c


  cc 

m
 
      

  
        

 m m


Adverse drug reactions were found to be the fifth leading cause of death globally. 13 % of
the patients suffered adverse drug reaction in UK, 17 % in Canada and 20% in Australia
and US in 2009 and it costs NHS £ 2 billion for 1,040,000 patients. Commonly affect people
with adverse drug reactions are those who have been prescribed wrong medicine by their
GPǯs or those who have responded adversely to the medicine. Most of the adverse drug
reactions are predictable. Children and old aged are prone to the risk of the adverse drug
reaction.

Some of the methods used to detect ADRs are anecdotal reporting, spontaneous reporting,
voluntary reporting, post-marketing surveillance. The limitation of animal experiments in
predicting the human safety and limitation of clinical trials makes pharmacovigilance
essential. Pharmacovigilance measures the risk, effectiveness of the drugs, evaluates the
benefit and risk and detects the adverse reactions. It acts as an early warning system and
ensures patient care and safety.

 Pharmacovigilance, Adverse Drug Reactions, Antidepressants, SSRIǯs

_____________________________________________________________________________

m Tricyclic antidepressants (TCAs) E.g.

Amitriptyline, Lofepramine etc.
  
!
Antidepressants are a class of drugs commonly
used in psychiatric conditions to treat mood
related symptoms like dysthymia, depression
etc. Antidepressants were discovered by two
physicians, Irving Selikoff and Edward
Robitzek who were conducting clinical trials
on two anti-tuberculosis agents
(isoniazid and iproniazid) for Hoffman-
LaRoche. They found during the trial that anti-
TB agent under trial also has mood alleviating
properties and lead to the discovery of two
class of 1st generation antidepressants.
Monoamine oxidase inhibitors (MAOIs) Ȃe.g.
Phenelzine, isocarboxazid etc.
Both TCAs and MAOIs were effective in
treating depression conditions but were cause
of several adverse effects.
SSRIǯs were 2nd generation antidepressants
and developed to overcome the adverse effects
of 1st generation antidepressants.
SSRIǯs are used to treat depression, anxiety
disorders and personality disorders. SSRIǯs act
by increasing the level of neurotransmitter
serotonin by blocking the reuptake of
c




serotonin thus more amount of serotonin will
bind to post synaptic cell.
e.g citalopram, fluoxetine, paroxetine.
Adverse effects of SSRIǯs are numerous some
of which are abnormal thoughts, anxiety,
agitation, blurred or changes in vision,
confusion, delusion, forgetfulness,
hallucination, impotence, mania, paranoia,
restlessness, seizures, suicidal thoughts,
twitching, withdrawal symptoms.(CHR
Int,2009)
SSRIs were less toxic than conventional
tricyclic drugs in overdose.
 cc 
(Hypersensitivity), Citalopram causes
alopecia(Aronson & Ferner, 2000).
#
 " It is dose and time dependent
reactions (Chronic). These are rare reactions
and accumulation of drug occurs in the body
over time. E.g. hypothalamic-pituitary-adrenal
axis suppression by corticosteroids (Aronson
& Ferner, 2000).
#
  It is time dependent reaction
(Delayed). This reaction is extremely rare and
related to the dose administered. There exists
a time gap between the administration of the
drugs and the reaction to occur. E.g.
Teratogenesis, Carcinogenesis, Tardive
  
  ! dyskinesia with neuroleptics (Aronson &
Any undesirable effect which could be linked
directly to a drug and is harmful for the patient
occurring at normally administered doses is
called as adverse drug reaction. Undesirable
effects may include any abnormal symptom or
lab test (WHO guidelines, 2009).
An adverse drug experience cannot be termed
as adverse drug reaction until it is directly
linked to a drug and is harmful to the patient
else itǯs just an adverse drug experience which
is coincidental with the drug intake.
"
 

   due to drug-drug interactions. E.g. dose of oral
#
  It is dose related (Augmented). Quite
common, predictable. Associated with the
pharmacological effect of the drugs and is non
fatal. E.g. Digoxin toxicity, Paroxetine
withdrawal reactions (Aronson & Ferner,
2000).
#
 $ It is non dose related (Bizarre). These
are very rare and cannot be predicted. No
association with the pharmacological effect of
the drug and is fatal. E.g. immune reactions
Ferner, 2003).
#
 % It is the withdrawal type reactions
(end of use). This reaction is rare and occurs
soon after use of a particular drug is stopped.
E.g. SSRIǯs withdrawal symptoms, Paroxetine
when stopped slowly over time leads to
reappearance of the symptoms and prominent
insomnia, bad dreams and restlessness.
(Aronson & Ferner, 2003).
#
 & It is the unexpected failure of therapy.
This type of reaction is common and is
associated with the administered dose and is
contraceptives have to be increased when
administered with enzyme inducing drugs
(Aronson & Edward, 2000).
ADRǯs are caused by prescribing wrong
medicines or high doses to the patients by
their GPǯs or due to polypharmacy (which can
cause drug Ȃ drug interaction). Elderly people
are more susceptible to drug Ȃdrug
interactions as they are on many medications
due to a number of health conditions they are
suffering from.
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  cc 

Methods and processes have been developed
to protect the society by early detection and
reporting, valid verification and quantification
of adverse drug reactions which includes
anecdotal reporting, voluntary reporting by
yellow card scheme, post marketing
epidemiological (surveillance) studies, in silico
search methods.
m
 
| Sometimes during the studies
confounding factors are not taken into
account which leads to erroneous
interpretation.
Number of new drugs entering the market
has increased over the decade and amount
of clinical and pre-clinical data is not
sufficient to establish the complete safety
 
 of the drug. The limitation of animal
experiments in predicting the human
WHO defines pharmacovigilance as DzThe
safety and limitation of clinical trials makes
science and actions taken to detect, assess,
pharmacovigilance essential.
understand and prevent adverse effects of
drugsdz (WHO, 2002). Pharmacovigilance measures the risk,
effectiveness of the drugs, evaluates the
Before a drug is approved for clinical trials on
benefit and risk and detects the adverse
humans, drugs has to show safety and efficacy
reactions (Meyboom, 2002). It acts as an
in animals but the competitive culture in
early warning system and ensures patient
pharmaceutical world has made companies to
care and safety and will in turn increase
be more concerned with efficacy rather than
public health.
safety.
 
Once safety and efficacy has been proved in
humans drug is marketed. But there are few
limitations of clinical trials.
 
| Clinical trials are conducted on relative
healthy patients and often elderly,
pregnant women and children are
excluded and volunteers are selected
following criteria.
| Sample size is relatively small limiting
chances to detect rare ADRǯs and the
results obtained from these studies are
applied to general population. (WHO
guidelines, 2009).
| Often clinical trials are conducted for a
short duration which limits the chances
of detecting long term consequences
such as carcinogenesis and are detected
during post marketing surveillance
(WHO guidelines,2009).

 
Y    

3 
  

It is the record of personal experiences by
patient or by doctor during the treatment. It is
different from data obtained from any
scientific analysis (Aronson & Edward, 2000).
3
 
 
This system is used to generate signal for ADR
and used to detect previously undetected
ADRǯs. This system relies on the discretion of
the physician, who decides whether the
adverse event is associated with the drug. Each
case reported is analyzed carefully, coded,
documented and is followed over time.
'()*Y" 
c




WHO-UMC defines signal for ADR as Dzreported
information on possible casual relationship
between an adverse event and a drug, the
relationship being unknown or incompletely
documented previouslydz (Edwards, Biriell
1994).
Signals are generated on the basis of two or
more reports. A signal comprises of data for
which hypothesis is generated and tested and
arguments, in favour of relationship or against
the relationship are made (Meyboom, 2002).
Signal is generated when data shows
possibility of relevance, then signal is
strengthened by assessing the evidence and
reaches maximum where the followed up is
done using literature search, WHO-UMC
international database, experimental data
from pharmacology, immunology (Meyboom
2002).
Plot of signal development showing relation
between time and knowledge of adverse effect.
See figure 1.
& + 

 Y ,-..- delivery system, new route of administration,
3/  0 
 substances in combination with other active
It is the responsibility of doctors, dentists,
carers, pharmacists, nurses, pharmaceutical
companies and all health care professionals to
 cc 
report any suspected case of adverse drug
reaction to Medicines and Healthcare products
Regulatory Agency (MHRA), even when it is a
well known adverse drug reaction or when its
is uncertain or unknown (British national
formulary, 2009).
Y 
ADRǯs could be reported using either
electronic form of yellow card or by reporting
at regional monitoring centers (Aronson &
Edward, 2000). National adverse drug
reactions monitoring centres and International
drug monitoring centres are a part of yellow
card reporting system.
Anyone (patient, physician, nurse or
pharmacist) can report about the ADRǯs using
yellow card. Information regarding the
reaction and their diagnosis is sent to National
centers which shares the information with the
WHO worldwide database for International
drug monitoring (Aronson & Edward, 2000).
In addition to yellow card method of ADR
reporting green form are used by Drug safety
and research unit to monitor the safety of the
drugs (British national formulary, 2009).
Patientǯs prescribed with selected new drugs
are identified and they are monitored (drug
safety and research unit, 2009). But the
submission of clinical data is not obligatory on
the part of general practitioner (drug safety
and research unit, 2009).
The newly licensed drugs which have new
contains new active substances, active
substance or drug which indicate altered risk
to benefit ratio are closely monitored by
MHRA and are denoted by black triangle ( )
(British national formulary, 2009). The
c




product bears the black triangle until the
safety data has been reviewed (British national
formulary, 2009).
MHRA urges all the healthcare professionals to
spontaneously report all the suspected
reaction by yellow cards associated with the
medical products bearing black triangle, even
 cc 
data from morbidity and mortality databases,
longitudinal patient databases and from
spontaneous reporting (WHO
guidelines,2009).
Epidemiological studies include cohort studies,
case control and case-cohort studies.
when they are not serious or occurring when
other drug is administered at the same time
(British national formulary, 2009).
" - Sample population is selected
which include 2 subset of population. One
contains exposed patients and other subset
includes unexposed patients, the two subsets
are compared from time to time see the
  difference in the results (NARANJO, et
al.,1982).
Medical literature is searched through for the
E.g. Cohort study was conducted to evaluate
cases of ADRǯs published in journals. the possible association between MMR vaccine
Literature search is very effective for detection and autism.
of ADRǯs and often cases are peer reviewed
and can be very useful in detecting rare ADRǯs "  ) sample population
(Tubert, Begaud u
 1992). contains people with disease and people
without disease and they are compared to see
3  
  the difference in previous medical exposure
Post marketing surveillance is important as it (NARANJO, et al.,1982). E.g. Case-control
can detect the ADRǯs which went undetected in studies confirmed the association between
clinical trials. Reyeǯs syndrome and Aspirin.

At MHRA, team of scientist and researchers

which includes physicians detect signals
(report which links a reaction to drug which
was unrecognized before) and evaluate the
association between drugs and reported
reaction. They analyze and determine the risk
leading to ADR on the basis of data collected.
After the risk factor is determined the CHM
and Pharmacovigilance expert advisory group
gives suggestions to the MHRA regarding the
safety profile of the drug (WHO
guidelines,2009). MHRA can introduce
restriction or issue special warnings or
withdraw the drug depending on the risk
associated with the drug.
In post marketing surveillance, data is
obtained from clinical studies, epidemiological
studies, data from pharmaceutical companies,
3$ 1 1 
 
WHO has setup worldǯs largest database at
Uppsala, Sweden. It is gets the ADR data from
47 countries, which are a part of WHO
programme for international drug monitoring.
Database has more than 2 million reports and
after each quarter additional 35,000 reports
are added. For the analysis of such a huge
database and eradicate the chance of false
reporting a special system was developed
known as Bayesian confidence propagation
neural network (BCPNN). This system takes
into account other variables and perfect for
finding ADRǯs linked to drug and can deal with
incomplete information (Bate, Lindquist u

c


  cc 

1998). BCPNN analyzes the large number of association of liver toxicity with nefazodone
ADRǯs reported through spontaneous reports. (Public citizen petition, 2003).

   
m In 1999, Spanish Pharmacovigilance database
m      system warned against the high incidence
rates of hepatotoxicity associated with
A cohort osteoporotic fracture in men study nefazodone (Public citizen petition, 2003).
was done in 6000 men of age 65 years to
establish a link between bone mineral density In 2001, Canadian Adverse Event Drug
and use of SSRIs (Culley u
.,2007). Reaction Monitoring Programme after
It was found out from the study that there analyzing a number of adverse event reports
exists a direct relationship between bone found that nefazodone was responsible for
density and use of SSRIs and it was revealed liver toxicity, hepatitis and necrosis in various
that use of SSRIs is associated with low bone
cases (Public citizen petition, 2003).
mineral density (Culley u
.,2007).
 
2  Ultimately in Jan 2001 nefazodone was
withdrawn from market after Swedish medical
imeldine was an SSRI used to treat unipolar
products agency made monitoring of liver
and bipolar depression. It was withdrawn
from the market in 1983 because of high enzyme mandatory.
incidence of hypersensitivity reactions with
 

 , 
 
fever, myalgia and polyradiculitis (Liljeqvist,
Edvardsson, 1989). 


Study done by Liljeqvist and Edvardsson
describes high number of probable side effects
being reported and in some patients
cardiovascular effects were produced due to
overdose abnormalities reported were sinus
tachycardia, ST-T changes and increase in QRS
width (Liljeqvist , Edvardsson, 1989).
Drug interaction between cytochrome P450
and SSRIs came into light when risk of cardiac
arrhythmias increased and was linked
to drug-drug interaction (Brown, 2008).
Studies published revealed that terfenadine
interacts enzymatically with ketoconazole
 
1
0 (Brown, 2008). As ketoconazole is inhibitor of
Cyp enzymes metabolism of terfenadine is also
Nefazodone was a weak SSRI and was used to
inhibited (Brown, 2008).
treat depression worldwide. It was withdrawn
in 2003 as a result of high incidence of liver As antidepressants requires duration
toxicity (Public citizen petition, 2003). treatment so the probability of concomitant
use of other drugs is very high, as a result
Analysis of adverse events reports by FDA
terfenadine later mibefradil and cisapride
revealed that there were 53 cases if liver
were withdrawn from the market due their
injury and many other cases of liver failure and
high potential of inhibition of CYP enzymes
several cases of death also (Public citizen
and ability to cause cardiac
petition, 2003).
arrhythmia(Brown, 2008).
Medical reports published in journals in
"
Australia in 1998 reported cases of jaundice
and drug induced hepatitis and showed the
c




Post marketing surveillance is very important
in reporting unknown and rare ADRs.
Spontaneous reporting system no information
about the rate of reaction but is very efficient
in generation of hypothesis and providing
early warnings.
The systems available are efficient but the
success of these systems relies on proper
utilization and awareness. References-
| A report by the citizens commission on
human rights International, 2009

| Aronson, J.K., Ferner, R.I. (2003). 


aol 327. 1222-1225.


| Bate, A., u
 (1998). Bayesian neural
network method for adverse drug
reaction signal generation. European
journal of clinical pharmacology. aol 54.
315-321.

| British national formulary [available
online]
http://bnf.org/bnf/bnf/current/29432.
htm?=dzadversedz dzreactionsdz
dztodzdzdrugsdz#hit [accessed on 25th Feb
2010]
| Brown, C.H. (2008). Overview of drug-
drug interaction with SSRIs. j


aol 33(1). HS-3-HS-19.
| Culley, C. u
(2007).Reporting on
Adverse Clinical Events: aolume 45,
Number 16.
| Edwards, I.R, Biriell, C. (1994) Drug
safety. aol 10. 93- 102.
| Liljeqvist, J. A., Edvardsson, N. (1989).
Torsade de Pointes tachycardia
induced by overdose of zimeldine.
Journal of Cardiovascular
Pharmacology. aol 14. 666-670.
| Meyboom, R.H.B.,( 2002). Data
assessment in pharamacovigilance
 cc 
[available online]
http://www.scribd.com/doc/1781915
8/Pharmacovigilance-Basics [accessed
on 25 Feb 2010]

| Naranjo, C.A., Usoabusto, U., Sellers,
E.M. (1982). Difficulties in assessing the
adverse drug reactions in clinical trails.
Prog Neuro. Psychopharmacol & Biol.
aol 6. 651-665.
| NHS UK , 2010 [available online]
http://www.nhs.uk/conditions/antide
pressant-
drugs/Pages/Introduction.aspx
[accessed on 15 Feb 2010]
| Public citizen petition, 2003 [available
online]
http://www.socialaudit.org.uk/4200H
RG.htm [accessed on 25th Feb 2010]
| Royal College of Psychiatrists,2009 [
available online]
http://www.rcpsych.ac.uk/mentalhealt
hinfoforall/problems/depression/antid
epressants.aspx [ accessed on 15 Feb
2010]
| Stricker, B.H., Psaty, B.M. (2004).
Detection, verification and
quantification of adverse drug
reactions.

. aol 329. 44-47

| WHO guidelines on the safety of
medicine [online]. Available from:
http://whqlibdoc.who.int/hq/2002/W
HO_EDM_QSM_2002.2.pdf [accessed 10
Dec 2009]