of patients and their caregivers on what is the risk of impulse control disorder , how they manifest, and even their impact on quality of life . Second , a timely diagnosis also has to rely on frequent interviews with both the patient and the caregiver , because the patient may sometimes be shy or even reluctant to report something because they feel ashamed .

Federica Santoro 20:32

Of course . So that's a really important message for patients , their carers, and healthcare professionals . Be vigilant and raise an alarm if you have a suspicion that there might be something at play here .

Coping strategies

Federica Santoro 20:45

We've talked about then the diagnosis , complicated as it may be . Once that has been made , what strategies can doctors or patients themselves adopt to deal with such behaviours and potentially counteract them ?

Michele Fusaroli 21:01

As soon as there is an even mild impairment of the biopsychosocial function of the patient or the caregivers , that is the time when an intervention is needed, before any severe or even irreversible deterioration of quality of life happens , such as those related with loss of employment , divorce, or legal issues . There isn't abundant evidence on how to manage these conditions . Here at UMC , I am using individual case safety reports to try to map how people are already managing these reactions in the real world , to identify some pitfalls and some good practices . Discontinuing the drug may suffice for third-generation antipsychotics . For dopamine agonists it is more challenging . A year after discontinuation , still 50% of the patients hasn't resolved .

Michele Fusaroli 21:56

A consensus group for managing impulsivity in Parkinson's disorders recently published an expert opinion-based guideline . They recognize the pivotal role of involved caregivers and of psychosocial interventions . For example , for pathological gambling and compulsive shopping , it may be extremely useful to restrict access to credit cards and to casinos and shops . For example, it can also be useful to restrict access to the internet , since many of these behaviours are enacted also online today , both gambling , compulsive shopping , hypersexuality, and so on . Sometimes it may also be necessary to seek legal support or even social support .

Michele Fusaroli 22:37

Concerning the pharmaceutical management instead , these experts could only agree on the need for closely monitoring and tapering down dopamine agonists at the first sign of impairment . In fact , cautiously , because there are some risks of withdrawal syndrome , of a long-term apathy and of worsening of the motor symptoms of Parkinson's disease itself as soon as we discontinue the drug . When this is not sufficient , then the management relies more on trial and error . There are some strategies that received more than 50% agreement in this expert opinion . That is still low as an agreement , but they are , for example , cognitive behavioural therapy, they are quetiapine , clozapine, or even deep brain stimulation that consists in surgically placing some electrodes in the brain to modulate its activity .

Federica Santoro 23:34

So, it is complicated , but there are ways to alleviate these conditions and I guess the general advice, as with any side effect, just never stop taking the drug unless you consult your physician, right ? There's a reason why you've been put on it in the first place .

Assessing impulsivity reports

Federica Santoro 23:52

Back to our social media questions . We have another query that came in from one of our listeners . Sudarshan in India asked something that is related to one of the projects you are working on here at UMC . He asks, how does pharmacovigilance work in these complicated scenarios ? As we've said , it's not always easy to differentiate the adverse event from the underlying disease . So, can you tell us , as a pharmacovigilance professional , how do you think when approaching both the identification but also the assessment of reports in these conditions ?

Michele Fusaroli 24:33

At the UMC , I am now investigating methylphenidate-related impulsivity . Methylphenidate is a psychostimulant drug that is used in ADHD to treat inattention and impulsivity , but its effects seem to be dependent on the baseline condition , for example , of neurotransmitter of the patient . There is some evidence that, in some cases , methylphenidate may aggravate or even cause impulsivity , and this is a 'black swan' , even more than antipsychotics . A drug used to treat a condition that , in certain situations , may cause it . How to deal with such a difficult situation ? Well , the first thing we need to do is to make sure that the reports we are looking at are actually of a suspected adverse drug reaction . We may also have , sometimes , a report , for example , of inefficacy: that is , the drug was taken to treat impulsivity but it didn't work and therefore impulsivity is still there .

Michele Fusaroli 25:32

Another report that we may observe is a resurgence of impulsivity because of a drug shortage . Therefore , like in the apothecary there wasn't any more methylphenidate , the patient stopped to take it and impulsivity came back . And narratives , when available , are extremely useful to differentiate between these different kinds of reports . When we have identified reports of suspected methylphenidate-induced impulsivity , then we can apply the usual causal indicators that we use in causality assessment . For example , we can look into the temporal relationship , into the exclusion of alternative causes . Yes , we know that there is always ADHD there as an underlying possible cause . We can look at the relation with the dose , at the challenge and re-challenge . So, what happened when we stopped the drug and we administered again the drug ? And , particularly important , as we have learned from the case of impulse control disorder , we can also look into the experience of the patient, that something happened , that something is different from before

Final advice

Michele Fusaroli 26:40

.

Federica Santoro 26:46

This is such a complicated topic . I think we've described so many aspects of it as challenging and difficult to approach . So, if you were to wrap up on an encouraging note , what would you say to patients who are dealing with such difficult conditions , or to healthcare and pharmacovigilance staff who are trying to help those patients ?

Michele Fusaroli 27:04

I often draw parallels between drug-induced impulse control disorders and Herman Melville's "Moby Dick" . At first , the great white whale serves as a driving force , even a purpose , for Captain Ahab . It is something positive that gives meaning to their life . Yet it evolves into an overwhelming obsession , a compulsion that ultimately drags Ahab into the depths of the sea . Similarly , impulsivity may start innocently and may even be positive , as we said for the honeymoon period in Parkinson's disease , but it can also escalate into a serious issue . Recognising when we are losing control and seeking help is therefore crucial .

Michele Fusaroli 27:47

We have to remember that a diagnosis is not a conviction . It is not a stigmatising label . A diagnosis is instead a tool to identify and address some needs that we have . To regain control , we must lean on the people that surround us . Caregiver involvement is still the best predictor of recovery from dopamine agonist-induced impulsivity . The message is that we don't have to face these battles alone . By relying on our loved ones , we can receive the treatment that we actually need while keeping control of our impulses . We can together navigate the depths while keeping our vessel steady and avoid being dragged into the abyss by our own personal white whale .

Federica Santoro 28:33

And I think we'll end on that encouraging note . Don't be afraid to speak up . If you have a suspicion that something's wrong , do talk with your loved ones or your healthcare professional . Well , thank you very much for taking the time to come on the show . Thanks .

Outro

Federica Santoro 29:07

That's all for now , but we'll be back soon with more conversations on medicines safety . If you'd like to know more about drug-induced impulsivity and Michele's research , check out the episode show notes for useful links . If you like our podcast , subscribe to it in your favourite player so you won't miss an episode , and spread the word on social media so other listeners can find us . Apart from these in-depth conversations with experts , we host a series called Uppsala Reports Long Reads , a selection of audio stories from UMC's pharmacovigilance news site , so do check that out, too . Uppsala Monitoring Centre is on Facebook , LinkedIn and X, and we'd love to hear from you . Send us comments or suggestions for the show or send in questions for our guests next time we open up for that . For Drug Safety Matters, I'm Federica Santoro . I'd like to thank Michele Fusaroli for his time , our listeners Nur Azra and Sudarshan for submitting questions , Matthew Barwick for production support, and of course you for tuning in . Till next time .