Although the effectiveness of pharmacologic treatments for ADHD has been
widely replicated, many children and adolescents with ADHD will receive
suboptimal treatment for a variety of reasons, including parental reluctance to
It is important to note that ADHD poses a huge economic burden to
Western society. A meta-analysis by Doshi et al. reports overall national incremental
costs of $143 to $266 billion in the United States.
8 The economic impact related to
adults with the disorder from productivity and income loss is greatest, although there
are also significant costs associated with youth with the disorder from educational
and health expenses. Further, the study documents significant “spillover costs” for
family members of individuals with ADHD.
Stimulants such as methylphenidate and amphetamine have been the mainstay of
ADHD treatment in children for more than 30 years, and recent studies have
demonstrated acute and long-term benefits in adolescents as well as adults.
Unfortunately, stimulants have not been consistently shown to decrease delinquency
rates. They have also been implicated with rare but serious side effects, and they
carry an elevated risk of diversion and abuse.
11–13 Pharmacologic alternatives to
stimulants have been identified in recent years and have proven to be useful, albeit
often as second-line agents among individuals who have significant side effects and
those with medical or psychiatric comorbidities.
behavioral psychotherapy have also been emphasized in recent years, and most
experts now contend that the combination of pharmacotherapy with family-based
cognitive behavioral interventions will generate the best long-term prognosis for
individuals with this disorder.
Recent landmark studies have helped clarify important aspects of diagnosis and
treatment with regard to ADHD. The Multimodal Treatment of Attention Deficit
Hyperactivity Disorder Study (MTA) is considered a groundbreaking study of
ADHD treatments and outcomes. The main findings were released in 1999, but
additional findings have been subsequently released. MTA was a multisite study that
differed from earlier studies of ADHD in that the duration of the study was
significantly longer (up to 14 months) and that the study compared the use of both
medication and cognitive behavior therapy, both alone and in combination with
routine community-based treatment. The central findings of MTA included the
following: (1) Medication alone and in combination with CBT was more effective
than intensive behavioral treatment alone or routine community-based care, (2) youth
receiving combined treatment required lower doses of medication, and (3) youth with
associated mental health issues, in addition to ADHD, had better outcomes with
combined treatment than with medication alone.
The question of medication treatment for preschool children presenting with
ADHD symptoms is a controversial issue. The “Preschool ADHD Treatment Study”
(PATS) is considered a landmark study in this arena. The majority of the findings
were released in 2006. The central findings include (1) preschool children tend to
respond better and with fewer adverse effects with lower doses of medication and
(2) preschool children are more sensitive to the adverse effects of psychostimulants
and require closer monitoring. In particular, younger children tend to have more
emotional adverse effects such as irritability and a tendency toward crying.
ADHD is a chronic neurobehavioral disorder, with an overall estimated prevalence
of 6% to 12% in school-aged children worldwide.
18 The Centers for Disease Control
and Prevention analyzed data from the 2006 National Survey of Children’s Health
and reported that the incidence of ADHD diagnoses has risen annually by an average
In 2006, 7.4% of US children aged 4 to 17 years
were diagnosed with ADHD. The DSM-5 reports that “ADHD occurs in most
cultures in about 5% of children and about 2.5% of adults.” The diagnosis is more
common in males with a ratio of 2:1 in children and 1.6:1 in adults.
hypothesized, however, that this gender predominance may be exaggerated because
the more overt hyperactive subtype is more common in boys and the less overt
inattentive subtype is more common in girls. As ADHD transitions into adulthood, the
prevalence falls to 4.4% (standard error 0.6), with a higher risk found in previously
married men who are unemployed and non-Hispanic white.
Various abnormal genetic and neurochemical abnormalities are associated with
ADHD. Estimates of heritability of ADHD range in the area of 0.7, indicating that
ADHD is one of the most heritable conditions in psychiatry.
demonstrated that the relative risk of ADHD is 6 to 8 times higher among first-degree
relatives of persons with ADHD compared with the general ADHD population.
Several candidate genes associated with ADHD have been identified, such as the
dopamine receptor, dopamine-transporter receptor, and serotonin transporter
22,23 Despite a small causal effect, no single gene is responsible for the
symptoms seen with ADHD, but rather these symptoms are likely the result of
interactions among several genes, which influence multiple neurotransmitters,
including serotonin, dopamine, and norepinephrine.
Multiple neuroimaging studies have documented consistent abnormalities in brain
structure and development with youth and adults with ADHD. Subjects with ADHD
have been shown to have reductions in global brain volume.
reduction in volume is most prominent in the prefrontal cortex, basal ganglia,
cerebellum, and parieto-temporal regions.
24 Functional magnetic resonance imaging
studies have also shown hypoperfusion with memory tests in the anterior cingulate
25 This area of the brain is responsible for behavioral and
functional abilities that may manifest in patients with ADHD as difficulties in
organization, mood, motivation, self-regulation, and ability to retain specific
information while performing a particular task, which are abilities referred to as
executive functioning. These findings are research population–based findings. These
studies are not yet useful in clinical practice for accurate diagnosis.
ADHD is a heterogeneous behavioral disorder with a variety of theorized etiologies.
Clearly, the research suggests a strong genetic component. However, to this point, no
specific genetic risk factor has been identified.
20 As a result, other environmental and
congenital etiologies have been considered and studied. Examples of studied
etiologies for ADHD include maternal smoking, dietary factors, prematurity/low
birth weight, and family environment/parenting behavior. Of these proposed factors,
low birth rate is the factor with the most confirming research evidence.
potential impact of parenting behavior, in particular, is a complex question as youth
with ADHD often present more significant challenges to parents. Further, as ADHD
is highly heritable, many parents of youth with ADHD may have ADHD themselves.
DIAGNOSIS, SIGNS, AND SYMPTOMS
The diagnosis of ADHD is a clinical diagnosis that may be supported by various
types of screening tools and neuropsychologic assessment. The diagnosis of ADHD
in a child is based upon the DSM-5 criteria (Table 89-1). The evaluation should
include clinical interviews with the patient and/or parent, physical examination
(including neurologic status), obtaining history regarding functional pattern in school
or daycare setting, evaluation for comorbid psychiatric disorders, and review of the
patient’s medical, social and family histories.
2 Other sources of valuable information
include performance reports (e.g., report cards or job reviews) and ADHD rating
scales scored in two different settings.
4 There are a number of validated rating scales
available both proprietarily and in the public domain. Some of the rating scales have
different versions for parents and teachers. Rating scales are helpful both for
diagnosis and for monitoring treatment outcome.
The recent publication of DSM-5 included a number of revisions to the diagnostic
criteria for ADHD. To meet criteria for ADHD, the child must have six or more
symptoms present in two different settings (e.g., home, school, etc.) for a minimum of
6 months. Furthermore, there must be evidence that these symptoms were present
before the age of 12 years. Based on these criteria, three types of ADHD are
identified: predominantly inattentive, predominately hyperactive/impulsive, and
combined. The diagnostic criteria require that the symptoms interfere with or impact
functioning in daily life so that care providers will look for symptoms that have a
negative impact on the child’s education, relationships, or social life (see Table 89-
1). On occasion, however, parents or teachers may “pressure” clinicians into writing
psychostimulant prescriptions for a “let’s see if it helps” trial. If the medication is
helpful, they may assume incorrectly that the diagnosis of ADHD is validated.
Additionally, DSM-5 eliminated the exclusion criteria for Autism Spectrum
Disorder. However, the DSM-5 mandates that the symptoms of ADHD “do not occur
exclusively during the course” of another psychiatric disorder.
Diagnostic Criteria for Attention Deficit Hyperactivity Disorder
home, school, or physician’s office.)
Careless mistakes or inattention to detail
Cannot follow instructions and does not complete tasks
Difficulty organizing tasks and activities
Avoids and/or dislikes chores or homework
Loses things needed for tasks and activities
Easily distracted by extraneous stimuli
Hyperactivity/Impulsivity Factor
home, school, or physician’s office.)
Fidgets with hands/feet or squirms in chair
Cannot remain seated in the classroom
Uncontrollable/inappropriate restlessness
Difficulty in engaging in play or leisure activities quietly
Often on the go and appearing driven by a motor
Blurts out answer prior to completion of question
Interrupts or intrudes on others
Establishing a diagnosis of ADHD in an adult who has never been treated for the
disorder during childhood is difficult. In adults, ADHD is a clinical diagnosis that
relies on their recollection of ADHD symptoms as a child to which DSM-5 criteria
validated for children are applied. Unlike teachers who are ordinarily familiar with
the symptoms associated with ADHD in children, spouses, coworkers, and
employers are often unfamiliar with ADHD as a disorder that can also affect adults.
They may attribute the individual’s difficulties to being lazy or to underachievement.
Between the ages of 10 and 25 years, the signs and symptoms of ADHD decrease in
frequency and severity by about 50% every 5 years but will generally persist into
In the differential diagnosis of ADHD, it is critically important to
distinguish ADHD from various behavioral, developmental, or medical conditions.
Psychiatric comorbidity is more common with ADHD as up to 87% of children will
be diagnosed with at least one additional psychiatric disorder and 67% have at least
Other psychiatric conditions that frequently coexist or imitate symptoms of ADHD
include conduct disorder, oppositional defiant disorder, Tourette syndrome,
depression, anxiety disorders, and obsessive–compulsive disorder. Of these
conditions, anxiety disorders and mood disorders are most commonly misdiagnosed
as ADHD. The comorbidity of ADHD and learning disabilities is both complex and
often leads to significant academic challenges. Studies suggest that 25% to 35% of
youth with ADHD will also have language-based or other learning disabilities.
Clinical wisdom suggests that ADHD often presents early in the child’s academic
career (e.g., kindergarten or first grade), whereas learning disabilities may present
later in the elementary years, when children are “reading to learn” rather than
“learning to read.” Medication is a central treatment component for ADHD, whereas
learning support and specialized teaching strategies are the interventions of choice
for youth with learning disabilities. Medications are not helpful for the treatment of
It has been known for decades that family histories from first-degree relatives of
probands with ADHD reveal increased rates of ADHD (25% concordance rate),
polysubstance dependence, antisocial personality disorder, depression, and anxiety
28 Children with ADHD are at an increased risk of having antisocial
behavior, depression, and substance abuse problems as adults. ADHD symptoms
persist into adulthood in the majority of these comorbid patients.
ADHD are usually self-sufficient, but they have poorer academic performance,
poorer job performance, and lower socioeconomic status than do their siblings. They
also have more frequent divorces, job changes, and car accidents. Most adults with
ADHD report a high level of subjective distress (79%) and interpersonal problems
Medical conditions often complicate the diagnosis of ADHD and should be
excluded before initiating treatment. These medical conditions include head injuries,
seizure disorders, metabolic disorders, cerebral infection, toxic exposures (e.g.,
chronic lead exposure), sleep problems, substance abuse, and hyperthyroidism.
QUESTION 1: M.T. is a 12-year-old girl who recently started middle school. M.T.’s mother calls the
you think about the differential diagnosis?
Depression is the most prominent diagnosis that comes to mind. However, it is
important to remember that comorbidity is quite common in youth with psychiatric
disorders. It is important to consider if there are underlying, less obvious disorders
or circumstances that may be contributing.
CASE 89-1, QUESTION 2: What are the next steps in the evaluation?
The pediatrician refers M.T. to a child/adolescent psychiatrist for evaluation. The
professionals help the parents request an educational assessment through the school.
The latter includes both an academic and psychologic assessments. The assessments
suggest underlying poor self-esteem. However, there is also evidence of slow
processing speed and other evidence of ADHD and executive functioning deficits.
The Vanderbilt rating scales confirm the diagnosis of ADHD.
There are a number of validated instruments to assist with the diagnosis and
clinical management of ADHD. Often, these instruments have a parent and teacher
version. Commonly used instruments include the Conners Global Index, the SNAP
IV, DuPaul Rating Scale for ADHD, and the Vanderbilt Rating Scale. Some rating
scales are proprietary and others such as the Vanderbilt is in the public domain.
CASE 89-1, QUESTION 3: What are the first-line interventions?
The psychiatrist provides psychoeducation to M.T. and her parents about ADHD.
They discuss that ADHD may be missed more commonly in girls, and that youth with
ADHD often develop concurrent depression, anxiety, conduct disorders, and
substance-use disorders because their experience in school and activities often leads
to feelings of inadequacy. Additionally, an Individualized Educational Plan (IEP) is
developed for M.T. to provide more supports in the school setting. Special
accommodations such as added time for exams, a seat in the front of the class, and the
availability of fidget toys are specified in the IEP.
M.T. continues in counseling with the social worker, in which they focus on
cognitive and behavioral strategies to manage both her ADHD symptoms and her
depression and poor self-esteem. All agree that it is prudent to hold off on any
medication for depression to see if the other interventions are effective in alleviating
The ADHD symptoms are tracked with Vanderbilt rating scales completed by
parents and teachers. Medication treatments for ADHD are discussed. With informed
consent, a trial of a psychostimulant is begun.
Optimal strategies to manage ADHD symptoms that are moderate to severe in nature
should focus on the combined use of behavioral and pharmacotherapy interventions.
It is important to recognize that ADHD is a chronic disorder with symptoms that
frequently continue into adolescence and adulthood. Before developing a treatment
plan, defined and realistic treatment goals should be established collaboratively with
the child, parent, and school.
Several ADHD consensus statements, practice parameters, and guidelines have
been developed, based on both evidence-based literature evaluation and expert
opinions, to assist clinicians in evaluating, diagnosing, and managing patients with
During the years, numerous psychosocial or educational programs have been studied
for their potential benefit in controlling ADHD symptoms and maximizing function.
Behavioral interventions have been among the most popular nonpharmacologic
approaches, with programs emphasizing the creation of a structured environment
containing minimal distractions both at home and in school. Contingency training is
another common component of behavioral therapy for ADHD, with children
receiving tokens for specific tasks or achievements, as well as punishments (e.g.,
revoking privileges) for maladaptive behaviors. Although most treatment guidelines
continue to advocate trying some type of structured behavioral modification, the
empiric evidence that such programs improve functioning or prognosis is certainly
not as strong as it is for pharmacotherapy.
The previously mentioned Multimodal Treatment Study of Children with ADHD
was a landmark study in reviewing the relative impact of medication and
14 The MTA Cooperative Group study, as it is commonly
known, was designed to compare long-term medication and behavioral treatments
with respect to efficacy and acceptability. A group of 579 children between 7 and 10
years of age with the combined type of ADHD were recruited and randomly assigned
to four different treatment groups: medication management, behavioral treatment,
medication plus behavioral treatment, or typical community treatment. Behavioral
interventions were delivered in a group-based recreational setting and included an 8-
week, 5-days/week, 9-hours/day, intensive program administered by a counselor or
aide. Once school started, the subjects in this arm of the study received 60 school
days of a part-time, behaviorally trained, paraprofessional aide who worked directly
with the child. In addition, the child’s teacher received 10 to 16 sessions of biweekly
consultation that focused on classroom behavior management strategies. Daily
behavior report cards were sent home to parents. At the same time, families were
involved in 27 group therapy meetings plus 8 individual family meetings. Of the
children receiving medication, 75% received methylphenidate, 10% received
dextroamphetamine, and 15% received pemoline, imipramine, clonidine, guanfacine,
or bupropion. After the 14-month study, it was concluded that drug treatment was
more effective than behavioral treatment according to parents’ and teachers’ ratings
of inattention, and teachers’ ratings of hyperactivity/impulsivity. Combined treatment
(drug treatment plus behavioral modification) was preferred by parents, but the
therapeutic advantage versus medication did not achieve statistical significance.
Combined treatment was significantly more effective than behavioral treatment and
community care for reducing ADHD symptoms, according to both parent and teacher
reports, but a subgroup analysis of children with comorbid conditions (e.g., conduct,
oppositional defiant, anxiety, or affective disorders) found behavior management to
be as effective as monotherapy. A 3-year follow-up study revealed that all four
interventions were equally effective in improving academic performance and social
functioning with time, but given the costly and labor-intensive nature of the
behavioral modification, in particular pharmacotherapy, it continues to be regarded
as the first-line treatment for children with at least moderate ADHD symptoms.
There have been a variety of school-based, clinic-based, and home-based
interventions to address ADHD symptoms, mainly with positive results.
Additionally, specialized summer treatment programs have been established to
provide more intensive intervention when school is not in session.
Stimulants are considered the most effective option to treat ADHD, with more than
60 years of clinical experience accrued. Currently there are two basic types of
stimulants marketed in the United States, methylphenidate based and amphetamine
based, and they have all been reported to improve academic performance and
behavior in children with ADHD (Table 89-2).
Overview of Common Drugs to Treat Attention Deficit Hyperactivity Disorder
Methylphenidate C-II Aptenso XR
Dexmethylphenidate C-II Focalin
Dextroamphetamine C-II Dexedrine
Vyvanse Long 30–70 mg a day 30–70 mg a day
Methamphetamine Desoxyn Long 5–25 mg a day No approved
Noradrenergic Reuptake Inhibitor
Atomoxetine Strattera Long 40–100 mg a day 40–100 mg a
disintegrating tablet; CD, controlled delivery.
A review of short-term clinical trials that evaluated the safety and efficacy of
stimulants in nearly 6,000 children and adults with ADHD showed a 75% to 80%
improvement in patients treated with stimulants compared with 5% to 30% treated
36 Although stimulant drugs are grouped as a class based on their
pharmacologic effect of increasing dopamine and norepinephrine levels in the
synapse, the mechanisms by which stimulant drugs exert this effect varies slightly.
These subtle differences in the mechanism of action support the possibility that
patients who respond partially to one stimulant may respond completely to another. In
fact, approximately 20% to 25% of those who respond poorly to one medication will
respond positively to another and up to 90% of children will respond if both are
37 Stimulants also are rapid acting and have predictable effects, with response
Methylphenidate and dexmethylphenidate block the reuptake of dopamine from the
synaptic cleft into the presynaptic neuron via the dopamine transporter protein.
Methylphenidate is metabolized into ritalinic acid via carboxylesterase CES1A1, a
The most common side effects of methylphenidate include appetite suppression,
insomnia, headache, nausea and vomiting, and abdominal pain.
A long-acting methylphenidate transdermal formulation is available. As with any
transdermal system, drug delivery can vary greatly because of heat and site-related
skin porosity differences. AUC and Cmax can increase 300% if the patch is applied
to an inflamed area and 250% if the patch area is exposed to heat such as going
outside and exercising in the sun.
2,41–43 The patch is applied to the hip area for 9
hours, and methylphenidate is steadily released and absorbed into the circulation for
about 11.5 hours. When compared to the oral long-acting Oros release system,
methylphenidate’s side effects were similar between the two products but
numerically higher in the transdermal arm compared to the oral arm. One side effect
exclusive to the patch is skin irritation which can occur from 3% to 40%.
Amphetamines, including mixed amphetamine salts, dextroamphetamine, and
lisdexamfetamine, enhance the release of both dopamine and norepinephrine from
storage vesicles in the presynaptic neuron and block their storage in addition to
blocking their reuptake from the synaptic cleft. They also have a weak MAOI
Dextroamphetamine is metabolized via CYP2D6. A strong inhibitor of 2D6 could
increase levels twofold. The long-acting prodrug lisdexamfetamine requires
enzymatic hydrolysis in the blood to cleave off the L-lysine portion of the molecule.
This leaves just dexamphetamine available for activity.
rapidly absorbed, but the step of hydrolysis results in a delayed release of
dextroamphetamine in the circulation allowing for once a day dosing.
Since approximately two-thirds of children and adolescents with ADHD respond
equally to methylphenidate or amphetamine products, the preferred agent should be
based on duration of action, formulation preferences, and cost.
89-2, stimulant preparations are classified based on duration (i.e., immediate [2–5
hours], intermediate [6–8 hours], and long-acting [10–12 hours]) and available
delivery systems. Long-acting formulations are preferable to intermediate and short
acting, because it provides uninterrupted benefit allowing the child to avoid going to
the school nurse for doses or lack of effect between doses.
options are biphasic, which provides an immediate-release (IR) dose then a second
long-acting dose a few hours later. For example, Ritalin LA, Metadate CD, Focalin
XR, and Adderall XR all contain both immediate and enteric-coated, delayed-release
beads that mimic the blood concentrations seen with immediate-release stimulant
preparations given twice daily. Although a prescription methamphetamine product
does have FDA approval for treatment of ADHD, no expert guidelines recommend it
because of high-abuse liability and neurotoxicity.
Both types of stimulants are similar in their side effect profiles. Adverse drug
reactions such as insomnia and appetite loss are mild, and tolerance often develops
within a few days. These reactions can be easily managed by adjustment in dose and
timing if necessary (Table 89-3). In a double-blind, crossover study comparing side
effects of methylphenidate and dextroamphetamine, surveyed parents reported
worsening appetite (vs. baseline) with methylphenidate; severe insomnia and
appetite suppression were reported with dextroamphetamine.
significantly more severe with methylphenidate (vs. dextroamphetamine) included
insomnia, appetite suppression, irritability, proneness to crying, anxiety, dysphoria,
49 Only 3.2% of patients treated with either drug discontinued the
medication because of side effects. Another head-to-head trial showed similar types
and rates of adverse effects for IR methylphenidate and IR dextro/levo
Managing Adverse Effects of Stimulants Used in Children with Attention Deficit
Decreased appetite, nausea, or
Schedule evening meals after medication has worn off
Encourage foods with high caloric density or nutritionalsupplements
Encourage evening/bedtime snack
Switch from long-acting to short-acting preparation
Consider a drug holiday when appropriate
Sleep disturbance Administer doses earlier in the day
If using a sustained-release product, consider changing to a shortacting preparation
Discontinue afternoon/evening dose
Behavioral rebound If using short-acting preparation, consider changing to a long-acting
Irritability Assess time of symptoms:
Related to peak: reduce dose or try long-acting preparation
Related to withdrawal: change to long-acting preparation
Evaluate for comorbid diagnosis
Dysphoria, moodiness, agitation,
Decrease dose or change to long-acting preparation
Dizziness Monitor blood pressure
Lower dose or change to long-acting preparation to reduce peak
Development or increase in tic
Consider trial of clonidine or guanfacine
Consider referral to physician
There is an association between stimulant use and growth retardation. The relative
impact of this seems minimal and can be reduced or eliminated with drug
51–53 There seems to be no loss of efficacy if the child does have a drug
holiday and stops the medication over weekends holidays or summer months.
risk of drug holidays is a worsening of symptoms and this may have impact on social
There was concern that the stimulants may have a cardiotoxicity risk. Population
studies suggest, however, that the overall risk of sudden death associated with
stimulant use has been shown to be the same, if not lower, than that of the general
55 Slight increases in BP and HR are seen with methylphenidate and
amphetamines, although ECG changes are very rare.
56–58 Clinicians should follow
current recommendations suggested by the American Academy of Pediatrics and the
American Heart Association, which advocate screening for a personal or family
history of cardiovascular disease in all children with ADHD. Continual monitoring
for these risks along with routine blood pressure and heart rate assessments should
59 Pretreatment ECGs are not required but recommended by the AHA
as general practice for all children. Stimulants should not be used in those with
known structural cardiac abnormalities.
For patients with ADHD only, it is recommended to initiate treatment with either a
methylphenidate or an amphetamine.
2,32–34 For patients who fail both types of
stimulants or when stimulants are not preferred, a trial of a non-stimulant is
warranted (Table 89-2). Non-stimulants are less effective than stimulants and usually
require at least 4 weeks until a full response is evident. A meta-analysis of 29
It found that the effect size of amphetamine and methylphenidate was
significantly greater than that for atomoxetine, bupropion, and modafinil (p = 0.02).
If atomoxetine fails or is not indicated, the α2
-adrenergic agonists clonidine and
guanfacine should be considered.
Atomoxetine inhibits the presynaptic norepinephrine transporter and is classified as
norepinephrine reuptake inhibitor (NRI). Clinical trials have shown that atomoxetine
is superior to placebo in reducing the symptoms of ADHD in children, adolescents,
62,63 However, trials comparing atomoxetine with stimulants have found
atomoxetine to be less effective.
Atomoxetine is likely to have some immediate benefit after initiation but unlike the
stimulants a longer trial of 6 to 8 weeks is recommended as efficacy continues to
grow. Atomoxetine requires a 10- to 14-day titration to achieve a therapeutic dose of
1 to 1.5 mg/kg/day to avoid nausea (12%), vomiting (15%), and asthenia (11%).
with stimulants, atomoxetine can also raise blood pressure and heart rate, with
reports of high systolic and diastolic blood pressures occurring in 8.6% and 5.2% of
pediatric subjects, respectively. Increases in heart rate of more than 110 beats/minute
and more than 25 beats/minute above baseline were observed in 3.6% of patients.
Atomoxetine is metabolized via CYP 450 2D6, with the major metabolite being 4-
hydroxyatomoxetine which is also a potent inhibitor of NE reuptake but at low
concentration levels. It has a half-life of 4 to 5 hours but can be extended by about 3
There have been postmarketing cases of reversible hepatic injury in association
with atomoxetine, but this is quite rare.
70 Baseline liver enzyme testing should be
performed, and evidence of jaundice or liver injury should warrant immediate
discontinuation. Atomoxetine also contains the warning regarding increased risk of
atomoxetine group was 5/1,357 (0.37%) and placebo group was 0/851 (0%).
despite the low risk, monitoring frequently for the first 3 months of treatment is
Clonidine and guanfacine are α2
-agonists that have been used for years off-label to
control hyperactive/impulsive or aggressive symptoms and insomnia.
believed to directly stimulate the postsynaptic norepinephrine receptors in the
prefrontal cortex and locus coeruleus. Guanfacine is most specific for the α-2a
receptor, while clonidine is less specific and agonizes α-2a, b, and c. The FDA has
approved extended-release formulations for clonidine and guanfacine both as
monotherapy and as adjuncts to stimulants. Clonidine and guanfacine are also
approved as adjuncts to stimulants for ADHD. Although they are a monotherapy
option, they are not considered as first line as they are less effective than stimulants.
They are particularly useful for behavioral comorbidities, such as aggression and
Guanfacine is primarily metabolized via CYP 3A4, and potent inhibitors can
increase blood levels by 200%. Guanfacine extended release provides
approximately 60% of the serum levels of the immediate-release version. Clonidine
is partially metabolized via CYP 2D6, although inhibitors of this pathway have only
minor changes in serum levels.
76 The extended-release version has an AUC
approximately 89% of the immediate release.
The side effect profile of α-2 agonists is quite different than the stimulants and
atomoxetine. Sedation and related side effects can occur in nearly 40% for both.
Reductions in BP and HR can occur and need to be monitored. Bradycardia (HR <
60 bpm) can occur in up to 20% of children with clonidine and is a side effect of
guanfacine also but to a lesser degree. This is likely because of guanfacine’s
specificity to α 2a. Rebound hypertension can occur if either of these medications are
Despite positive studies with immediate-release formulations, the short duration of
action makes them less desirable than the QD dosing of guanfacine ER and the BID
dosing clonidine extended-release formulation.
Either stimulant groups are considered first line and in this case methylphenidate
10 mg qam is tried. After steadily increasing the dose to 30 mg qam the parents feel
that there is minimal change in attention, but that there are significant side effects of
CASE 89-1, QUESTION 5: What would be the next trial of medication for M.T.?
Expert guidelines state that if medication is decided upon then the greatest efficacy
is from the stimulants. Neither stimulant is considered superior to the other and initial
choice should be based on the comfort level of the clinician and patient/parent
acceptance. If the initial choice of stimulant is ineffective, it is recommended to trial
the other stimulant class. By doing this 90% of children will display efficacy.
Therefore, the next trial for M.T. should be the initiation of dextroamphetamine 5 mg
qam and titrate as tolerated to a maximum of 40 mg a day.
CASE 89-1, QUESTION 6: M.T. is showing some improvement on 10 mg qam of immediate-release
the next step of pharmacotherapy for M.T.?
Increasing the dose to 30 mg qam is possible. Although a switch from a stimulant
to atomoxetine could be tried, data have shown that atomoxetine is less effective than
stimulants. Experts recommend that combination therapy of a stimulant and an α-2
agonist is appropriate, and studies have shown an increase in efficacy from
monotherapy to combination therapy.
TOURETTE’S SYNDROME AND TIC DISORDER
Tourette’s syndrome is neuropsychiatric condition which has tics as a hallmark
symptom. Children with ADHD have a higher risk of comorbid tic disorder than the
general population; however, stimulants are relatively safe in this population. As an
example, the Tourette’s Syndrome Study Group contrasted the effect of
methylphenidate, clonidine, and the combination of the two to placebo in the
treatment of 136 children (7–14 years old) diagnosed with ADHD and Tourette
77 The group concluded that prior recommendations to avoid
methylphenidate in these children because of concerns of worsening tics were
unsupported. As such, expert recommendations are that a child with ADHD should
start on methylphenidate, and if tics emerge or worsen then a switch to atomoxetine
or clonidine is warranted. A meta-analysis of studies with subjects who have ADHD
and Tourette’s syndrome concluded that methylphenidate shows the greatest
improvement in ADHD symptoms without worsening tics in most kids. α-2 Agonists
offer less efficacy in ADHD symptoms but greater control over tics compared to
methylphenidate. Atomoxetine offers benefit on both groups of symptoms and is an
32,74,75 Amphetamines should be avoided because although they do treat ADHD
symptoms, they have a higher chance of worsening tics compared to
A review regarding treatment of tic disorders without comorbid ADHD states that
the α-2 agonists guanfacine and clonidine are recommended as first-line options.
Guanfacine may be preferred because of less sedation than clonidine.
Anxiety disorders are more frequently comorbid in the ADHD child (approximately
ninefold) and adult (approximately fourfold) compared to the frequency seen in the
general population. Despite the fact that the anxiety disorder may be a separate
illness, anxiety symptoms in the child can be directly related to poor performance
because of ADHD symptoms. Treatment with a stimulant that subsequently improves
performance will reduce the anxiety. However, some children after a trial with a
stimulant will not have an anxiety reduction or it may even worsen. At this point a
trial with atomoxetine is recommended over treating the anxiety with an SSRI and
Despite the fact that stimulants are medications with an abuse risk, multiple studies
have shown a protective effect against developing a substance-use disorder with
80 Using a stimulant for ADHD in a
current substance abuser has contradictory results. Stimulants do treat the ADHD
symptoms but not as robustly as those without a concurrent substance-use disorder.
They do not seem to reduce the substance use but clearly do not worsen it.
opinion suggests that those with current substance-use disorders should be tried on
non-stimulant options first, but stimulants are not fully contraindicated and can be
used with close monitoring. There is growing data to support that there is a high rate
of diversion of stimulants in the college population. One report correlated an
increased incidence of diversion with increased difficulty of the academic
If misuse and diversion are of concern, methylphenidate comes as a transdermal
patch formulation, and dextroamphetamine is available as a hard to abuse prodrug
Despite the potential for being less effective than a stimulant, atomoxetine has
preferred benefits in specific patient subtypes. Because it is not a stimulant, its risk
of abuse and diversion are low and is preferred in patients with an addictions
disorder history or living in a household where someone other than the patient (e.g.,
parent or sibling) has an addiction disorder and may take the patients medications.
Stimulants may cause psychosis. This is because of the enhancement of DA centrally.
If the child is acknowledging hallucinations or exhibiting bizarre behavior then
cessation of the stimulant is required. A rechallenge can occur but at a lower dose. If
a child stabilized on the medication starts to exhibit psychotic symptoms then one
should assess for drug interactions. The methylphenidate transdermal patch
formulation can have greater unexpected fluctuations in blood levels because of a
greater range of absorption compared to the oral formulations.
the transdermal patch is influenced by placement site and temperature of the skin.
Treating this side effect with an antipsychotic is not recommended.
Bupropion has been shown to be effective compared to placebo, but it is less
effective than stimulants in treatment of ADHD.
67 Randomized, controlled trials have
established the effectiveness of bupropion as an alternative to the psychostimulants in
the treatment of ADHD in children, adolescents, and adults.
common adverse effects encountered with bupropion in ADHD studies were
dermatologic reactions and seizures. Dermatologic reactions occurred twice as often
with bupropion compared with placebo. Severe bupropion-induced urticaria
required discontinuation in 5.5% (4 of 72) of the patients in one study.
risk of seizures increases by about fourfold if extended-release doses of greater than
450 mg/day or greater than 400 mg/day sustained-release doses of bupropion doses
88 Although there are no case reports of seizures in children receiving
therapeutic doses of bupropion, it is recommended to limit doses to less than 6
mg/kg/day in the treatment of ADHD and to avoid using bupropion in patients with a
Modafinil has been found to be effective in the treatment of prepubescent, adolescent,
89,90 The 2006 Pediatric FDA advisory committee
reviewed the efficacy and safety of modafinil for ADHD and determined the drug
was effective but rejected its approval for ADHD based on concerns about safety.
Twelve of 933 patients developed a skin rash, with one case thought to be Stevens–
TRICYCLIC ANTIDEPRESSANTS (TCAS) AND SEROTONIN AND
NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIS)
As recently as 2007 guidelines reported, TCAs could be an option for ADHD.
However, their poor tolerability and dangerous effect on cardiac conduction has
resulted in more recently published guidelines in 2011 and 2014 to not recommend
The SNRI venlafaxine has shown efficacy in both adolescents and adults with
ADHD. This is a legitimate choice for comorbid anxious or depressed older patients,
but because of antidepressants having a risk of increasing suicidal thinking in
children, other options should be tried first. Adults often have this comorbidity and
venlafaxine in that population is more likely to be used.
There have been a number of studies that have tried to discern if certain diets may
result in ADHD. One of the most famous regimens is the Feingold Diet. Recent
reviews on the topic have found the evidence to be of low quality and of small
benefit. Most studies have not been blinded and when efficacy is noted it is of lower
rates than the FDA-approved pharmacotherapies. Additionally, there is a practical
limitation to the implementation of these diets as it eliminates many of the foods that
are regular parts of American meals. At this time it does seem reasonable to assume
that some children’s ADHD-like behavior may be related to intolerance to certain
dyes, artificial sweeteners, and flavors. One should not discourage a parent to
promote healthier food selection for their child, but the effectiveness of lowering
their symptoms is marginal. Additionally, if a child has a delay in administration of
pharmacotherapy because of trials of different types of diets then this could result in
persistency of symptoms longer than is necessary.
Many companies have created dietary supplements that have been touted as
effective remedies for treating and preventing ADHD, but convincing results derived
from rigorous trials are currently lacking and are likely to benefit a very few children
with food allergies or intolerances.
92–94 For instance, the use of very high doses of
vitamins or minerals has been promoted as a possible intervention, but all
randomized, controlled trials conducted to evaluate the effectiveness of megavitamin
therapy have been negative to date.
95 Omega-3 fatty acids have been considered as
possible treatments for ADHD, based largely on population studies demonstrating an
association between high dietary intake and a reduced risk of various
neuropsychiatric disorders. Omega-3 supplementation, specifically EPA content, may
have a small benefit as monotherapy. Studies of omega-3 as an adjunct to stimulants
have shown little added benefit.
96,97 Similarly, there have been reports of zinc, iron,
magnesium, Hypericum (St. John’s wort), and gingko all relieving ADHD symptoms,
but the evidence to support these interventions is very limited at the present time.
There have been other somatic treatments aimed at relieving ADHD symptoms that
may prove to be beneficial in the years ahead.
98 Several small randomized studies
have reported benefits with neurofeedback, in which children are trained to modify
certain brain activities demonstrated on electroencephalographic tracings (e.g.,
increased slow wave or α activity). Preliminary evidence also supports the
exploration of meditation as an effective
intervention for ADHD, particularly mindfulness-based methods that have proven
to be particularly helpful for depression and chronic pain conditions.
interventions have included cognitive-behavioral therapy, social skills training
programs and computer-based cognitive training programs. Early studies of some of
these intervention strategies have been promising and there is need for further
research to establish efficacy.
35 Regarding acupuncture a recent systematic review
failed to find any studies of sufficient rigor to include in their analysis.
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Depression is a common and often chronic disorder that may manifest at
any time in one’s life. Diagnostic criteria for major depression include a
minimum of five symptoms persisting for at least 2 weeks. One of these
symptoms must be either depressed mood or anhedonia. Suicidal
ideation should be assessed in all patients.
A variety of treatment modalities are available for the management of
depression. These include prescription medications, psychotherapy, and
somatic treatments. Prescription medications and/or psychotherapy are
indicated for depressive symptoms that are moderate to severe in
nature, whereas somatic treatments are for severe refractory cases.
All of the prescription medications that are currently available are
equally effective and possess the same delayed onset of therapeutic
effects. Selection of an antidepressant is based on many factors,
including previous response to medication, age, reproduction status, and
both medical and psychiatric comorbidities.
SSRIs are regarded as the initial treatment of choice for most depressed
patients. They are inexpensive and effective for comorbid anxiety
conditions, and possess a lower side effect burden than other
antidepressants overall. Side effects are generally mild and transient.
Educating the patient regarding side effects, how to monitor for efficacy,
and the duration of treatment is important action for successful
The goal of antidepressant treatment is remission of symptoms. Once
remission is achieved, the general recommendation is to continue the
effective antidepressant regimen for a minimum of 6 months.
Because only half of depressed patients will achieve remission with the
first antidepressant selected, clinicians should have a comprehensive
understanding of the role many antidepressants may have in optimizing
outcomes. Clinicians should be familiar with switching antidepressants in
patients with an incomplete response, and the merits of augmentation
Untreated depression in children under 18 has a significant risk of Case 86-3 (Questions 1, 2)
suicide. Treatment consists of talking therapy and specific
antidepressants, which is different than the broad options available to
Depression and chronic pain are commonly comorbid, and
pharmacologic treatment that addresses both is recommended. This
makes the SNRI class of antidepressants preferred.
In general, depressive disorders are enormous health concerns that are often
misdiagnosed or undertreated. The physical and social dysfunction associated with
depression is profound and is believed to outweigh many other chronic medical
conditions, including hypertension, diabetes, and arthritis.
Study determined that the degree of impairment in depressed individuals is
comparable to that seen in patients with chronic heart disease.
ramifications of depression are tremendous and place an overwhelming burden on
our society. In 2000, the estimated cost of depression in the United States was $83.1
billion annually, with most of these costs ($51.5 billion) attributed to lost
productivity and absenteeism in the workplace.
Since World War II, the lifetime incidence of depression has been rising steadily in
studied populations. The annual incidence of all mood disorders is approximately
10% in the adult population, and 1 in 15 adults (6.7%) will suffer from an episode of
major depression during any 12-month period.
4 Various studies from Europe and the
United States have estimated the 1 year and lifetime prevalence to be 4.1% and
5 Although the incidence of depression is remarkably similar
across various races and ethnic groups, the illness may be slightly more common in
lower socioeconomic classes and women having double the incidence than men.
The onset of depression occurs most commonly in the late 20s, but there is a wide
range, and the first episode may actually present at any age. Genetic factors appear to
play a major role in the cause of depression. The offspring of depressed individuals
are 2.7 times more likely to have depression if one parent is afflicted, and 3.0 times
more likely if both parents suffer from depression.
monozygotic (identical) twins range from 54% to 65%, whereas the corresponding
rates in dizygotic (fraternal) twins range from 14% to 24%.
predispose individuals to an earlier onset of depression (younger than 30 years of
8 Additionally, there is clear evidence that depression may occur as a result of
stressful events (i.e., environmental factors) in one’s life. These factors include a
difficult childhood, physical or verbal abuse, pervasive low self-esteem, death of a
loved one, loss of a job, and the end of a serious relationship. Acute depressive
episodes are often attributed to a combination of environmental and genetic factors.
For instance, individuals carrying a genetic predisposition to mood disorders may
undergo a stressful experience that ultimately triggers the manifestation of depressive
symptomatology. Depression may also occur spontaneously among people who
appear to lack any obvious genetic or environmental predisposition.
When assessing a person for depression, it is important to recognize the level of
impairment due to the symptoms. Just as with all biologic systems, the body can
function well within a particular range (e.g., serum potassium or BP). Mood is not
different; as long as the depressive symptoms are not prolonged or impairing, there
would be no reason to aggressively treat. Once the depression is severe enough to
impact functioning or induce harm, it requires treatment.
Major depressive disorder (MDD) may manifest as a single episode, but it is more
commonly a series of recurrent events. Thus, in most patients, depression is a chronic
5 The frequency of recurrent episodes is highly variable, with some people
experiencing discrete episodes separated by many years of relatively normal mood
(euthymia), and others experiencing residual symptoms between episodes that may
never completely remit. The risk of future episodes appears to increase
disproportionately with the chronicity of the illness. For instance, after the first
episode there is a 50% likelihood of a second episode. After the second, there is a
70% chance of a third, and with the third episode comes nearly a 90% incidence of a
Classification of Depressive Disorders
Persistent depressive disorder
Disruptive mood dysregulation disorder
Premenstrual dysphoric disorder
Substance/medication-induced depressive disorder
Depressive disorder due to another medical condition
Other specified depressive disorder
Unspecified depressive disorder
Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013.
The Diagnostic and Statistical Manual 5th edition (DSM-5) describes different
types of depressed states. These include disruptive mood dysregulation disorder,
MDD, persistent depressive disorder, premenstrual dysphoric disorder,
substance/medication-induced depressive disorder, depressive disorder due to
another medical condition, other specified depressive disorder, and unspecified
depressive disorder (Table 86-1).
9 The different types of depressive disorders may
then be subclassified using cross-sectional symptom features, or specifiers. For
example, the phrase “with anxious distress” which infers that there are anxiety
symptoms such as worry and feeling keyed up. The term “with mixed features” infers
that there are manic or hypomanic symptoms. The term “with melancholic features” is
used when patients possess primary neurovegetative symptoms, early morning
awakening, marked psychomotor agitation or retardation, and significant anorexia or
weight loss. Melancholia is often a more severe form of depression, and it often
lacks apparent environmental triggers.
It may also be less likely than other forms
of depression to remit spontaneously. The phrase “with atypical features” is used
when depressive symptoms include weight gain, hypersomnia, leaden paralysis, or
rejection sensitivity. When hallucinations or delusions occur in patients who are
primarily depressed, the phrase “with mood congruent or mood incongruent
psychotic features” is applicable to the mood disorder. Other diagnostic specifiers
used in DSM-5 include “with catatonia,” and “with peripartum onset,” and “with
Persistent depressive disorder is a type of depressive illness characterized by
fewer symptoms and less intensity than major depression, but the course is much
more chronic with symptoms being present most of the time for at least 2 years. In
practice, the detection of persistent depressive disorder may be difficult to make
because patients often do not seek treatment because they are still functional (e.g., go
to school, work, care for children) but they have significant morbidity. They will
have less satisfaction with work and will get fewer promotions and poor raises. The
treatment for persistent depressive disorder has traditionally focused on
psychotherapy, but evidence suggests that antidepressant medications may actually be
Symptoms of depression may be induced or exacerbated by numerous medical
illnesses or medications (Tables 86-2 and 86-3).
1,5,10 Consequently, DSM-5 specifies
that whenever an medical event is temporally related to the onset of depressive
symptoms, the patient does not fit the criteria for major depression, even if all other
9 The rationale for this stipulation is that if the medical illness is
successfully treated or the offending agent is discontinued, the depressive illness
would spontaneously resolve, eliminating the need for psychiatric intervention.
Although lists of medical illnesses or medications are helpful, the clinician should be
aware that the actual evidence demonstrating an association between depression and
specific organic causes is limited. If a medication or condition is suspected of
causing depression, the chronologic association should be investigated rigorously
before other action is taken. Additionally, a patient with a medical illness such as a
hormonal abnormality may have depressive symptoms from the condition but can
additionally have concomitant MDD. Treating the medical condition will likely
lessen the severity but the MDD will still have to be treated as well.
Selected Medical Conditions That May Mimic Depression
American Psychiatric Association. 2010.
Selected Medications That May Induce Depression
Gonadotropin-releasing hormone agonists
Oral and implanted oral contraceptives
High-dose lipophilic β-blockers
Psychother Psychosom. 2004;73(4):207–215.
For a diagnosis of MDD to be made, symptoms must be present for at least 2 weeks
and must not be precipitated or influenced by a medical illness or medication
(according to DSM-5 criteria). Individuals must possess at least five symptoms, one
of which is either depressed mood or anhedonia (diminished interest or pleasure in
activities). The other seven symptoms are as follows:
Change in appetite or significant weight loss or gain
Psychomotor agitation or retardation
Feelings of worthlessness or inappropriate guilt
Poor concentration (or difficulty making decisions)
Recurrent thoughts of death or suicidal
The diagnostic criteria also state that the mood disturbance must cause marked
distress or result in clinically significant impairment of social or occupational
functioning. Additionally, the symptoms cannot be due to a medical or organic illness
The monoamine hypothesis proposed that decreased synaptic concentrations of
norepinephrine (NE) and/or serotonin (5-HT) caused depression. The NE depletion
theory was originally based on the observation that reserpine, which depleted
catecholamine stores in the central nervous system (CNS), was capable of causing
12,13 This theory evolved into the permissive hypothesis, which
emphasized a greater role for serotonin in promoting or “permitting” a decline in NE
function. Specifically, this hypothesis suggests that low concentrations of serotonin or
NE in the CNS precipitated depressive symptoms. Studies have shown that a 5-HT
synthesis deficiency is correlated with depression. This has been shown in both
persons genetically unable to produce 5-HT and those who have depleted precursors
14,15 Selective serotonin reuptake inhibitor (SSRI) and serotonin and
norepinephrine reuptake inhibitor (SNRI) antidepressants, which functionally include
the tricyclic antidepressants (TCAs), are believed to relieve depression by inhibiting
the reuptake of serotonin alone or serotonin and NE from the synapse up into the
neuron, effectively increasing neurotransmitter concentrations in the synaptic
16,17 Mirtazapine and MAOIs work via different mechanisms, but also increase
5-HT and NE (and DA for the MAOIs).
Diagnostic Criteria for Depressive Episode
change from previous functioning. One of the symptoms must be either depressed mood or loss of
Depressed mood most of the day, nearly every day
Loss of interest in pleasurable activities most of the day, nearly every day
Significant change in weight or appetite (increase or decrease) when not dieting
Insomnia or hypersomnia nearly every day
Fatigue or loss of energy nearly every day
Diminished ability to think or concentrate, or indecisiveness
Feelings of worthlessness or excessive or inappropriate guilt nearly every day
Psychomotor agitation or retardation nearly every day
Recurrent thoughts of death or suicidal ideation
schizoaffective, delusional, or bipolar disorder.
Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013.
Depression has been associated with changes in presynaptic and postsynaptic
receptor densities (or sensitivities) that have been described as being downregulated
18 Changes include a decrease in postsynaptic α-adrenergic receptor
sensitivity, along with alterations in the sensitivities of the α-adrenergic,
), and serotonin receptor subtypes (5-HT1A and 5HT2A). For
example, SSRIs can increase the efficiency of serotonergic neurotransmission acutely
(through reuptake blockade), but their therapeutic effects are linked temporally with
increased release of serotonin through downregulation of presynaptic autoreceptors
19 This downstream impact explains why there is a delay in maximal
efficacy seen with all antidepressants.
As our understanding of neurobiology increases, it has been found that other
antidepressants. Such mechanisms include blockade of substance P and antagonism of
corticotropin-releasing factor or corticosteroid receptors.
Along with dysregulated neurotransmitter systems, neuroendocrine abnormalities may
contribute to the development of depression. Depressed patients often have abnormal
thyroid function tests (including low triiodothyronine [T3
25 Clinical hypothyroidism can also induce depressive symptoms,
and thyroid supplementation can reverse this pathology, suggesting an indirect
association between mood disorders and thyroid homeostasis.
pituitary–adrenal (HPA) axis may also influence the manifestation of depression,
with a relative hyperactivity of this system commonly reported in depressed
27,28 Pituitary and adrenal glands are often enlarged in depressed patients,
and concentrations of corticotropin-releasing factor are often elevated during
depressive episodes and decline with the administration of antidepressant
medications or electroconvulsive therapy (ECT).
22,29 Exogenous administration of
corticotropin-releasing factor has elicited classic symptoms of depression in
laboratory animals (including decreased appetite, anxiety, insomnia, and decreased
In humans, medications that block postsynaptic corticosteroid receptors
have also displayed antidepressant properties.
Interestingly, serotonin has been
recognized as a strong influence on the HPA axis (and vice versa). Activation of the
postsynaptic serotonin receptors (5-HT2
) along the hypothalamic paraventricular
nucleus can stimulate corticotropin-releasing hormone–secreting neurons. Loss of
hippocampal volume in major depression leads to increased levels of circulating
glucocorticoids, which leads to neuronal apoptosis.
chronic stimulation of the HPA axis has been implicated in potentially reducing gray
matter loss in humans. It should be noted that the relationship between hippocampal
volume and depression is not consistently observed and that various factors may
33 Corticosteroids can also modulate serotonin synthesis,
22 However, the data in this area are inconsistent because
different medications will have differing effects on cortisol despite being effective as
well as depressive subtypes showing different effects on cortisol.
inflammatory cytokines are seen in prospective and postmortem studies of depressed
patients but, again, is not consistent.
Over the last few years, significant scientific advances have been made in genetics
and pharmacogenomics. Several genes have been implicated in predictive response
or adverse effects to antidepressants. Pharmacodynamic targets have focused on
serotonin transporters (5-HTTLPR), tryptophan hydroxylase enzymes 1 and 2 (TPH1
and TPH2), 5-HT1A and 5-HT2A receptors, brain-derived neurotrophic factor
(BDNF), G-protein β-3 subunit (GNB3), and monoamine oxidase enzymes and p-
glycoprotein; pharmacokinetic targets have been focused on polymorphic variations
in CYP1A2, CYP2C19, CYP2D6, and CYP3A4 enzymes.
serotonin transporter SLC6A4 gene have been associated with remission and
response rate in a meta-analysis of 1,435 patients.
38 Researchers found that patients
with the ss genotype are less likely to reach remission during SSRI treatment and take
longer to achieve 50% symptom improvement compared to those with the ll
genotype. A recent review stated the genes SLC6A4, HTR2A, BDNF, GNB3,
FKBP5, ABCB1, and cytochrome P450 genes (CYP2D6 and CYP2C19) as being the
best correlated with depression.
40 A major challenge with pharmacogenomic studies
lies in the difficulty of defining unambiguous drug response phenotypes in complex
diseases, such as depression. Most likely there are multiple genes that are involved
in disease phenotype, drug response, and toxicity. Gene–environment interactions
undoubtedly also play a role in the determination of these phenotypes.
Imaging studies (including computed tomography, magnetic resonance imaging,
positron emission tomography, and single-photon emission computed tomography)
suggest that patients with depression have regional brain dysfunction, most often
affecting the limbic structures and prefrontal cortex. Alterations in cerebral blood
flow and/or metabolism in the frontal–temporal cortex and caudate nucleus are
associated with common depressive symptoms such as dysphoria, anhedonia,
hopelessness, and flat affect.
Increased firing of the amygdala in the left hemisphere
has been linked in positron emission tomography studies with the future development
42 Because subtypes of depression have been linked to different
regional dysfunctions, a network hypothesis began to emerge that may lead to
improvements in depression diagnosis and targeted treatments.
seemingly increased hippocampal loss that is consistent with severity and duration of
Behavioral rating scales have been used for many years in drug efficacy studies and
are widely advocated for routine use in the clinical arena today. Rating scales are
helpful in assessing the severity of mental illness, quantifying changes in target
symptoms, and determining treatment efficacy, but they are not diagnostic. Rating
scales can vary in length, content, and format, and can be completed by providers,
patients, researchers, family members, or conservators. Numerous depression scales
have been developed, including the Hamilton Rating Scale for Depression (HAMD17 or HAM-D21
), the Hospital Anxiety and Depression Scale (HADS), the Beck
Depression Inventory (BDI), the Montgomery-Åsberg Depression Rating Scale
(MADRS), the Center for Epidemiological Studies Depression (CES-D) Scale, the
Patient Health Questionnaire (PHQ-9), and the Quick Inventory of Depressive
45–51 Because 30% to 50% of cases are
not detected in primary care, enhancing education of the clinicians in this area has
shown some benefit. Generally, a two-step process of screening with a simple
questionnaire, such as the PHQ-9 or the HADS, and then a more thorough evaluation
if the screening results in a positive score are the recommended methods of detecting
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