April 23, 2024 • 30 mins
Medicines can affect our personality in positive ways, but they may also lead to destructive behaviours that can damage our relationships, finances, and overall quality of life. Michele Fusaroli from the University of Bologna explains how to diagnose and treat drug-induced impulse control disorders.
Tune in to find out:
- Which medicines may cause impulsivity
- What the ‘four knights’ of impulsivity are
- How patient stories can help detect these conditions
Want to know more?
This review by Daniel Weintraub summarises twenty years of research on impulse control disorders in Parkinson’s disease.
In 2003, Driver-Dunckley and colleagues in the US published the first case series linking pathological gambling to dopamine agonists.
In 2016, the US Food and Drug Administration warned about impulse-control problems associated with the antipsychotic drug aripiprazole.
Michele and colleagues in Italy have investigated the mechanisms and burden of drug-induced impulsivity.
In their 2024 guidelines for managing impulsivity in Parkinson's disease, an expert consensus group highlighted the pivotal role of caregivers and of psychosocial interventions.
Finally, these are the Drug Safety Matters episodes cited in the interview:
- Catching black swans
- When drugs damage the liver
- Empowering patients as partners
- Why we should listen to patients
Join the conversation on social media
Follow us on X, LinkedIn, or Facebook and share your thoughts about the show with the hashtag #DrugSafetyMatters.
Got a story to share?
We’re always looking for new content and interesting people to interview. If you have a great idea for a show, get in touch!
About UMC
Read more about Uppsala Monitoring Centre and how we work to advance medicines safety.
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Federica Santoro (00:15):
Aside from our body, medicines can affect our
mind, too.
That's how drugs likeantidepressants or sedatives
work, after all.
But what happens when thoseeffects on our behaviour are
unwanted?
When the medicines we take tokeep our health in check alter
our personality in odd ordangerous ways?
(00:40):
My name is Federica Santoro, andthis is Drug Safety Matters, a
podcast by Uppsala MonitoringCentre, where we explore current
issues in pharmacovigilance andpatient safety.
Joining me today is MicheleFusaroli, medical doctor and
pharmacovigilance scientist fromthe University of Bologna in
(01:02):
Italy.
Michele is fascinated by thearea of research where medicine
and behavioural science overlap,so it's no surprise that he
chose to focus his PhD studieson behavioural effects of drugs
and specifically on impulsivity.
He is currently visiting UMCfor a research collaboration and
(01:26):
as he's also a big fan of thispodcast, I just had to invite
him to the studio for a chat.
He explained how impulsivitymanifests, which drugs cause it,
how to cope with it, and muchmore.
I hope you enjoy listening.
Hi, Michele, and welcome toDrug Safety Matters.
(01:56):
I'm really glad you could maketime for this interview and come
here to talk about yourresearch and behavioural side
effects of drugs.
How are you feeling today?
Michele Fusaroli (02:08):
I'm really good, I'm really excited because
of the opportunity to talk withyou and with the listeners of
Drug Safety Matters about myresearch.
This podcast has been alwaysinvaluable to me because of how
it allows you to access otherworkers' perspective, and I
(02:29):
believe experiences like DrugSafety Matters are vital for
fostering collaboration andallow us to advance
pharmacovigilance together.
Federica Santoro (02:34):
What an endorsement.
Well, I'm really glad to hearthat you found the podcast
useful and I hope listeners willfind that these episodes spark
ideas for collaboration.
So, let's get right into it.
I'm really looking forward tolearning more about behavioural
side effects, because I have thefeeling it's a topic that's not
(02:58):
discussed nearly enough.
Even in everyday life, right,as patients taking medicines, we
tend to think more about howmedicines affect our body, and
not so much our mind andbehaviour.
So, why is that?
Why is there so little talkabout such side effects?
Michele Fusaroli (03:18):
I believe we are still entrenched into
Descartes' body-mind dualism.
Descartes was a 17th centuryFrench philosopher and scientist
that theorised that the bodyand the mind are two separate
entities.
This way of thinking has twoeffects that make behavioural
side effects some sort ofinvisible: under-reporting and
(03:40):
under-acknowledgement.
First, we, as patients,under-report behavioural side
effects due to our reluctance toacknowledge that organic
conditions and exposure tosubstances may influence our
behaviours, our thoughts, ourchoices – those components of
what we define as our identity.
(04:01):
Imagine, after taking amedication for Parkinson's
disease, for example, we performan action that we would
normally not perform, that evenfeels strange to us.
For example, we enter into a carshop and we spend all our money
in buying an extremelyexpensive car.
Well, in this situation, we maynot report these strange things
(04:24):
that happen to us just becausewe fear judgment, because we
feel responsible.
Second, we, as healthcarepractitioners, under-acknowledge
behavioural side effectsbecause medical education taught
us to diagnose and treat onlyorganic conditions, up to the
point that psychosocialconditions are of interest to us
(04:45):
only if they have a tangibleand measurable substrate.
Even mild physiological drugeffects, like a small increase
in blood pressure, are morereadily acknowledged than severe
behavioural changes.
For example, our patient maytake a drug for schizophrenia
and just after that, they maydevelop aggressivity.
In this situation, just becausewe were taught to do that, we
(05:13):
may hurriedly think thatschizophrenia may be enough to
explain this anger, to explainthis episode, and maybe we are
not even thinking about apotential role of the medication
.
To sum up, the reason for solittle talk of behavioural side
effects is that there are bothunder-reporting and
under-acknowledgement.
Federica Santoro (05:30):
And we'll try to dissect those elements a
little more in the rest of theinterview.
We advertised, as usual, theinterview on our social media
channels, and one of ourlisteners cited an example of
how drugs can affect cognition.
She cited tamoxifen, which is adrug normally used to treat
(05:53):
breast cancer, and how it can,on occasion, induce brain fog.
Have you heard about thatreaction?
Michele Fusaroli (06:00):
Indeed, there is evidence that tamoxifen may
be toxic for neural cells andtherefore may result in a loss
of focus and even in memoryimpairment.
Another well-established effectof drugs on cognition and
behaviour is that ofirritability and aggressivity
associated with chronic use ofcorticosteroids.
(06:20):
Well, all drugs have adversedrug reactions, and still we
need their beneficial effect, atleast as long as the underlying
disease is worse than the sideeffects themselves.
Federica Santoro (06:32):
Absolutely.
It's always about weighing thebenefits against the risks.
But you're more of an expert onbehaviour rather than cognition
, as far as I understand, andyou specialise in a particular
kind of behavioural side effectsknown as drug-induced impulse
control disorders.
Now, I know that may sound likea mouthful for our listeners,
(06:53):
but don't worry, we will explainwhat they are.
Let's start with the basics,then.
How do these disorders manifest?
Michele Fusaroli (07:01):
If you have a drug-induced impulse control
disorder, it means that you havea difficulty in resisting the
urges or temptation to behave ina certain way, and this in turn
affects your well-being and mayeven harm people around you.
Four main manifestations, termedas the 'four knights' of
impulsivity, have an apocalypticeffect on the quality of life
(07:24):
of patients and their families.
They are drug-inducedpathological gambling,
hypersexuality, compulsiveshopping, and overeating.
However, impulse controldisorders vary widely and they
can take any form in thespectrum of human behaviours,
and they usually align with thecultural roles, social roles,
(07:46):
and even life experiences of thepatient.
For instance, historically,hypersexuality has been more
prevalent among men andcompulsive shopping among women,
and these conditions aredistributed nowadays a bit more
equally, and this also reflectsa change in our society and in
our culture.
In some Islamic countries,impulsivity may affect some
(08:09):
otherwise completely normalreligious behaviours, such as
resulting in excessive charityor compulsive reading of the
Quran, even many hours per day.
Another example is that ofindividuals with administrative
jobs, who may compulsivelyorganise documents, for example,
and there are also case reportsin the literature that describe
(08:31):
some patients writing poems orlove letters up to 12 hours per
day.
Federica Santoro (08:37):
So I guess the manifestation varies depending
on who you are and what younormally like to do or what kind
of activities you're drawn to.
Michele Fusaroli (08:45):
Exactly.
Federica Santoro (08:46):
What drugs are more likely to cause these
types of disorders, and is itknown why?
Michele Fusaroli (08:53):
There are two drug classes with an established
role in increasing impulsivity: dopamine agonists, which are (08:55):
undefined
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 candirectly enhance dopaminergic
(09:16):
activity in the nucleusaccumbens, that is, a region of
the brain involved in bothphysiological motivation and
pathologic addiction.
We also know that they mayswitch off a serotonergic
pathway that normally modulatesdopamine levels in the nucleus
accumbens.
Given these mechanisms'speculations, we may also
(09:38):
imagine that antidepressants andpsychostimulants 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 stillhave much research to do in
front of us to really understandthem.
Federica Santoro (09:58):
What about frequency?
So, how often do these sideeffects manifest with these
drugs?
Michele Fusaroli (10:07):
Exact frequencies are unknown.
This is also because of lack ofa clear definition of when
impulsivity becomes a disorderand also because there is an
extremely heterogeneous time toonset.
We can have impulsivity days ormonths or even years after the
first administration of themedication.
For this reason, estimatesrange from 2 to 60% in different
(10:32):
study designs with differentimpulsivity definitions.
A plausible estimate is thataround 50% of patients taking
dopamine agonists developimpulse control disorders within
five years.
For third-generationantipsychotics instead, the
frequency is even less clear.
(10:52):
There is some idea, someevidence that supports an even
higher risk relative to dopamineagonists, but these may also be
distorted by the fact that itseems that third-generation
antipsychotics may causeimpulsivity in just days or
weeks.
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 arepre-existing depression and
impulsivity traits, for example,if someone has novelty-seeking
personality, or it is morecommon for males, for young
people, or for people that had ahistory of alcoholism, of
smoking, or even excessivecoffee consumption.
(11:34):
Other possible risk factors forimpulsivity are higher doses of
dopamine agonists and alsocertain genetic factors may play
a role.
Federica Santoro (11:45):
From everything you've said, it can't
be easy to live with an impulsecontrol disorder, and you've
mentioned a few examples, butcan you help us understand
exactly how patients areimpacted.
Like, to what extent do thesedisorders affect quality of life
?
Michele Fusaroli (12:02):
The impact of impulse control disorders varies
greatly depending on theirexpression and severity.
Mind that the impact ofimpulsivity may not always be
negative, it may also bepositive.
In fact, individuals withParkinson's disease usually have
lower levels of dopamine in thenucleus accumbens and therefore
(12:22):
also lower motivation.
And when they start gettingdopamine agonists we sort of
normalise their dopamine levelsin the nucleus accumbens, we
boost motivation and creativity.
And what the patientsexperience in the first months
of dopamine agonist treatment isan actual honeymoon period in
which they start again gettinginvolved in activities, in which
(12:46):
they even develop new hobbies.
However, problems arise whenimpulsivity gets out of control.
In this situation, thepathologic behaviours consume
the entire life of theindividual and it can have a
serious impact on the financialstability, on the social
relationships, on the employmentof the individual.
(13:07):
It can even cause legal issues.
Moreover, there are alsoexpressions that are more
specific to the behaviour.
Pathological gambling andcompulsive shopping, for example
, result more often in higherloss of money and therefore can
have more problem in financialstability and in the social
relationships.
Hypersexuality, instead, isusually associated with marital
(13:30):
problems, with sexuallytransmitted diseases, depending
on the age also in unintendedpregnancy and sexual dysfunction
.
Overeating instead can lead toobesity, metabolic syndrome,
sleep apnoea.
And we don't have to think thatother behaviours that are not
among these four have no impacton the quality of life.
(13:51):
For example, even a seeminglyharmless compulsive gardening
may cause excessive expenditureof money and may result in the
patient staying outside in thegarden 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 beginwith.
Something to keep in mind.
Let's move on to the diagnosisnow, which I imagine must be
really challenging, not leastbecause of what you said earlier
, that it can be reallydifficult to distinguish
(14:28):
compulsive actions from normalones.
I mean, behaviour, even in anormal situation, occurs on a
spectrum, so how do you tellwhat's normal from pathological?
So, if we go back in time, canyou tell me how these disorders
were identified in the firstplace?
Michele Fusaroli (14:46):
I think the first time was in 2003, when
Driver- Dunckley and colleaguesfrom the Barrow Neurological
Institute in Phoenix published astudy, a case series, with nine
cases of pathological gamblingthat developed after taking
dopamine agonists.
What raised a concern and asuspicion of adverse drug
(15:06):
reaction was not the time toonset, because the average was
around 20 months.
It wasn't even the frequency,because it wasn't really
significantly higher than whatexpected based on the entire
population.
What raised a concern was theseriousness of the event.
These patients started gamblingwithout any control.
(15:28):
They started losing more andmore money and even one patient
committed suicide after anextremely severe episode of
gambling.
Interestingly, reducing thedose or switching to alternative
medication showed promise inmitigating this condition and
also, as we said before,subsequent research highlighted
(15:49):
that there is an extremedifference between the low
motivational drive that isimplicit in Parkinson's disease
and the extreme motivationaldrive that we observe when
patients take dopamine agonists.
Federica Santoro (16:03):
And what about the other class of drugs you
mentioned at the beginning, sothese third- generation
antipsychotics?
Was it even trickier toassociate abnormal behaviours to
those types of drugs, sincethey are used in conditions like
psychosis or bipolar disorderthat are already marked by
(16:25):
impulsivity?
How did it work out for thosedrugs?
Michele Fusaroli (16:29):
Yeah, it was more challenging.
In fact, third-generationantipsychotics- induced
impulsivity may be consideredthat sort of 'black swan' that
François Montastruc spoke aboutin the last episode: therefore,
an event, a reaction that iscompletely unexpected and also
particularly serious.
Healthcare providers initiallyblamed the disease and not the
(16:53):
drug.
For example, they attributedthe impulsivity episode to
schizophrenia or to a bipolardisease.
Consequently, when in 2014 adisproportionality analysis on
the FDA adverse event reportingsystem found a signal of
potential adverse drug reactionbetween aripiprazole and impulse
(17:14):
control disorders, most of thereports were from patients, not
from doctors.
Doctors, in fact, started toreport only after 2016, when an
FDA warning came out.
The key factor aiding in thedetection of this signal was the
patient's experience, just afew days after taking the first
(17:36):
dose of aripiprazole, of anextreme loss of control.
Also, behaviours that they mayhave shown before the first
administration of the drug, forexample, they are patients that
may be more susceptible togambling and to compulsive
shopping and hypersexualitybecause of the underlying
disease, started spiralling downand they completely resolved
(18:01):
after the discontinuation of thedrug.
I think that the journey ofdiscovery of impulse control
disorders induced by third-generation antipsychotics has an
important message for us.
That is to listen to thepatients.
Patients should be acknowledgedas the main expert of their
disease, of their experience ofdisease, and they should be
(18:25):
actively involved as primarystakeholders in clinical
practice, but also in signaldetection and signal refinement.
Federica Santoro (18:35):
And that message truly resonates with us.
We have at least two episodesin the archives on patient
engagement and patient voices inpharmacovigilance, but you
raise so many important points.
It's also so fascinating tohear what sparks that initial
suspicion.
I think that's what makes thejob of pharmacovigilance
(18:56):
professionals so interesting.
So, we've looked at the pastand how these conditions were
first identified.
Back to present day (19:05):
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 byRita Baião, you know that
diagnosis in medicine is usuallybased on well-defined
diagnostic criteria, and theproblem here is that we really
don't have those diagnosticcriteria.
There are some scales that canbe used to diagnose and stage
(19:36):
impulsivity in Parkinson'sdisease, like QUIP and Ardouin,
but they have extremelywell-recognised limitations.
For example, they consider onlya few possible behaviours as
manifestation.
They don't include, for example, kleptomania that may be one of
the manifestations ofdrug-induced impulsivity.
(19:57):
Timely diagnosis shouldtherefore rely on two main
factors.
The first is education ofpatients and their caregivers on
what is the risk of impulsecontrol disorder, how they
manifest, and even their impacton quality of life.
Second, a timely diagnosis alsohas to rely on frequent
(20:19):
interviews with both the patientand the caregiver, because the
patient may sometimes be shy oreven reluctant to report
something because they feelashamed.
Federica Santoro (20:32):
Of course.
So that's a really importantmessage for patients, their
carers, and healthcareprofessionals.
Be vigilant and raise an alarmif you have a suspicion that
there might be something at playhere.
We've talked about then thediagnosis, complicated as it may
be.
Once that has been made, whatstrategies can doctors or
(20:54):
patients themselves adopt todeal with such behaviours and
potentially counteract them?
Michele Fusaroli (21:01):
As soon as there is an even mild impairment
of the biopsychosocial functionof the patient or the
caregivers, that is the timewhen an intervention is needed,
before any severe or evenirreversible deterioration of
quality of life happens, such asthose related with loss of
employment, divorce, or legalissues.
(21:22):
There isn't abundant evidenceon how to manage these
conditions.
Here at UMC, I am usingindividual case safety reports
to try to map how people arealready managing these reactions
in the real world, to identifysome pitfalls and some good
practices.
Discontinuing the drug maysuffice for third-generation
(21:45):
antipsychotics.
For dopamine agonists it ismore challenging.
A year after discontinuation,still 50% of the patients hasn't
resolved.
A consensus group for managingimpulsivity in Parkinson's
disorders recently published anexpert opinion-based guideline.
They recognize the pivotal roleof involved caregivers and of
(22:08):
psychosocial interventions.
For example, for pathologicalgambling and compulsive shopping
, it may be extremely useful torestrict access to credit cards
and to casinos and shops.
For example, it can also beuseful to restrict access to the
internet, since many of thesebehaviours are enacted also
online today, both gambling,compulsive shopping,
(22:29):
hypersexuality, and so on.
Sometimes it may also benecessary to seek legal support
or even social support.
Concerning the pharmaceuticalmanagement instead, these
experts could only agree on theneed for closely monitoring and
tapering down dopamine agonistsat the first sign of impairment.
In fact, cautiously, becausethere are some risks of
(22:52):
withdrawal syndrome, of along-term apathy and of
worsening of the motor symptomsof 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 thatreceived more than 50% agreement
(23:14):
in this expert opinion.
That is still low as anagreement, but they are, for
example, cognitive behaviouraltherapy, they are quetiapine,
clozapine, or even deep brainstimulation that consists in
surgically placing someelectrodes in the brain to
modulate its activity.
Federica Santoro (23:34):
So, it is complicated, but there are ways
to alleviate these conditionsand I guess the general advice,
as with any side effect, justnever stop taking the drug
unless you consult yourphysician, right?
There's a reason why you'vebeen put on it in the first
place.
Back to our social mediaquestions.
(23:55):
We have another query that camein from one of our listeners.
Sudarshan in India askedsomething that is related to one
of the projects you are workingon here at UMC.
He asks, how doespharmacovigilance work in these
complicated scenarios?
As we've said, it's not alwayseasy to differentiate the
(24:18):
adverse event from theunderlying disease.
So, can you tell us, as apharmacovigilance professional,
how do you think whenapproaching both the
identification but also theassessment of reports in these
conditions?
Michele Fusaroli (24:33):
At the UMC, I am now investigating
methylphenidate-relatedimpulsivity.
Methylphenidate is apsychostimulant drug that is
used in ADHD to treatinattention and impulsivity, but
its effects seem to bedependent on the baseline
condition, for example, ofneurotransmitter of the patient.
There is some evidence that, insome cases, methylphenidate may
(24:56):
aggravate or even causeimpulsivity, and this is a
'black swan', even more thanantipsychotics.
A drug used to treat acondition that, in certain
situations, may cause it.
How to deal with such adifficult situation?
Well, the first thing we needto do is to make sure that the
reports we are looking at areactually of a suspected adverse
(25:18):
drug reaction.
We may also have, sometimes, areport, for example, of
inefficacy (25:22):
that is, the drug was taken to treat impulsivity
but it didn't work and thereforeimpulsivity is still there.
Another report that we mayobserve is a resurgence of
impulsivity because of a drugshortage.
Therefore, like in theapothecary there wasn't any more
methylphenidate, the patientstopped to take it and
(25:45):
impulsivity came back.
And narratives, when available,are extremely useful to
differentiate between thesedifferent kinds of reports.
When we have identified reportsof suspected
methylphenidate-inducedimpulsivity, then we can apply
the usual causal indicators thatwe use in causality assessment.
(26:06):
For example, we can look intothe temporal relationship, into
the exclusion of alternativecauses.
Yes, we know that there isalways ADHD there as an
underlying possible cause.
We can look at the relationwith the dose, at the challenge
and re-challenge.
So, what happened when westopped the drug and we
administered again the drug?
(26:26):
And, particularly important, aswe have learned from the case
of impulse control disorder, wecan also look into the
experience of the patient, thatsomething happened, that
something is different frombefore.
Federica Santoro (26:46):
This is such a complicated topic.
I think we've described so manyaspects of it as challenging
and difficult to approach.
So, if you were to wrap up onan encouraging note, what would
you say to patients who aredealing with such difficult
conditions, or to healthcare andpharmacovigilance staff who are
trying to help those patients?
Michele Fusaroli (27:04):
I often draw parallels between drug-induced
impulse control disorders andHerman Melville's "Moby Dick".
At first, the great white whaleserves as a driving force, even
a purpose, for Captain Ahab.
It is something positive thatgives meaning to their life.
Yet it evolves into anoverwhelming obsession, a
compulsion that ultimately dragsAhab into the depths of the sea
(27:27):
.
Similarly, impulsivity maystart innocently and may even be
positive, as we said for thehoneymoon period in Parkinson's
disease, but it can alsoescalate into a serious issue.
Recognising when we are losingcontrol and seeking help is
therefore crucial.
We have to remember that adiagnosis is not a conviction.
(27:50):
It is not a stigmatising label.
A diagnosis is instead a toolto identify and address some
needs that we have.
To regain control, we must leanon the people that surround us.
Caregiver involvement is stillthe best predictor of recovery
from dopamine agonist-inducedimpulsivity.
(28:11):
The message is that we don'thave to face these battles alone
.
By relying on our loved ones,we can receive the treatment
that we actually need whilekeeping control of our impulses.
We can together navigate thedepths while keeping our vessel
steady and avoid being draggedinto 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 thatsomething's wrong, do talk with
your loved ones or yourhealthcare professional.
Well, thank you very much fortaking the time to come on the
show.
Thanks.
(29:07):
That's all for now, but we'll beback soon with more
conversations on medicinessafety.
If you'd like to know moreabout drug-induced impulsivity
and Michele's research, checkout the episode show notes for
useful links.
If you like our podcast,subscribe to it in your
favourite player so you won'tmiss an episode, and spread the
word on social media so otherlisteners can find us.
(29:27):
Apart from these in-depthconversations with experts, we
host a series called UppsalaReports Long Reads, a selection
of audio stories from UMC'spharmacovigilance news site, so
do check that out, too.
Uppsala Monitoring Centre is onFacebook, LinkedIn and X, and
(29:49):
we'd love to hear from you.
Send us comments or suggestionsfor the show or send in
questions for our guests nexttime we open up for that.
For Drug Safety Matters, I'mFederica Santoro.
I'd like to thank MicheleFusaroli for his time, our
listeners Nur Azra and Sudarshanfor submitting questions,
(30:12):
Matthew Barwick for productionsupport, and of course you for
tuning in.
Till next time.
Aside from our body, medicines can affect our
mind, too.
That's how drugs likeantidepressants or sedatives
work, after all.
But what happens when thoseeffects on our behaviour are
unwanted?
When the medicines we take tokeep our health in check alter
our personality in odd ordangerous ways?
(00:40):
My name is Federica Santoro, andthis is Drug Safety Matters, a
podcast by Uppsala MonitoringCentre, where we explore current
issues in pharmacovigilance andpatient safety.
Joining me today is MicheleFusaroli, medical doctor and
pharmacovigilance scientist fromthe University of Bologna in
(01:02):
Italy.
Michele is fascinated by thearea of research where medicine
and behavioural science overlap,so it's no surprise that he
chose to focus his PhD studieson behavioural effects of drugs
and specifically on impulsivity.
He is currently visiting UMCfor a research collaboration and
(01:26):
as he's also a big fan of thispodcast, I just had to invite
him to the studio for a chat.
He explained how impulsivitymanifests, which drugs cause it,
how to cope with it, and muchmore.
I hope you enjoy listening.
Hi, Michele, and welcome toDrug Safety Matters.
(01:56):
I'm really glad you could maketime for this interview and come
here to talk about yourresearch and behavioural side
effects of drugs.
How are you feeling today?
Michele Fusaroli (02:08):
I'm really good, I'm really excited because
of the opportunity to talk withyou and with the listeners of
Drug Safety Matters about myresearch.
This podcast has been alwaysinvaluable to me because of how
it allows you to access otherworkers' perspective, and I
(02:29):
believe experiences like DrugSafety Matters are vital for
fostering collaboration andallow us to advance
pharmacovigilance together.
Federica Santoro (02:34):
What an endorsement.
Well, I'm really glad to hearthat you found the podcast
useful and I hope listeners willfind that these episodes spark
ideas for collaboration.
So, let's get right into it.
I'm really looking forward tolearning more about behavioural
side effects, because I have thefeeling it's a topic that's not
(02:58):
discussed nearly enough.
Even in everyday life, right,as patients taking medicines, we
tend to think more about howmedicines affect our body, and
not so much our mind andbehaviour.
So, why is that?
Why is there so little talkabout such side effects?
Michele Fusaroli (03:18):
I believe we are still entrenched into
Descartes' body-mind dualism.
Descartes was a 17th centuryFrench philosopher and scientist
that theorised that the bodyand the mind are two separate
entities.
This way of thinking has twoeffects that make behavioural
side effects some sort ofinvisible: under-reporting and
(03:40):
under-acknowledgement.
First, we, as patients,under-report behavioural side
effects due to our reluctance toacknowledge that organic
conditions and exposure tosubstances may influence our
behaviours, our thoughts, ourchoices – those components of
what we define as our identity.
(04:01):
Imagine, after taking amedication for Parkinson's
disease, for example, we performan action that we would
normally not perform, that evenfeels strange to us.
For example, we enter into a carshop and we spend all our money
in buying an extremelyexpensive car.
Well, in this situation, we maynot report these strange things
(04:24):
that happen to us just becausewe fear judgment, because we
feel responsible.
Second, we, as healthcarepractitioners, under-acknowledge
behavioural side effectsbecause medical education taught
us to diagnose and treat onlyorganic conditions, up to the
point that psychosocialconditions are of interest to us
(04:45):
only if they have a tangibleand measurable substrate.
Even mild physiological drugeffects, like a small increase
in blood pressure, are morereadily acknowledged than severe
behavioural changes.
For example, our patient maytake a drug for schizophrenia
and just after that, they maydevelop aggressivity.
In this situation, just becausewe were taught to do that, we
(05:13):
may hurriedly think thatschizophrenia may be enough to
explain this anger, to explainthis episode, and maybe we are
not even thinking about apotential role of the medication
.
To sum up, the reason for solittle talk of behavioural side
effects is that there are bothunder-reporting and
under-acknowledgement.
Federica Santoro (05:30):
And we'll try to dissect those elements a
little more in the rest of theinterview.
We advertised, as usual, theinterview on our social media
channels, and one of ourlisteners cited an example of
how drugs can affect cognition.
She cited tamoxifen, which is adrug normally used to treat
(05:53):
breast cancer, and how it can,on occasion, induce brain fog.
Have you heard about thatreaction?
Michele Fusaroli (06:00):
Indeed, there is evidence that tamoxifen may
be toxic for neural cells andtherefore may result in a loss
of focus and even in memoryimpairment.
Another well-established effectof drugs on cognition and
behaviour is that ofirritability and aggressivity
associated with chronic use ofcorticosteroids.
(06:20):
Well, all drugs have adversedrug reactions, and still we
need their beneficial effect, atleast as long as the underlying
disease is worse than the sideeffects themselves.
Federica Santoro (06:32):
Absolutely.
It's always about weighing thebenefits against the risks.
But you're more of an expert onbehaviour rather than cognition
, as far as I understand, andyou specialise in a particular
kind of behavioural side effectsknown as drug-induced impulse
control disorders.
Now, I know that may sound likea mouthful for our listeners,
(06:53):
but don't worry, we will explainwhat they are.
Let's start with the basics,then.
How do these disorders manifest?
Michele Fusaroli (07:01):
If you have a drug-induced impulse control
disorder, it means that you havea difficulty in resisting the
urges or temptation to behave ina certain way, and this in turn
affects your well-being and mayeven harm people around you.
Four main manifestations, termedas the 'four knights' of
impulsivity, have an apocalypticeffect on the quality of life
(07:24):
of patients and their families.
They are drug-inducedpathological gambling,
hypersexuality, compulsiveshopping, and overeating.
However, impulse controldisorders vary widely and they
can take any form in thespectrum of human behaviours,
and they usually align with thecultural roles, social roles,
(07:46):
and even life experiences of thepatient.
For instance, historically,hypersexuality has been more
prevalent among men andcompulsive shopping among women,
and these conditions aredistributed nowadays a bit more
equally, and this also reflectsa change in our society and in
our culture.
In some Islamic countries,impulsivity may affect some
(08:09):
otherwise completely normalreligious behaviours, such as
resulting in excessive charityor compulsive reading of the
Quran, even many hours per day.
Another example is that ofindividuals with administrative
jobs, who may compulsivelyorganise documents, for example,
and there are also case reportsin the literature that describe
(08:31):
some patients writing poems orlove letters up to 12 hours per
day.
Federica Santoro (08:37):
So I guess the manifestation varies depending
on who you are and what younormally like to do or what kind
of activities you're drawn to.
Michele Fusaroli (08:45):
Exactly.
Federica Santoro (08:46):
What drugs are more likely to cause these
types of disorders, and is itknown why?
Michele Fusaroli (08:53):
There are two drug classes with an established
role in increasing impulsivity: dopamine agonists, which are (08:55):
undefined
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 candirectly enhance dopaminergic
(09:16):
activity in the nucleusaccumbens, that is, a region of
the brain involved in bothphysiological motivation and
pathologic addiction.
We also know that they mayswitch off a serotonergic
pathway that normally modulatesdopamine levels in the nucleus
accumbens.
Given these mechanisms'speculations, we may also
(09:38):
imagine that antidepressants andpsychostimulants 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 stillhave much research to do in
front of us to really understandthem.
Federica Santoro (09:58):
What about frequency?
So, how often do these sideeffects manifest with these
drugs?
Michele Fusaroli (10:07):
Exact frequencies are unknown.
This is also because of lack ofa clear definition of when
impulsivity becomes a disorderand also because there is an
extremely heterogeneous time toonset.
We can have impulsivity days ormonths or even years after the
first administration of themedication.
For this reason, estimatesrange from 2 to 60% in different
(10:32):
study designs with differentimpulsivity definitions.
A plausible estimate is thataround 50% of patients taking
dopamine agonists developimpulse control disorders within
five years.
For third-generationantipsychotics instead, the
frequency is even less clear.
(10:52):
There is some idea, someevidence that supports an even
higher risk relative to dopamineagonists, but these may also be
distorted by the fact that itseems that third-generation
antipsychotics may causeimpulsivity in just days or
weeks.
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 arepre-existing depression and
impulsivity traits, for example,if someone has novelty-seeking
personality, or it is morecommon for males, for young
people, or for people that had ahistory of alcoholism, of
smoking, or even excessivecoffee consumption.
(11:34):
Other possible risk factors forimpulsivity are higher doses of
dopamine agonists and alsocertain genetic factors may play
a role.
Federica Santoro (11:45):
From everything you've said, it can't
be easy to live with an impulsecontrol disorder, and you've
mentioned a few examples, butcan you help us understand
exactly how patients areimpacted.
Like, to what extent do thesedisorders affect quality of life
?
Michele Fusaroli (12:02):
The impact of impulse control disorders varies
greatly depending on theirexpression and severity.
Mind that the impact ofimpulsivity may not always be
negative, it may also bepositive.
In fact, individuals withParkinson's disease usually have
lower levels of dopamine in thenucleus accumbens and therefore
(12:22):
also lower motivation.
And when they start gettingdopamine agonists we sort of
normalise their dopamine levelsin the nucleus accumbens, we
boost motivation and creativity.
And what the patientsexperience in the first months
of dopamine agonist treatment isan actual honeymoon period in
which they start again gettinginvolved in activities, in which
(12:46):
they even develop new hobbies.
However, problems arise whenimpulsivity gets out of control.
In this situation, thepathologic behaviours consume
the entire life of theindividual and it can have a
serious impact on the financialstability, on the social
relationships, on the employmentof the individual.
(13:07):
It can even cause legal issues.
Moreover, there are alsoexpressions that are more
specific to the behaviour.
Pathological gambling andcompulsive shopping, for example
, result more often in higherloss of money and therefore can
have more problem in financialstability and in the social
relationships.
Hypersexuality, instead, isusually associated with marital
(13:30):
problems, with sexuallytransmitted diseases, depending
on the age also in unintendedpregnancy and sexual dysfunction
.
Overeating instead can lead toobesity, metabolic syndrome,
sleep apnoea.
And we don't have to think thatother behaviours that are not
among these four have no impacton the quality of life.
(13:51):
For example, even a seeminglyharmless compulsive gardening
may cause excessive expenditureof money and may result in the
patient staying outside in thegarden 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 beginwith.
Something to keep in mind.
Let's move on to the diagnosisnow, which I imagine must be
really challenging, not leastbecause of what you said earlier
, that it can be reallydifficult to distinguish
(14:28):
compulsive actions from normalones.
I mean, behaviour, even in anormal situation, occurs on a
spectrum, so how do you tellwhat's normal from pathological?
So, if we go back in time, canyou tell me how these disorders
were identified in the firstplace?
Michele Fusaroli (14:46):
I think the first time was in 2003, when
Driver- Dunckley and colleaguesfrom the Barrow Neurological
Institute in Phoenix published astudy, a case series, with nine
cases of pathological gamblingthat developed after taking
dopamine agonists.
What raised a concern and asuspicion of adverse drug
(15:06):
reaction was not the time toonset, because the average was
around 20 months.
It wasn't even the frequency,because it wasn't really
significantly higher than whatexpected based on the entire
population.
What raised a concern was theseriousness of the event.
These patients started gamblingwithout any control.
(15:28):
They started losing more andmore money and even one patient
committed suicide after anextremely severe episode of
gambling.
Interestingly, reducing thedose or switching to alternative
medication showed promise inmitigating this condition and
also, as we said before,subsequent research highlighted
(15:49):
that there is an extremedifference between the low
motivational drive that isimplicit in Parkinson's disease
and the extreme motivationaldrive that we observe when
patients take dopamine agonists.
Federica Santoro (16:03):
And what about the other class of drugs you
mentioned at the beginning, sothese third- generation
antipsychotics?
Was it even trickier toassociate abnormal behaviours to
those types of drugs, sincethey are used in conditions like
psychosis or bipolar disorderthat are already marked by
(16:25):
impulsivity?
How did it work out for thosedrugs?
Michele Fusaroli (16:29):
Yeah, it was more challenging.
In fact, third-generationantipsychotics- induced
impulsivity may be consideredthat sort of 'black swan' that
François Montastruc spoke aboutin the last episode: therefore,
an event, a reaction that iscompletely unexpected and also
particularly serious.
Healthcare providers initiallyblamed the disease and not the
(16:53):
drug.
For example, they attributedthe impulsivity episode to
schizophrenia or to a bipolardisease.
Consequently, when in 2014 adisproportionality analysis on
the FDA adverse event reportingsystem found a signal of
potential adverse drug reactionbetween aripiprazole and impulse
(17:14):
control disorders, most of thereports were from patients, not
from doctors.
Doctors, in fact, started toreport only after 2016, when an
FDA warning came out.
The key factor aiding in thedetection of this signal was the
patient's experience, just afew days after taking the first
(17:36):
dose of aripiprazole, of anextreme loss of control.
Also, behaviours that they mayhave shown before the first
administration of the drug, forexample, they are patients that
may be more susceptible togambling and to compulsive
shopping and hypersexualitybecause of the underlying
disease, started spiralling downand they completely resolved
(18:01):
after the discontinuation of thedrug.
I think that the journey ofdiscovery of impulse control
disorders induced by third-generation antipsychotics has an
important message for us.
That is to listen to thepatients.
Patients should be acknowledgedas the main expert of their
disease, of their experience ofdisease, and they should be
(18:25):
actively involved as primarystakeholders in clinical
practice, but also in signaldetection and signal refinement.
Federica Santoro (18:35):
And that message truly resonates with us.
We have at least two episodesin the archives on patient
engagement and patient voices inpharmacovigilance, but you
raise so many important points.
It's also so fascinating tohear what sparks that initial
suspicion.
I think that's what makes thejob of pharmacovigilance
(18:56):
professionals so interesting.
So, we've looked at the pastand how these conditions were
first identified.
Back to present day (19:05):
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 byRita Baião, you know that
diagnosis in medicine is usuallybased on well-defined
diagnostic criteria, and theproblem here is that we really
don't have those diagnosticcriteria.
There are some scales that canbe used to diagnose and stage
(19:36):
impulsivity in Parkinson'sdisease, like QUIP and Ardouin,
but they have extremelywell-recognised limitations.
For example, they consider onlya few possible behaviours as
manifestation.
They don't include, for example, kleptomania that may be one of
the manifestations ofdrug-induced impulsivity.
(19:57):
Timely diagnosis shouldtherefore rely on two main
factors.
The first is education ofpatients and their caregivers on
what is the risk of impulsecontrol disorder, how they
manifest, and even their impacton quality of life.
Second, a timely diagnosis alsohas to rely on frequent
(20:19):
interviews with both the patientand the caregiver, because the
patient may sometimes be shy oreven reluctant to report
something because they feelashamed.
Federica Santoro (20:32):
Of course.
So that's a really importantmessage for patients, their
carers, and healthcareprofessionals.
Be vigilant and raise an alarmif you have a suspicion that
there might be something at playhere.
We've talked about then thediagnosis, complicated as it may
be.
Once that has been made, whatstrategies can doctors or
(20:54):
patients themselves adopt todeal with such behaviours and
potentially counteract them?
Michele Fusaroli (21:01):
As soon as there is an even mild impairment
of the biopsychosocial functionof the patient or the
caregivers, that is the timewhen an intervention is needed,
before any severe or evenirreversible deterioration of
quality of life happens, such asthose related with loss of
employment, divorce, or legalissues.
(21:22):
There isn't abundant evidenceon how to manage these
conditions.
Here at UMC, I am usingindividual case safety reports
to try to map how people arealready managing these reactions
in the real world, to identifysome pitfalls and some good
practices.
Discontinuing the drug maysuffice for third-generation
(21:45):
antipsychotics.
For dopamine agonists it ismore challenging.
A year after discontinuation,still 50% of the patients hasn't
resolved.
A consensus group for managingimpulsivity in Parkinson's
disorders recently published anexpert opinion-based guideline.
They recognize the pivotal roleof involved caregivers and of
(22:08):
psychosocial interventions.
For example, for pathologicalgambling and compulsive shopping
, it may be extremely useful torestrict access to credit cards
and to casinos and shops.
For example, it can also beuseful to restrict access to the
internet, since many of thesebehaviours are enacted also
online today, both gambling,compulsive shopping,
(22:29):
hypersexuality, and so on.
Sometimes it may also benecessary to seek legal support
or even social support.
Concerning the pharmaceuticalmanagement instead, these
experts could only agree on theneed for closely monitoring and
tapering down dopamine agonistsat the first sign of impairment.
In fact, cautiously, becausethere are some risks of
(22:52):
withdrawal syndrome, of along-term apathy and of
worsening of the motor symptomsof 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 thatreceived more than 50% agreement
(23:14):
in this expert opinion.
That is still low as anagreement, but they are, for
example, cognitive behaviouraltherapy, they are quetiapine,
clozapine, or even deep brainstimulation that consists in
surgically placing someelectrodes in the brain to
modulate its activity.
Federica Santoro (23:34):
So, it is complicated, but there are ways
to alleviate these conditionsand I guess the general advice,
as with any side effect, justnever stop taking the drug
unless you consult yourphysician, right?
There's a reason why you'vebeen put on it in the first
place.
Back to our social mediaquestions.
(23:55):
We have another query that camein from one of our listeners.
Sudarshan in India askedsomething that is related to one
of the projects you are workingon here at UMC.
He asks, how doespharmacovigilance work in these
complicated scenarios?
As we've said, it's not alwayseasy to differentiate the
(24:18):
adverse event from theunderlying disease.
So, can you tell us, as apharmacovigilance professional,
how do you think whenapproaching both the
identification but also theassessment of reports in these
conditions?
Michele Fusaroli (24:33):
At the UMC, I am now investigating
methylphenidate-relatedimpulsivity.
Methylphenidate is apsychostimulant drug that is
used in ADHD to treatinattention and impulsivity, but
its effects seem to bedependent on the baseline
condition, for example, ofneurotransmitter of the patient.
There is some evidence that, insome cases, methylphenidate may
(24:56):
aggravate or even causeimpulsivity, and this is a
'black swan', even more thanantipsychotics.
A drug used to treat acondition that, in certain
situations, may cause it.
How to deal with such adifficult situation?
Well, the first thing we needto do is to make sure that the
reports we are looking at areactually of a suspected adverse
(25:18):
drug reaction.
We may also have, sometimes, areport, for example, of
inefficacy (25:22):
that is, the drug was taken to treat impulsivity
but it didn't work and thereforeimpulsivity is still there.
Another report that we mayobserve is a resurgence of
impulsivity because of a drugshortage.
Therefore, like in theapothecary there wasn't any more
methylphenidate, the patientstopped to take it and
(25:45):
impulsivity came back.
And narratives, when available,are extremely useful to
differentiate between thesedifferent kinds of reports.
When we have identified reportsof suspected
methylphenidate-inducedimpulsivity, then we can apply
the usual causal indicators thatwe use in causality assessment.
(26:06):
For example, we can look intothe temporal relationship, into
the exclusion of alternativecauses.
Yes, we know that there isalways ADHD there as an
underlying possible cause.
We can look at the relationwith the dose, at the challenge
and re-challenge.
So, what happened when westopped the drug and we
administered again the drug?
(26:26):
And, particularly important, aswe have learned from the case
of impulse control disorder, wecan also look into the
experience of the patient, thatsomething happened, that
something is different frombefore.
Federica Santoro (26:46):
This is such a complicated topic.
I think we've described so manyaspects of it as challenging
and difficult to approach.
So, if you were to wrap up onan encouraging note, what would
you say to patients who aredealing with such difficult
conditions, or to healthcare andpharmacovigilance staff who are
trying to help those patients?
Michele Fusaroli (27:04):
I often draw parallels between drug-induced
impulse control disorders andHerman Melville's "Moby Dick".
At first, the great white whaleserves as a driving force, even
a purpose, for Captain Ahab.
It is something positive thatgives meaning to their life.
Yet it evolves into anoverwhelming obsession, a
compulsion that ultimately dragsAhab into the depths of the sea
(27:27):
.
Similarly, impulsivity maystart innocently and may even be
positive, as we said for thehoneymoon period in Parkinson's
disease, but it can alsoescalate into a serious issue.
Recognising when we are losingcontrol and seeking help is
therefore crucial.
We have to remember that adiagnosis is not a conviction.
(27:50):
It is not a stigmatising label.
A diagnosis is instead a toolto identify and address some
needs that we have.
To regain control, we must leanon the people that surround us.
Caregiver involvement is stillthe best predictor of recovery
from dopamine agonist-inducedimpulsivity.
(28:11):
The message is that we don'thave to face these battles alone
.
By relying on our loved ones,we can receive the treatment
that we actually need whilekeeping control of our impulses.
We can together navigate thedepths while keeping our vessel
steady and avoid being draggedinto 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 thatsomething's wrong, do talk with
your loved ones or yourhealthcare professional.
Well, thank you very much fortaking the time to come on the
show.
Thanks.
(29:07):
That's all for now, but we'll beback soon with more
conversations on medicinessafety.
If you'd like to know moreabout drug-induced impulsivity
and Michele's research, checkout the episode show notes for
useful links.
If you like our podcast,subscribe to it in your
favourite player so you won'tmiss an episode, and spread the
word on social media so otherlisteners can find us.
(29:27):
Apart from these in-depthconversations with experts, we
host a series called UppsalaReports Long Reads, a selection
of audio stories from UMC'spharmacovigilance news site, so
do check that out, too.
Uppsala Monitoring Centre is onFacebook, LinkedIn and X, and
(29:49):
we'd love to hear from you.
Send us comments or suggestionsfor the show or send in
questions for our guests nexttime we open up for that.
For Drug Safety Matters, I'mFederica Santoro.
I'd like to thank MicheleFusaroli for his time, our
listeners Nur Azra and Sudarshanfor submitting questions,
(30:12):
Matthew Barwick for productionsupport, and of course you for
tuning in.
Till next time.
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