Drugs Used In the Treatment of

Attention-Deficit/Hyperactivity Disorder (ADHD)

Overview• History of ADHD• Definition & Features• Etiological Factors• Symptoms and Diagnosis: DSM-IV criteria• Treatment

History of ADHDMid-1800s: Minimal Brain DamageMid 1900s: Minimal Brain Dysfunction1960s: Hyperkinesia1980: Attention-Deficit Disorder (ADD).

• With or Without Hyperactivity

1987: Attention Deficit Hyperactivity Disorder1994-present: ADHD subtypes:

Primarily Inattentive Primarily Hyperactive Combined Type

Definition & Features• ADHD is a neurobehavioral developmental disorder affecting about 3-

5% of the world's population. It typically presents during childhood, and is characterized by a persistent pattern of impulsiveness and inattention, with or without a component of hyperactivity.

• is a neurobehavioral developmental disorder affecting about 3-5% of the world's population. It typically presents during childhood, and is characterized by a persistent pattern of impulsiveness and inattention, with or without a component of hyperactivity. ADHD occurs twice as commonly in boys as in girls. Though previously regarded as a childhood diagnosis, studies completed during the last few decades have shown that ADHD often continues throughout adulthood - though generally with a reduction in hyperactivity.

• The most common symptoms of ADHD are:• Impulsiveness: a person who acts quickly without thinking things

through. • Hyperactivity: a person who is unable to sit still. • Inattention: a person who daydreams or seems to be in another world.

If Untreated ADHD Persists to Adulthood leading to: - School underachievement---------------Career underemployment- Impulsive actions---------------------------Impulsive life decisions- Experimentation with drugs, smoking, alcohol------------------substance use disorders-Careless behaviour------------------------serious fatal traffic accidentsAdults with ADHD:1. More likely to be suspended, expelled, or drop out of school.2. Higher traffic citations.3. Auto accidents.4. Substance Abuse.5. Unemployed, quit jobs, or get fired.6. Increased divorce rates.Cost to Society:Health Care costs associated with ADHD are conservativelyestimated at $3.3 Billion annually

Causes of ADHD 1-Structural Differences in ADHD 2- Decrease Dopamine in the synaptic cleft 3- Genetic Origin in ADHD 4- Environmental factors in ADHD 5- Essential Fatty Acids Deficiency

1- Structural Differences:1- Smaller Right cerebellar volume (corrected for brain size]2- Decreased prefrontal volume & activation (Particularly Right hemisphere which cause problems with focused attention)3- Overall brain volume is 3% smaller in ADHD4- Decreased blood flow in certain parts of the brain

2- Decrease Dopamine in the synaptic cleft

1- Concentration of dopamine in a prefrontal cortex plays a major role in motor control and attention

2- Dopamine are received by different dopamine receptor (DRD1-5) and re-uptake by dopamine transporter (DAT) on pre-synaptic neurons

3- Amount of dopamine depend on the:- Availability of intra-vesicle Dopamine and Sensitivity of DAT

4- In this case less dopamine in the synaptic cleft induce ADHD

3- Genetic Origin:

Researchers believe that a large majority of ADHD arises from a combination of various genes, many of which affect dopamine transporters. Candidate genes include:

1- DAT1 (dopamine transporter gene)2- DRD4 (dopamine receptor D4 gene)3- DRD54- DBH (dopamine beta hydroxylase)

4- Environmental factors in ADHD:Approximately 9-20 percent of the ADHD symptoms can be attributed to

environmental (nongenetic) factors. Environmental factors implicated include alcohol and tobacco smoke exposure during pregnancy and lead and mercury exposure after birth. Smoking relation to ADHD could be due to nicotine causing hypoxia (lack of oxygen) in uterus. Complications during pregnancy and birth—including premature birth—might also play a role.

1- Prenatal exposure to nicotineMaternal smoking, second-hand exposure2- Prenatal exposure to other neurotoxinsLead, poly-biphenyls, etc3- Prematurity

5- Essential Fatty Acids Deficiency: Studies on Essential Fatty Acid levels in Attention Deficit Disordersubjects vs. non- ADD ADHD subjects indicate that the ADHD groups had significantly

lower concentrations of key essential fatty acids than did the control groups, and about 40% of the ADHD group showed these signs of EFA deficiency:

• Increased thirst• Frequent urination• Dry skin• Dry or brittle hairLow levels of Omega 6 EFAs contributed to higher incidents of illness (colds, flu, etc.), and

deficits in Omega 3 EFAs contributed to problems with learning, behavior, sleep, and temper. Preliminary evidence suggests that Omega-3/Omega-6 supplementation reduces ADHD symptoms.

• ADHD Is Not Usually Caused by:• - Too much TV• - Food allergies• - Excess sugar• - Food additives• NOR BY• - Parents or poor home life• - Teachers or poor Schools

Neurobiological mechanisms

• PET scans measure the activity of various parts of the brain. The image on the right illustrates glucose metabolism in the brain of a person diagnosed with ADHD while doing an assigned task. The image on the left illustrates glucose metabolism in the brain of a normal subject when given that same task. PET scan study found that global cerebral glucose metabolism was 8% lower in medication-naive adults who had been diagnosed as ADHD while children.

• In one study a delay in development of certain brain structures by an average of three years occurred in ADHD elementary school aged patients. The delay was most prominent in the frontal cortex and temporal lobe, which are believed to be responsible for the ability to control and focus thinking. In contrast, the motor cortex in the ADHD patients was seen to mature faster than normal, suggesting that both slower development of behavioral control and advanced motor development might be required for the fidgetiness that characterize an ADHD diagnosis.

• The same laboratory had previously found involvement of the "7-repeat" variant of the dopamine D4 receptor gene, which accounts for about 30 percent of the genetic risk for ADHD

Diagnosis of ADHD• Based on the Diagnostic and Statistical Manual of Mental Disorders (

DSM-IV ) three types of ADHD are classified:

1.ADHD Predominantly Inattentive Type2.ADHD, Predominantly Hyperactive-Impulsive Type3.ADHD, Combined Type

DSM-IV: The Diagnostic and Statistical Manual of Mental Disorders published by the American Psychiatric Association provides a common language and standard criteria for the classification of mental disorders

Diagnosis of ADHD

• Based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV ) three types of ADHD are classified:

• ADHD Predominantly Inattentive Type: if criterion 1A is met but criterion 1B is not met for the past six months

• ADHD, Predominantly Hyperactive-Impulsive Type: if Criterion 1B is met but Criterion 1A is not met for the past six months.

• ADHD, Combined Type: if both criteria 1A and 1B are met for the past 6 months• The terminology of ADD expired with the revision of the most current version of

the DSM. Consequently, ADHD is the current nomenclature used to describe the disorder as one distinct disorder which can manifest itself as being a primary deficit resulting in hyperactivity/impulsivity (ADHD, predominately hyperactive-impulsive type) or inattention (ADHD predominately inattentive type) or both (ADHD combined type).

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DSM-IV criteriaI. Either A or B:• A. Six or more of the following symptoms of inattention have been present for at least 6 months to a point

that is disruptive and inappropriate for developmental level: 1. Often does not give close attention to details or makes careless mistakes in schoolwork, work, or other

activities. 2. Often has trouble keeping attention on tasks or play activities. 3. Often does not seem to listen when spoken to directly. 4. Often does not follow instructions and fails to finish schoolwork, chores, or duties in the workplace (not due

to oppositional behavior or failure to understand instructions). 5. Often have trouble organizing activities. 6. Often avoids, dislikes, or doesn't want to do things that take a lot of mental effort for a long period of time

(such as schoolwork or homework). 7. Often loses things needed for tasks and activities (e.g. toys, school assignments, pencils, books, or tools). 8. Is often easily distracted. 9. Often forgetful in daily activities.

• B. Six or more of the following symptoms of hyperactivity-impulsivity have been present for at least 6 months to an extent that is disruptive and inappropriate for developmental level:

• Hyperactivity: 1.Often fidgets with hands or feet or squirms in seat. 2.Often gets up from seat when remaining in seat is expected. 3.Often runs about or climbs when and where it is not appropriate (adolescents or adults

may feel very restless). 4.Often has trouble playing or enjoying leisure activities quietly. 5.Is often "on the go" or often acts as if "driven by a motor". 6.Often talks excessively.

• Impulsiveness: • Often blurts out answers before questions have been finished. • Often has trouble waiting one's turn. • Often interrupts or intrudes on others (e.g., butts into conversations or games). • II. Some symptoms that cause impairment were present before age 7 years.• III. Some impairment from the symptoms is present in two or more settings (e.g.

at school/work and at home).• IV. There must be clear evidence of significant impairment in social, school, or

work functioning.• V. The symptoms do not happen only during the course of a Pervasive

Developmental Disorder, Schizophrenia, or other Psychotic Disorder. The symptoms are not better accounted for by another mental disorder (e.g. Mood Disorder, Anxiety Disorder, Dissociative Disorder, or a Personality Disorder).

Methods of treatment• Methods of treatment often involve some combination of medications, behavior

modifications, life style changes, and counseling.• 1- Behavioral Treatments:• Many believe that concepts such as, self-regulation, self-monitoring, and effortful

control are at the center of the functional impairments regarding ADHD. There are Cognitive-Behavioral interventions designed to improve these areas and boost self-efficacy, social competence, and emotional control, which can affect attention and self-regulation. One such program is the Challenge Software Program. This program uses media in the form of interactive videos and games to grab and hold an inattentive child's attention and engage them in the process quickly. The program also offers measurable Pre and Post outcomes to illustrate improvement.

• Family therapy has shown little benefit in the treatment of ADHD. Education to help parents understand ADHD has shown short term benefits.

2- Pharmacological Treatment:

• 1- First line treatment (Stimulant Medications):• Stimulant medications are the most clinically and cost effective method of

treating ADHD. Stimulants have 80 % response rate. No significant differences between the various drugs in terms of efficacy or side effects have been found. About 70% of children improve after being treated with stimulants. Medications, however, are not recommended for pre-school children with ADHD. Stimulants, in the short term, have been found to be safe in the appropriately selected patient and appear well tolerated over 5 years of treatment.

• Long term safety, however, has not been determined. There are no randomized controlled trials assessing the harms or benefits of treatment beyond two years.[8] The American Heart Association and the American Academy of Pediatrics feels that it is prudent to carefully assess children for heart conditions before treating them with stimulant medications. The FDA has added black box warning to some ADHD medications. Amphetamines have warnings about potential for abuse, drug dependence, and sudden death.

1-Amphetamine

• Amphetamine and dextroamphetamine, together with methamphetamine and methylphenidate, comprise a group of drugs with very similar pharmacological properties. They are substrates for the neuronal uptake transporters for noradrenaline, serotonin and dopamine, and cause release of these mediators producing the acute effects described below. With prolonged use, they are neurotoxic, causing degeneration of amine-containing nerve terminals and eventually cell death. This effect is probably due to the accumulation of reactive metabolites of the parent compounds within the nerve terminals. Amphetamine, and related drugs such as methamphetamine are a group of drugs that act by increasing levels of norepinephrine, serotonin, and dopamine in the brain. It includes prescription CNS drugs commonly used to treat attention-deficit disorder (ADD) and attention-deficit hyperactivity disorder (ADHD) in adults and children. It is also used to treat symptoms of traumatic brain injury and the daytime drowsiness symptoms of narcolepsy and chronic fatigue syndrome. Initially it was more popularly used to diminish the appetite and to control weight.

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The main central effects of amphetamine-like drugs are

• locomotor stimulation • euphoria and excitement • stereotyped behaviour • anorexia. • In addition, amphetamines have peripheral sympathomimetic actions such as: . producing a rise in blood pressure . Inhibition of gastrointestinal motility.

• In experimental animals, amphetamines cause increased alertness and locomotor activity, and increased grooming; they also increase aggressive behaviour. With large doses of amphetamines, stereotyped behaviour occurs. This consists of repeated actions, such as licking, gnawing, rearing or repeated movements of the head and limbs. These activities are generally inappropriate to the environment, and with increasing doses of amphetamine they take over more and more of the behaviour of the animal. These behavioural effects are evidently produced by the release of catecholamines in the brain, because pretreatment with 6-hydroxydopamine, which depletes the brain of both noradrenaline and dopamine, abolishes the effect of amphetamine, as does pretreatment with α-methyltyrosine, an inhibitor of catecholamine biosynthesis. Similarly, tricyclic antidepressants and monoamine oxidase inhibitors potentiate the effects of amphetamine, presumably by blocking amine reuptake or metabolism.

• Amphetamine-like drugs cause marked anorexia, but with continued administration this effect wears off in a few days and food intake returns to normal.

• In humans, amphetamine causes euphoria; with intravenous injection, this can be so intense as to be described as 'orgasmic'. Subjects become confident, hyperactive and talkative, and sex drive is said to be enhanced. Fatigue, both physical and mental, is reduced by amphetamine, and many studies have shown improvement of both mental and physical performance in fatigued, although not in well-rested, subjects. Mental performance is improved for simple tedious tasks much more than for difficult tasks, and amphetamines have been used to improve the performance of soldiers, military pilots and others who need to remain alert under extremely fatiguing conditions.

• It has also been in vogue as a means of helping students to concentrate before and during examinations, but the improvement caused by reduction of fatigue can be offset by the mistakes of overconfidence.

• Clinical uses:1. Appetite suppressant 2.ADHD 3.Narcolepsy and chronic fatigue syndrome4.Treatment-resistant depression

• Along with methylphenidate, amphetamine is one of the standard treatments for ADHD. Beneficial effects for ADHD can include:

• Improved impulse control• Improved concentration• Decreased sensory over stimulation• Decreased irritability and decreased anxiety. • Amphetamines are sometimes used to augment anti-depressant therapy in

treatment-resistant depression.• As appetite suppressants in humans and weight loss is still approved in

some countries, but is regarded as obsolete and dangerous in others because of its tendency to cause pulmonary hypertension, which can be so severe as to necessitate heart-lung transplantation.

Adverse effects: • Cardiovascular:

• Vasoconstriction • Tachycardia • Palpitation

• Ear, nose, and throat: • Decongestant • Xerostomia

• Eye: • Mydriasis • Relaxation of ciliary muscle

• Gastrointestinal: • Decreased secretions • Decreased peristalsis

• Genitourinary: • Urinary retention • Erectile dysfunction

• Others: • Decrease in appetite/weight loss • Euphoria • Insomnia • Visual disturbance• Aggressiveness

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Amphetamines Summary:• The main effects are:

• increased motor activity • euphoria and excitement • anorexia • with prolonged administration, stereotyped and psychotic behaviour.

• Effects are due mainly to release of catecholamines, especially noradrenaline and dopamine. • Stimulant effect lasts for a few hours and is followed by depression and anxiety. • Tolerance to the stimulant effects develops rapidly, although peripheral sympathomimetic effects

may persist. • Amphetamines may be useful in treating narcolepsy, and also (paradoxically) to control

hyperkinetic children (ADHD). They are no longer used as appetite suppressants because of the risk of pulmonary hypertension.

• Amphetamine psychosis, which closely resembles schizophrenia, can develop after prolonged use.

• Contraindications• CNS Stimulants • Agitated states • Patients with a history of drug abuse • Glaucoma• MAOI use • Stimulants such as amphetamines elevate cardiac output and blood pressure making them dangerous for

use by patients with a history of heart disease or hypertension. Also, patients with a history of drug dependence or anorexia should not be treated with amphetamines due to their addictive and appetite suppressing properties. Amphetamines can cause a life-threatening complication in patients taking MAOI antidepressants. Amphetamine is not suitable for patients with a history of glaucoma.

• Amphetamines have also been shown to pass through into breast milk. Because of this, mothers taking medications containing amphetamines are advised to avoid breastfeeding during their course of treatment.

2- Methylphenidate

• Methylphenidate (MPH) is a prescription stimulant commonly used to treat Attention-deficit hyperactivity disorder, or ADHD. It is also one of the primary drugs used to treat the daytime drowsiness symptoms of narcolepsy and chronic fatigue syndrome. The drug is seeing early use to treat cancer-related fatigue.[4] Brand names of drugs that contain methylphenidate include Ritalin (Ritalina, Rilatine, Attenta, Methylin, Penid, Rubifen.

• Mechanism of action:• The means by which methylphenidate affects people diagnosed with ADHD are not well

understood. Some researchers have theorized that ADHD is caused by a dopamine imbalance in the brains of those affected. Methylphenidate is a norepinephrine and dopamine reuptake inhibitor, which means that it increases the level of the dopamine neurotransmitter in the brain by partially blocking the dopamine transporter (DAT) that removes dopamine from the synapses. This inhibition of DAT blocks the reuptake of dopamine and norepinephrine into the presynaptic neuron, increasing the amount of dopamine in the synapse. It also stimulates the release of dopamine and norepinephrine into the synapse. Finally, it increases the magnitude of dopamine release after a stimulus, increasing the salience of stimulus. The stimulants do not work paradoxically. They stimulate portions of the brain that are underactive by increasing dopamine and norepinephrine in the striatum and prefontal cortex. An alternate explanation which has been explored is that the methylphenidate affects the action of serotonin in the brain.

• Indications• ADHD • Narcolepsy • Treatment-resistant depression • Appetite suppressant• Antidepressant augmentation• Methylphenidate is a central nervous system (CNS) stimulant, reducing

impulsive behavior, and facilitating concentration on work and other tasks. Adults who have ADHD often report that methylphenidate increases their ability to focus on tasks and organize their lives.

Side effects:

1-Cardiovascular: Arrhythmia or increase in blood pressure 2- Endocrinal: Appetite loss 3- Eye: Blurred vision 4- Gastrointestinal: Nausea/vomiting, abdominal pain 5- Musculoskeletal: Muscle twitches 6- Neurological: Insomnia, drowsiness, dizziness, headache 7- Psychological: Psychosis (abnormal thoughts or hallucinations)

Contraindications:

• Use of tricyclic antidepressants: (e.g. desipramine), as methylphenidate may dangerously increase their plasma concentrations, leading to potential toxic reactions (mainly, cardiovascular effects).

• Use of MAO Inhibitors:, such as phenelzine (Nardil) or tranylcypromine (Parnate), and certain other drugs. methylphenidate should not be given to patients who suffer from the following conditions: Severe Arrhythmia, Hypertension or Liver damage.

suspected risks to health:

• In a 2005 study, only "minimal effects on growth in height and weight were observed" after 2 years of treatment. "

• In February 2005, a team of researchers from The University of Texas M. D. Anderson Cancer Center led by R.A. El-Zein announced that a study of 12 children indicated that methylphenidate may be carcinogenic.

3- Methamphetamine

• Methamphetamine , also known as methylamphetamine, N-methylamphetamine or desoxyephedrine, is a psychostimulant and sympathomimetic drug. It is a member of the family of phenylethylamines. The dextrorotatory (S-isomer) dextromethamphetamine can be prescribed to treat attention-deficit hyperactivity disorder, though unmethylated amphetamine is more commonly prescribed. Narcolepsy and obesity can also be treated by the aforementioned isomer under the brand name Desoxyn. It is considered a second line of treatment, used when amphetamine and methylphenidate cause the patient too many side effects. It is only recommended for short term use (~6 weeks) in obesity patients because it is thought that the anorectic effects of the drug are short lived and produce tolerance quickly, whereas the effects on CNS stimulation are much less susceptible to tolerance. It is also used illegally for weight loss and to maintain alertness, focus, motivation, and mental clarity for extended periods of time, and for recreational purposes.

• Methamphetamine enters the brain and triggers a cascading release of norepinephrine, dopamine and serotonin. To a lesser extent methamphetamine acts as a dopaminergic and adrenergic reuptake inhibitor and in high concentrations as a monamine oxidase inhibitor (MAOI). Since it stimulates the mesolimbic reward pathway, causing euphoria and excitement, it is prone to abuse and addiction. Users may become obsessed or perform repetitive tasks such as cleaning, hand-washing, or assembling and disassembling objects. Withdrawal is characterized by excessive sleeping, eating, and depression-like symptoms, often accompanied by anxiety and drug-craving. Users of methamphetamine sometimes take sedatives such as benzodiazepines as a means of easing their "come down".

• Methamphetamine has the potential to cause addiction. An addiction to methamphetamine typically occurs when a person begins to use the drug as a stimulant, because of its enhancing effects on pleasure and sex, alertness and ability to concentrate. Over time, however, the effectiveness decreases, and users find that they need to take higher doses to get the same results.

Pharmacology

• Methamphetamine is a potent central nervous system stimulant which affects neurochemical mechanisms responsible for regulating heart rate, body temperature, blood pressure, appetite, attention, mood and responses associated with alertness or alarm conditions. The acute physical effects of the drug closely resemble the physiological and psychological effects of an epinephrine-provoked fight-or-flight response, including increased heart rate and blood pressure, vasoconstriction (constriction of the arterial walls), bronchodilation, and hyperglycemia (increased blood sugar). Users experience an increase in focus, increased mental alertness, and the elimination of fatigue, as well as a decrease in appetite.

• The methyl group is responsible for the potentiation of effects as compared to the related compound amphetamine, rendering the substance on the one hand more lipid soluble and easing transport across the blood brain barrier, and on the other hand more stable against enzymatic degradation by MAO. Methamphetamine causes the norepinephrine, dopamine and serotonin(5HT) transporters to reverse their direction of flow. This inversion leads to a release of these transmitters from the vesicles to the cytoplasm and from the cytoplasm to the synapse (releasing monoamines in rats with ratios of about NE:DA = 1:2, NE:5HT= 1:60), causing increased stimulation of post-synaptic receptors. Methamphetamine also indirectly prevents the reuptake of these neurotransmitters, causing them to remain in the synaptic cleft for a prolonged period (inhibiting monoamine reuptake in rats with ratios of about: NE:DA = 1:2.35, NE:5HT = 1:44.5).

• Methamphetamine is a potent neurotoxin, shown to cause dopaminergic degeneration. High doses of methamphetamine produce losses in several markers of brain dopamine and serotonin neurons. Dopamine and serotonin concentrations, dopamine and 5HT uptake sites, and tyrosine and tryptophan hydroxylase activities are reduced after the administration of methamphetamine. It has been proposed that dopamine plays a role in methamphetamine induced neurotoxicity because experiments which reduce dopamine production or block the release of dopamine decrease the toxic effects of methamphetamine administration. When dopamine breaks down it produces reactive oxygen species such as hydrogen peroxide. It is likely that the oxidative stress that occurs after taking methamphetamine mediates its neurotoxicity. It has been demonstrated that a high ambient temperature increases the neurotoxic effects of methamphetamine.

• Indications:• Attention deficit hyperactivity disorder • Extreme obesity • Narcolepsy • • Methamphetamine addicts may lose their teeth abnormally quickly, a condition known as "meth mouth".

This effect is not caused by any corrosive effects of the drug itself, which is a common myth. According to the American Dental Association, meth mouth "is probably caused by a combination of drug-induced psychological and physiological changes resulting in xerostomia (dry mouth), extended periods of poor oral hygiene, frequent consumption of high calorie, carbonated beverages and tooth grinding and clenching." Similar, though far less severe symptoms have been reported in clinical use of other amphetamines, where effects are not exacerbated by a lack of oral hygiene for extended periods.

• Like other substances which stimulate the sympathetic nervous system, methamphetamine causes decreased production of acid-fighting saliva and increased thirst, resulting in increased risk for tooth decay, especially when thirst is quenched by high-sugar drinks.

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2- Second Line Treatment (Non-Stimulant Medications): 1- Atomoxetine (Strattera): - Mode of Action: prevents the reuptake of norepinephrine - Recently associated with increased suicide 2- Bupropion (Wellbutrin): Discussed in antidepressants 3- Venlafaxine (Effexor XR ): Discussed in antidepressants

4- TCADs (Tofranil): Discussed in antidepressants

3- Third line treatment:

- Minimal use - Too many side effects 1- Clonidine 2- Guanfacine