1
ADHD: Non-Stimulant drugs
Or Other drugs
Or Second-line drugs
MRM
‫دكترمحمد رضا محمدي‬
‫فوق تخصص روانپزشكي كودك و نوجوان‬
‫استاد روانپزشكي و‬
‫رئيس مركز تحقيقات روانپزشکی و روانشناسی‬
‫دانشگاه علوم پزشكي تهران‬
‫بيمارستان روزبه‬
‫‪3‬‬
‫‪Email: mohammadimr@tums.ac.ir‬‬
‫تعريف اختالل نقص توجه و بيش فعالي‬
‫بر اساس ‪DSM – IV-TR‬‬
‫‪Attention Deficit Hyperactivity Disorder‬‬
‫)‪(ADHD‬‬
‫عبارت است از يك الگوي مقاوم نارسایی و نقص توجه و بيشفعالي كه با‬
‫تكرار و شدت بيشتر از كودكان سالم و مشابه از لحاظ سن و جنس بروز‬
‫مينمايد ‪.‬‬
‫‪4‬‬
ADHD is defined

Inattentiveness
• disorganised, forgetful, does not invest
effort
• brief and changing activities

Hyperactivity
• depending on context

Impulsiveness
• action without reflection
5
Prevalence of disorder

IRAN

Tehran: 3%-5%
Children 8.6 % –Adolescent 8.3 %

Khorramabad: 3%-6%

Other Studies: 2 % -20 %

6
Principles of psychological treatment

Identify specific problems

Analyze contingencies (events)

Enhance adult attending

Teach effective instruction

Token economy

Time-out + rapid novel rewards

Self- management
7
Interventions in the classroom

Proximity to teacher

Managed transitions

Letting off energy

Classroom aide
• operant conditioning
• peer advice

Rule government

Clarity of goal

speed of feedback
8
Treatments

Education

Cognitive-Behavior therapy

School modification

Triple P: Positive Parents Program
Psychopharmacology

Stimulant drugs

Other drugs

Non-Stimulant drugs
Or Second-line drugs
9
Medication types

Stimulant drugs:

Methylphenidate

Dexamphetamine

Adderall

Extended-release MP
10
Why is Methylphenidate (Ritalin)
effective in ADHD?
Its mechanism(s) of action are not
understood
•Most commonly prescribed psychoactive drug in
children.
• In the USA, 4-6 million children are treated with
methylphenidate every day.
•Has been used for over 40 years for ADHD.
11
Why stimulants fail
 They are not being taken
Extended release; education; motivational
 The dose is wrong
Monitor dose range to High dose; distribute;
second stimt.
 Adverse effects limit
benefit Manage symptomatically; modify dose
 The diagnosis is wrong
 The disorder is refractory
Second-line drugs; CBT approaches
12
‫عوارض جانبي ريتالين‬
‫شايع‪:‬‬
‫‪ -1‬كاهش اشتها‬
‫كاهش وزن بدن‬
‫‪-2‬‬
‫با شيوع كمتر‪ -:‬سردرد‪ ،‬سرگيجه ‪ ،‬تهوع ‪،‬‬
‫درد معده ‪ ،‬افزايش ضربان قلب‪.‬‬
‫ درد قفسه سينه ‪ ،‬درد مفاصل ‪ ،‬حركات‬‫غير ارادي بدن‪.‬‬
‫‪ -‬بثورات پوستي ‪ ،‬كهير ‪ ،‬اكيموز‬
‫‪ -3‬عصبانيت و پرخاشگري‬
‫‪ -‬تب بدون دليل شناخته شده‬
‫‪ -4‬اشكال دربه خواب رفتن‬
‫نادر‪:‬تاري ديد ‪ ،‬تشنج ‪ ،‬تغيرات خلقي ‪،‬‬
‫‪13‬‬
‫گلو درد ‪ ،‬پسيكوز‬
SSRIs

Fluoxetine

Citaloprame

sertraline
14
Trial evidence








Atomoxetine
Haloperidol
Imipramine
Clonidine
Bupropion
Pemoline
Nicotine
Carbamazepine
15
Few Trial

Guanfacine

Moclobemide (MAoI)

Venlafaxine

Risperidone
16
Antidepressants

Imipramine
Amitriptyline
Desipramine
Nortriptiline

Bupropion
75-300

Clomipramine
25-100
Tranylcipromine
Clorgyline
Pargyline
5-15
5-20






20-100 mg
20-100 mg
20-100 mg
10-50
17
α2-Agonists

Guanfacine
0.5-4.0

Clonidine
0.05-0.3
18
miscellaneous

Buspirone
5-30

Diphenhydramine
75-150

Nicotine (only adult) 7-21

Modafinil
mg patch
100-400 mg
19
Anticonvulsants

Carbamazepine
50-800
(serum level)

Valproate
50-600
(serum level)

Phenytoin
50-300
20
Antipsychotics

Thioridazine
25-150

Halopridol
0.5-5

Chlorpromazine
25-150

Risperidone
0.25-2
21
Precursors






Tryptophan (precursor of serotonin)
Tyrosine
(precursor of dopamine & norepinephrine)
70-100
100-400
Phenyalanine (precursor of dopamine &
norepinephrine)
100-400
Levo-DOPA (precursor of dopamine &
norepinephrine)
Deanol (precursor of acetylcholine)
>500
22
Others

β Blockers
Propranolol
Caffeine
10-100
100-450
23
Clinical Trial in Iran

Theophilline
3/4 mg/kg/day

Ritalin + ZN
55 mg/day

Selegiline
5-10 mg

Pasipay
0.04 mg/kg/day

Modafinil
100-400 mg
24
Clinical Trial in Iran

Ginkgo Biloba
240-600mg

Buspirone
5-10 mg

Bupropion
37.5-150 mg
25
1- Mohammadi, M.R., Ghanizadeh, A., Alaghband-rad, J.,
Tehranidoost, M., Mesgarpour, B., Soori, H.
Selegiline in comparison with methylphenidate in
attention deficit hyperactivity disorder children and
adolescents in a double-blind, randomized clinical
trial
(2004) Journal of Child and Adolescent
Psychopharmacology, 14 (3), pp. 418-425. Cited 16
times.
2- Mohammadi, M.R., Kashani, L., Akhondzadeh, S.,
Izadian, E.S., Ohadinia, S.
Efficacy of Theophylline compared to
methylphenidate for the treatment of attentiondeficit hyperactivity disorder in children and
adolescents: A pilot double-blind randomized trial
(2004) Journal of Clinical Pharmacy and
26
Therapeutics, 29 (2), pp. 139-144. Cited 16 times.
3- Mohammadi, M.R., Mostafavi, S.A., Keshavarz, S.A.,
Eshraghian, M.R., Hosseinzadeh, P., HosseinzadehAttar, M.J., Kooshesh, S.M.A., Chamari, M.,
Akhondzadeh, S.
Melatonin effects in methylphenidate treated
children with attention deficit hyperactivity
disorder: A randomized double blind clinical trial
(2012) Iranian Journal of Psychiatry, 7 (2), pp. 8792. Cited 2 times.
4- Mohammadi, M.-R., Hafezi, P., Galeiha, A.,
Hajiaghaee, R., Akhondzadeh, S.
Buspirone versus methylphenidate in the
treatment of children with attention- deficit/
hyperactivity disorder: Randomized double-blind
study
(2012) Acta Medica Iranica, 50 (11), pp. 723728. Cited 1 time.
5- Mohammadi, M.-R., Kazemi, M.-R., Zia, E., Rezazadeh,
S.-A., Tabrizi, M., Akhondzadeh, S.
Amantadine versus methylphenidate in children and
adolescents with attention deficit/hyperactivity disorder: A
randomized, double-blind trial
(2010) Human Psychopharmacology, 25 (7-8), pp. 560565. Cited 9 times.
6- Mostafavi, S.A., Mohammadi, M.R., Hosseinzadeh, P.,
Eshraghian, M.R., Akhondzadeh, S., Hosseinzadeh-Attar,
M.J., Ranjbar, E., Kooshesh, S.M.A., Keshavarz, S.A.
Dietary intake, growth and development of children with
ADHD in a randomized clinical trial of ritalin and
melatonin co-administration: Through circadian cycle
modification or appetite enhancement?
(2012) Iranian Journal of Psychiatry, 7 (3), pp. 114-119.
7- Akhondzadeh, S., Mohammadi, M.-R., Khademi, M.
Zinc sulfate as an adjunct to methylphenidate for the
treatment of attention deficit hyperactivity disorder in
children: A double blind and randomized trial
[ISRCTN64132371]
(2004) BMC Psychiatry, 4, art. no. 9, . Cited 69 times.
8- Kahbazi, M., Ghoreishi, A., Rahiminejad, F., Mohammadi,
M.-R., Kamalipour, A., Akhondzadeh, S.
A randomized, double-blind and placebo-controlled trial
of modafinil in children and adolescents with attention
deficit and hyperactivity disorder
(2009) Psychiatry Research, 168 (3), pp. 234-237. Cited 39
times.
9- Amiri, S., Mohammadi, M.-R., Mohammadi, M.,
Nouroozinejad, G.-H., Kahbazi, M., Akhondzadeh, S.
Modafinil as a treatment for AttentionDeficit/Hyperactivity Disorder in children and
adolescents: A double blind, randomized clinical
trial
(2008) Progress in Neuro-Psychopharmacology and
Biological Psychiatry, 32 (1), pp. 145-149. Cited 37
times.
10- Salehi, B., Imani, R., Mohammadi, M.R., Fallah, J.,
Mohammadi, M., Ghanizadeh, A., Tasviechi, A.A.,
Vossoughi, A., Rezazadeh, S.-A., Akhondzadeh, S.
Ginkgo biloba for Attention-Deficit/Hyperactivity
Disorder in children and adolescents: A double
blind, randomized controlled trial
(2010) Progress in Neuro-Psychopharmacology and
Biological Psychiatry, 34 (1), pp. 76-80. Cited 24 times.
11- Zarinara, A.-R., Mohammadi, M.-R., Hazrati, N.,
Tabrizi, M., Rezazadeh, S.-A., Rezaie, F.,
Akhondzadeh, S.
Venlafaxine versus methylphenidate in pediatric
outpatients with attention deficit hyperactivity
disorder: A randomized, double-blind
comparison trial
(2010) Human Psychopharmacology, 25 (78), pp. 530-535. Cited 14 times.
12- Akhondzadeh, S., Mohammadi, M.R., Momeni, F.
Passiflora incarnata in the treatment of
attention-deficit hyperactivity disorder in
children and adolescents
(2005) Therapy, 2 (4), pp. 609-614. Cited 14 times.

13- Abbasi, S.-H., Heidari, S., Mohammadi, M.-R., Tabrizi,
M., Ghaleiha, A., Akhondzadeh, S.
Acetyl-L-carnitine as an adjunctive therapy in the
treatment of attention-deficit/hyperactivity disorder
in children and adolescents: A placebo-controlled trial
(2011) Child Psychiatry and Human
Development, 42 (3), pp. 367-375. Cited 6 times.
14- Jafarinia, M., Mohammadi, M.-R., Modabbernia, A.,
Ashrafi, M., Khajavi, D., Tabrizi, M., Yadegari, N.,
Akhondzadeh, S.
Bupropion versus methylphenidate in the treatment
of children with attention-deficit/hyperactivity
disorder: Randomized double-blind study
(2012) Human Psychopharmacology, 27 (4), pp. 411418. Cited 4 times.
15- Mohammadi, M.R., Soleimani, A.A.,
Farahmand, Z., Keshavarzi, S., Ahmadi, N.
A comparison of effectiveness of regulation
of working memory function and
methylphenidate on remediation of attention
deficit hyperactivity disorder (ADHD)
(2014) Iranian Journal of
Psychiatry, 9 (1), pp. 25-30.
Conclusions from trial

Medication is more powerful than
cognitive behavioural therapy (CBT)

Research treatment better than routine

Many advantages in adding medication
to behavioural
34
Comparison of treatments (1)
Meta analysis of 124 trials
1/4
1/2
1
Effect size:
hyperactivity
Effect size: CPT
0/8
SD
0/6
0/4
0/2
0
Stimulant
Tricyclic
Behaviour
Pre-post differences in means / SD pre-treatment
35
Where does drugs bind in the human
brain?
PET studies show that drugs binds predominantly to
striatum in the human brain where it binds to DA
transporters.
36
Pharmacokinetics of
Methylphenidate in Human Brain
Methylphenidate when injected intravenously enters
the brain rapidly but has a slow clearance
37
‫نوروترانسميترها‬
‫نوروترانسميترهاي متعددي در فيزيوپاتولوژي ‪ ADHD‬نقش دارند از مطالعات‬
‫حيواني مشخص شده كه ‪ Locus ceruleus‬داراي نرونهاي نورآدنرژيك فراوان‬
‫ميباشد و نقش كليدي در فيزيوپاتولوژي ‪ ADHD‬دارد‪ .‬اين فرضيه با داروهايي كه‬
‫نقش مثبت در درمان ‪ ADHD‬دارند يعني محركها تأييد ميگردد‪.‬‬
‫در حقيقت محركها از طريق تأثير بر روي نور اپي نفرين و دوپامين عمل مينمايند‪.‬‬
‫محركها مانند ريتالين و دكستروآمفتامين از طريق افزايش كاتكل آمين ها (افزايش‬
‫آزادسازي و جلوگيري از بازجذب آنها) تأثير درماني دارند‪. .‬‬
‫‪38‬‬
DAT Occupancy (%)
Ritalin Binding to Dopamine Transporters
100
80
60
40
typical dose
(0.5 mg/kg)
20
0
0.0 0.2 0.4 0.6 0.8 1.0
Dose (mg/kg)
Oral MP at therapeutic doses occupies > 50 % DA
transporters. Estimated ED50 (dose required to occupy
50% of the DA transporters) corresponds to 0.25 mg/kg.
39
What are the effects of therapeutic doses
of oral MP on extracellular DA?
With MP
Without MP
DA
DA
DA
DA DA DA
DA
DA
DA
DA
DA
DA
DA
DA
DA
MP
DA
DA
DADADA DA
DA
DA
DA
DADA
DA DA DADA
DA
MP
Hypothesis 1
Hypothesis 2
Autoreceptor activation
decreases DA release
blunting DA signals.
DAT blockade
amplifies DA
40
signals.
What are the levels of DA transporter
blockade achieved by MP at the doses used
therapeutically for the treatment of ADHD?
Placebo
20 mg
40 mg
MP given orally at therapeutic doses binds
very efficiently to DA transporters.
41
ADHD Without MP
MP’s increase of
extracellular DA
would amplify the
weak DA signals
in ADHD subjects.
ADHD With MP
DA
DA
DA
DA
DA
DA
MP
DA
DA
DA
DA DADADA DA
DA
DA
DADA
DA DA DA
Amplification of DA signals would
enhance task-specific signaling
(DA decreases background firing
and increases signal-to-noise in
target neurons), improving
attention and decreasing
distractibility
42
‫آدنوزين يك ‪ Neuromodulator‬مهاري‬
‫نقش آدنوزين بعنوان يك نورومدوالتور مهاري در سيستم‬
‫اعصاب مركزي در دو دهه گذشته بيان شده است‪ .‬مطالعات‬
‫متعددي بر روي حيوانات بازگو كننده نقش مهاري آدنوزين بر‬
‫روي بسياري از نوروترانسميترها از جمله نوراپي نفرين و‬
‫دوپامين است ‪ .‬لذا آنتاگونيستهاي آدنوزين مانند كافئين و‬
‫تئوفيلين ميتوانند در درمان ‪ ADHD‬مؤثر باشند‪.‬‬
‫‪43‬‬
‫انواع آدنوزين‬
‫آدنوزين بعنوان يك نرومدوالتور در دستگاه عصبي مركزي تقريبا در همه‬
‫سيناپسها وجود دارد و از طريق گيرنده هاي اختصاص ي در سطح سلول‬
‫اثر ميكند‪ .‬گيرنده هاي آدنوزين به زير گروههاي‬
‫‪A3,A4 ،A2b ،A2a ،A1‬‬
‫تقسيم ميشوند‪ .‬اين گيرنده ها توزيع گسترده اي در ‪ CNS‬دارند و با‬
‫بسياري از سيستم هاي نوروترنسميتري در تعامل هستند‪ .‬بر همين‬
‫مبناست كه تصور ميشود از تركيبات مؤثر بر گيرنده هاي آدنوزين ميتوان‬
‫در درمان بسياري از اختالالت عصبي رواني استفاده كرد ‪.‬‬
‫‪44‬‬
ِAdenosine:
Inhibitory Neuromodulator
DA
DA
DA
Adenosine
DA
DA
DA
DA
DA
DA
DA
DA
DA
DA
DA
DA
DA
DA
DA
45
‫مكانيسم اثر تئوفيلين‬
‫آزاد سازي ‪ Ritalin‬اگر مكانيسم اثر داروهاي محرك مانندد دوپدامين و ندور اپدي نفدرين‬
‫باش د ددد آنگ د دداه مهاركنن د ددده ه د دداي گزانتين د ددي آدن د ددوزين مانن د دددكافئين و ب ص د ددو تئ د ددوفيلين‬
‫ميتوانند كاربرد درماني داشته باشند زيرا آدنوزين اثر مهاري بر روي آزاد سدازي دوپدامين‬
‫و ند ددوراپي نفد ددرين دارد؛ لد ددذا مهاركنند ددده هد دداي آدند ددوزين مانند ددد تئد ددوفيلين باع د د اف د دزايش‬
‫فعاليت دوپامين و نور اپي نفرين مي شوند‪ .‬بعبارتي با اما بصورت غير مسدتقيم؛ لدذا در‬
‫اين مطالعه ‪ Ritalin‬مكانيسم مشابه‬
‫ما براي اولين بار اثر ب ش ي ‪ Ritalin‬را با تئوفيلين مقايسه مي كنيم ‪.‬‬
‫‪46‬‬
ِTheophyline
Mechanism
DA
DA
Theophyline
DA
DA
DA
DA
DA
DA
DA
DA
DA
DA
DA
DA
DA DA
DA
DA
47
Thanks
48