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Mohammadi, Akhondzadeh, Fadaei et al
126
Iranian J Psychiatry 4:4, Fall 2009
Selegiline in Comparison with Methylphenidate in Treatment
of Adults with Attention Deficit Hyperactivity Disorder:
A Double-blind, Randomized Trial
Mohammad
Mohammadi, MD
1, 2
Shahin Akhondzadeh, PhD
2
Farbod Fadai, MD
1, 3
Mohammad Reza Mohammadi, MD
2
1 Islamic Azad University, Medical
Sciences Branch of Tehran,
Tehran, Iran
2 Psychiatry & Psychology
Research Center, Roozbeh
Hospital, Tehran University of
Medical Sciences, Tehran, Iran
3 University of Social Welfare
and Rehabilitation Sciences, Razi
Hospital Tehran, Iran
Corresponding author:
Mohammad Mohammadi,
Psychiatric Research Center,
Tehran University of Medical
Sciences, Roozbeh Hospital,
South Kargar Ave. 1333 795914
Tehran, Iran
Tel:+98-21-55413540
Fax:+98-21-55421959
E-mail:
dr.m.mohamadii@gmail.com
Objective: Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most
common mental disorders in childhood and it continues to adulthood without
proper treatment. Stimulants have been used in treatment of ADHD for many
years and the efficacy of methylphenidate (MPH) in the treatment of adults
with ADHD has been proven to be acceptable according to meta-analysis
studies. However, there are some concerns about stimulants. Finding other
effective medications for the treatment of adult ADHD seems necessary. We
tried a monoamine oxidase inhibitor, Selegiline, as there are some theoretical
and experimental evidences for the efficacy of this medication .
Method: Forty patients were randomized to receive Selegiline or
methylphenidate in an equal ratio for an 8-week double-blind clinical trial.
Each patient filled the CAARS self report screening form before starting to
take the medication and in weeks 2-4-6 and 8. Patients were also assessed
by a psychiatrist at the baseline and on each 14 days up to the 8 weeks
period.
Results: The mean score of the two groups- receiving Selegiline or
methylphenidate- decreased over the 8 weeks. There was not a significant
difference between the two groups. The most prevalent side-effect of
methylphenidate was decrease of appetite and for Selegiline change in sleep
pattern .
Conclusion: Selegiline is as effective as methylphenidate in the treatment of
adults with Attention-Deficit/Hyperactivity Disorder. Selegiline can be an
alternative medication for the treatment of adult ADHD If its clinical efficacy is
proven by other larger studies .
Keywords: Adult, Attention deficit disorder with hyperactivity, Methylphenidate,
Selegiline,
Attention-Deficit/Hyperactivity Disorder (ADHD) is
one of the most common mental disorders in
childhood. It affects 3-6% of school-age children (1, 2).
Some recent evaluations report the prevalence of 5.3%
in childhood (3). The disorder is characterized by
symptoms of hyperactivity, impulsivity and inattention.
ADHD continues into adolescence and adulthood
without treatment in about 60% of the cases. Therefore,
the prevalence of the disorder among adults is at least
1-3% (4). Even some studies report the prevalence to
be 1.2-7.3%. The estimated prevalence of DSM–IV
adult ADHD over ten countries around the world was
3.4%. Prevalence estimates were significantly higher
than this average in France (7.3%), U.S (5.2%) and
Netherlands (5%); and significantly lower in Colombia
(1.9%), Lebanon (1.8%), Mexico (1.9%) and Spain
(1.2%) (5).
The following disabilities were found in 30-day
functioning associated with adult attention-deficit
hyperactivity disorder diability in: self-care, mobility
and cognition. The clinical presentation of ADHD
often changes with increase in age as the patient moves
from childhood to adulthood. The symptoms of
inattention and impulsivity are more likely to persist
into adulthood than symptoms of hyperactivity. The
diagnosis of ADHD in adults might be debatable
because before the publication of the fourth edition of
Diagnostic and Statistical Manual of Mental Disorders
(DSM-IV), the disorder seemed to apply only to
children (6). In addition, the diagnosis of ADHD is
dependent on the clinician’s experience. Some
physicians aren’t still well-informed of the
manifestations and importance of this disorder in
adulthood.
Comorbidity is common among patients with ADHD.
In children and especially in adolescents, comorbid
disorders are often difficult to recognize ,but the
existence of a comorbid condition is correlated with
greater likelihood that the symptoms will persist into
adulthood. In adults with ADHD, comorbidity of
Original Article
Iran J Psychiatry 2009; 4:126-130
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Effect of Selegiline in Adult ADHD
Iranian J Psychiatry 4:4, Fall 2009
127
several other psychiatric diagnoses is common and
requires broader and more comprehensive treatment
goals (7).
Diagnosis of adult ADHD is a longitudinal process
requiring the documentation of ADHD symptoms with
onset at not older than 7 years of age (pervasive as
demonstrated in a variety of settings and severe enough
to interfere with school) and occupation and social
functioning. Adults must have childhood-onset and
persistent current symptoms of ADHD to be diagnosed
with the disorder. Adults with ADHD often present
with marked inattention, distractibility, organization
difficulties, and poor efficiency reflected in life
histories of academic and occupational failures. (8)
Stimulants have been used in the treatment of
childhood ADHD for 60 years and the efficacy of
methylphenidate (MPH) in the treatment of adults with
ADHD has been proven to be acceptable according to
meta-analysis studies (9, 10). However, there are some
concerns about stimulants. Up to 30% of those affected
with ADHD may not respond to stimulants or may not
be able to tolerate associated side effects such as
appetite suppression, sleep disturbance, mood
difficulties, or exacerbation of comorbid tic disorders
(11).
A review of an article assessing the abuse potential of
methylphenidate, states that the drug has a behavioral
pharmacological profile similar to other abused
stimulants. Overall 80% of the studies reviewed
indicated that methylphenidate functions behaviorally
in a manner similar to D-amphetamine or cocaine. It
means that MPH produces comparable reinforcing,
discriminative-stimulus, or subjective effects similar to
those (12).
Some findings support a multisystem dysfunction
underlying ADHD pathophysiology (13).
Selegiline is a type B monoamine oxidase inhibitor
(MAOI), and by inhibiting the breakdown of dopamine
and increasing synaptic dopamine levels it is expected
to be beneficial in the treatment of ADHD (14).
Selegiline is metabolized to amphetamine and
methamphetamine, stimulant compounds that may be
useful in the treatment of ADHD (15).
Selegiline produced dose-dependent changes in
monoamine metabolites and DOPA plasma levels.
Dopaminergic indices were associated with ADHD
symptom severity and noradrenergic indices with
persistence tasks (13).
Effects of chronic Selegiline administration on
hyperactive behavior and brain monoamine levels have
been studied in spontaneously hypertensive rats, and
the results showed that selegiline could reduce
hyperactivity and deficient sustained attention. The
positive effect of selegiline on impulsiveness has been
discussed to be due to either normalization of an
asymmetric dopaminergic activity in the nucleus
accumbens ,or in a restoration of normal dopamine
function in the prefrontal cortex (16).
Some clinical trials report the efficacy of Selegiline in
child ADHD. One of them indicates that Selegiline
may target specific symptoms of ADHD including:
sustained attention, the learning of novel information,
hyperactivity, and peer interactions. Because this drug
did not specifically reduce symptoms of impulsivity,
Selegiline may be a preferred treatment for individuals
who present with the primarily inattentive subtype of
ADHD (17). Another study reports a significant
improvement over the 60 days of treatment with
Selegiline from the teachers’ and parents’ assessment
scales (18). Treating child ADHD with Selegiline is as
effective as methylphenidate with less side-effects of
decreased appetite, difficulty falling asleep and
headaches (17, 19).
However, it has been reported that Selegiline treatment
is not more effective than placebo in adults (20).
Therefore, the authors designed this study to observe
the efficacy of Selegiline in the treatment of adult
ADHD.
Materials and Methods
Study Participants
The outpatient adults with ADHD were given CAARS
self report screening form (Conners’ Adult ADHD
Rating Scale, 1999) and those with a high total score
on the scale were interviewed by a psychiatrist (21).
Interviewing with each one’s partner helped to make
the diagnosis more accurate. Those who met the DSM-
IV diagnostic criteria for ADHD were placed for the
recruitment procedure. Those who had been previously
diagnosed with a psychiatric disorder were excluded.
The exclusion criteria are as follows: suffering from a
significant chronic medical disease like a history of
seizures, a cerebra-vascular accident, a cardiovascular
disease and current abuse or dependence on drugs
within 6 months, pregnancy and breast-feeding. After a
description of adult ADHD and the structure of the
study, a consent form was obtained by each volunteer
patient in order to consider the ethical standards of the
Helsinki Declaration of 1975 revised in 2000.
Eventually 28 men and 12 women aged 18-46 (mean
31.15 with SD of 7.046) completed the study procedure
(22).
Study Design
The CAARS utilizes short, long, and screening self-
report and observer rating scale forms. The instrument
is designed for individuals aged 18 to 50 years and
older. (21) The scales address ADHD symptoms as
described in the Diagnostic and Statistical Manual
Fourth Edition. This form had been translated to Farsi
(Persian) and had been normalized by ICSS (Institute
for Cognitive Science Studies in Tehran). Those with a
total score of 30 and above were interviewed by a
psychiatrist. Each one underwent a standard clinical
assessment consisted of a psychiatric evaluation with a
detailed history of childhood to consider WURS
(Wender Utah Rating Scale, 1993), a structured
diagnostic interview and a medical history. The
partners of these probable patients with ADHD were
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Mohammadi, Akhondzadeh, Fadaei et al
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Iranian J Psychiatry 4:4, Fall 2009
also questioned about the presence and severity of the
symptoms as an observer’s view.
Patients were randomized to receive Selegiline or
methylphenidate in an equal ratio. The assignments
were kept in sealed, opaque envelops until the point of
allocation. The randomization and allocation process
were done by the secretary of the private clinic. Each
patient was randomly assigned to receive treatment
either with Selegiline (starting with 5mg/day to a
maximum of 15mg/day) in group 1 ,or
methylphenidate (starting with 10mg/day to a
maximum of 40mg/day) in group 2 for an 8-week
double-blind clinical trial. All the involved people in
the study- the psychiatrist, the rater and the patients-
were blind to assignments. Each patient filled CAARS
self report screening form before starting to take
medication and in weeks 2-4-6 and 8.
Patients were also assessed by a psychiatrist at the
baseline and on each 14 days up to the 8 weeks period.
Twenty patients refused to complete the study in each
treatment group (ten from group 1 and ten from group
2). Their responses to the scale were unreliable as they
consumed the medication irregularly. Therefore, 20
patients in each group completed the 8-weeks medical
treatment.
Statistical Analysis
A two-way repeated measures analysis of variance
(time– treatment interaction) was used; the two groups
(Selegiline and methylphenidate) were considered as a
between-subjects factor (group) and the scale total
score (CAARS self report screening form) was used
during the treatment as the within-subjects factor
(time). In addition, a one-way repeated measures
analysis of variance with a two-tailed post-hoc Tukey
mean comparison test were performed on the change in
CAARS self report screening form scores from the
baseline.
Results were considered significant with P≤0.05. To
compare the demographic data and frequency of side
effects between the protocols, Fisher's exact test was
performed. To consider, α=0.05, β=0.2, the final
difference between the two groups, at least score of 5
on the Teacher and Parent ADHD Rating Scale, S=5
and power=0.8, the sample size was calculated at least
15 in each group.
Results
There were no significant differences between the two
groups in terms of gender, age, ethnicity and baseline
score of CAARS self-report screening form.
The table demonstrates the data of those participants
who completed the study procedure (Table 1).
The mean scores of the two groups are demonstrated in
Fig. 1. There were no significant differences between
the two groups at week 0 (baseline) on CAARS self-
report screening mean score. Both groups showed a
significant improvement over the 8 weeks of treatment
and the trend seemed linear.
Table1. Data of Participants
Selegiline
Group
Meth
ylphenidate
Group
Female 6 6
Male 14 14
Age (Mean + SD) 31.60 + 6.30
(Year)
30.48 + 7.59
(Year)
Baseline CAARS
Score
49.60 + 5.39 50.10 + 5.66
Ethnicity All Persian All Persian
Table 2. Clinical Complications and Side Effects
Complications
Selegili
ne
Methylphenidate
P
Difficulty Falling
Asleep
2 10 S
Increased Sleep 7 1 S
Abdominal Pain 3 4 NS
Headache 2 2 NS
Decreased Appetite 2 9 S
Nausea 3 4 NS
Irritability 1 3 NS
Anxiety,
nervousness
2 4 NS
Dry mouth 3 3 NS
S=Significant, NS= Non-Significant
The difference between the two treatment strategies
was not significant as indicated by the effect of groups,
the between-subjects factor. The trend of treatment
effect was the same in both groups over time.
A number of probable side effects were studied (Table
2). Nine side effects were observed over the trial all of
which were mild and tolerable. In the frequency of side
effects, the difference between the Selegiline and
methylphenidate groups was not significant except for
sleep pattern changes and decreased appetite.
Decreased appetite and
difficulty falling asleep
were observed more frequently in the methylphenidate
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Effect of Selegiline in Adult ADHD
Iranian J Psychiatry 4:4, Fall 2009
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group and increased sleep was observed more in the
Selegiline group.
Discussion
In this double blind, randomized, controlled study of
adults with ADHD, we found a statistically significant
effect of Selegiline and methylphenidate for treatment
of ADHD. No significant differences were observed
between the two groups on the Conners’ Rating Scale
scores. This finding is in agreement with some
previous studies that have indicated a positive effect of
selegiline in the treatment of ADHD. As suppression of
appetite and difficulty falling asleep were reported less
in the Selegiline group, Selegiline can be a
considerable therapeutic agent for patients facing these
problems on MPH.
For many years, methylphenidate (MPH) has been one
of the first-line treatments for attention-
deficit/hyperactivity disorder. As some children with
ADHD didn’t respond adequately to stimulants and
some encountered serious problems like deleterious
reduction in their appetite, the need for finding a non-
stimulant medication emerged. Moreover, prescribing a
stimulant agent in patients with comorbid disorders
such as tic disorder is not acceptable (23). The short
half-life of MPH was also a reason of some discontent
with the drug especially from a parental view.
Managing adult ADHD with psychotherapy seems
more effective than child ADHD (23). However, many
of adult sufferers need a medication. The literature
supports the efficacy of MPH for treatment of adult
ADHD (10, 24-27). Nevertheless, we encountered all
the defects of stimulants mentioned about child ADHD
in the adult form of the disorder. In addition, there is a
serious concern about behavioral pharmacological
profile of MPH since it functions in a manner similar to
D-amphetamine or cocaine and has abuse and
dependency potential like other psycho-stimulants (12 .(
Atomoxetine, a non-stimulant agent, is known as a
pharmacological intervention for children aged 6 years
and over with ADHD (28). There are also some
evidence supporting the efficacy of bupropion,
clonidine, modafinil and tricyclic anti-depressants in
treatment of ADHD (29-31).
As a multi-modal intervention is considered to be an
optimum therapeutic approach for most of psychiatric
disorders, having a variety of choices of medications is
also advisable.
Limitations
The small number of participants (considering that
diagnosing and obtaining the agreement and
satisfaction of adults with ADHD is a difficult task)
should be considered and therefore further research in
this field is needed .
Conclusion
The results of this study should be considered
preliminary, as some other researches reported little
efficacy of Selegiline. Managing parents who have
under-treatment ADHD children who themselves suffer
from ADHD seems easier than other adults with the
disorder. It can be a useful hint for studies where
objections of adults with ADHD halt any interventions.
Selegiline significantly improved symptoms of adult
ADHD and was well tolerated by participants of this
study. It is as effective as methylphenidate in the
treatment of adults with ADHD. As Selegiline has anti
depressive effects, it can especially be used in adults
with ADHD who suffer from comorbidity of mood
disorders.
Selegiline can be a good alternative medication for the
treatment of ADHD.
Conflict of interest
None declared.
Acknowledgements
We thank the participants and their families. Further,
the authors would like to extend their appreciation to
the members of PPRC. This study was performed as a
research project with the support of Psychiatry and
Psychology Research Center (PPRC) of Tehran
University of Medical Sciences.
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