Effectiveness of methylphenidate in adults with phenylketonuria and attention-deficit/hyperactivity disorder: An N-of-1 series

Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism
with a prevalence of 1 to 5 in 10.000 individuals. When dietary treatment is
not started early in life, neurological abnormalities develop such as
microcephaly, severe intellectual disability (ID), and impaired motor
functioning, caused by prefrontal white matter pathology and impaired monoamine
synthesis, including dopamine depletion. Psychiatric disorders often occur,
such as attention-deficit/hyperactivity disorder (ADHD).
Since neonatal screening started in 1974, enabling an early dietary treatment,
patients have near-normal cognitive outcomes. However, adults born before the
start of newborn screening affected by ID and ADHD symptoms often present with
behavioral problems due to their late or untreated PKU. This negatively impacts
functioning and quality of life of the patient and their caregivers, and
results in intensive, costly care.
PKU is an autosomal recessive disorder caused by defective activity of the
enzyme phenylalanine hydroxylase (PAH) which converts Phe to tyrosine (Tyr), a
precursor of dopamine. Without treatment, Phe levels rise, Tyr is limited, and
available Tyr competes with Phe to cross the blood-brain barrier, resulting in
lower levels of Tyr available to synthesize dopamine. In idiopathic ADHD,
decreased attention, restlessness, and impaired learning have been associated
with decreased levels of extracellular frontal and striatal dopamine. In PKU, a
molecular imaging study has suggested reduced striatal brain dopamine levels in
PKU, supporting the hypothesis that executive functioning deficits in adult PKU
may be associated with cerebral dopamine deficiency. The results of this study
also suggested a relationship between the availability of striatal dopamine and
degree of impulsivity, a major symptom of ADHD. Targeting the dopamine
imbalance may improve ADHD symptoms and even a broader domain of functioning in
late or untreated PKU.
Currently, behavioral problems in patients with late or untreated PKU are often
treated with antipsychotic drugs targeting the dopamine system by blocking
postsynaptic dopamine receptors, that may induce or aggravate parkinsonian
features, and even worsen behavioral problems due to the already
hypodopaminergic state. Instead, the first-line choice of treatment for ADHD
features methylphenidate (MPH), a dopamine reuptake inhibitor, may be
beneficial in PKU by raising brain dopamine availability. As currently no
evidence is available, there is a call from caregivers as well as health care
professionals for investigation of the effectiveness of MPH for ADHD symptoms.

The randomized controlled trial (RCT) is widely considered as the gold standard
method for demonstrating the effectiveness of an intervention. However, an RCT
at population level is significantly hampered when it comes to rare disorders
due to comorbidities and rarity of the conditions. Hence, reliable conclusions
about the effectiveness of the intervention cannot be clearly drawn due to
matching issues.
The N-of-1 methodology has been considered an appropriate alternative study
design to demonstrate causality of a symptomatic intervention in relatively
stable disorders at an individual level and with reversible outcome measures.
N-of-1 series are multiple cross-over placebo-controlled randomized trials
within an individual patient. N-of-1 series are suitable in examining the
effectiveness of interventions in diverse and relatively small populations.
Combining the results of several N-of-1 trials potentially yields information
that may be generalized at population level. N-of-1 trials enable
within-subject comparisons as the crossover efficiently provides flexibility in
the performance at an individual level, and therewith, demonstrate the relative
effectiveness at an individual level. Thus, N-of-1 series take variability in
treatment responses between individuals into account. Furthermore, multiple
opportunities are provided to maximize adherence and care that is both
patient-centered and evidence based. Overall, N-of-1 trials provide more
rigorous evidence for treatment decisions at individual levels, closely succeed
indications of causality between agent and effect as the key to studying
interaction is replication, and enhance precision when these treatment effects
are heterogeneous between individuals.
The value of N-of-1 trials is increasingly acknowledged, and applied to various
disorders including schizophrenia, cerebral palsy, traumatic brain injury,
inflammatory bowel disease, cystic fibrosis, attention-deficit/hyperactivity
disorder, obstructive airway diseases and migraine. Moreover, the N-of-1 design
was used to evaluate cognitive and behavioural effects of methylphenidate in
children with Williams syndrome concluding that methylphenidate is a useful
adjunct in the treatment of some children with that syndrome.
We will examine the effectiveness of methylphenidate in patients with
late-diagnosed PKU and ADHD symptoms, using an N-of-1 series. We consider that
N-of-1 trials to study treatment effects of methylphenidate on ADHD symptoms
are appropriate given that: 1) ADHD has a chronic and stable clinical course;
2) methylphenidate has a rapid onset and termination of actions; and 3)
caregivers seek for confirmation for the use of stimulants because of biases
and doubts. In this way, structured and evidence-based decisions can be made
for an individual patient at short notice. In addition, little is known about
the effectiveness of methylphenidate in patients with PKU with comorbid ADHD,
as pharmacologically an increase of dopamine might have a beneficial effect.
Our study results will provide crucial information about the effectiveness of
methylphenidate for ADHD symptoms in PKU.

Primary Objective: To determine the effectiveness of methylphenidate in
reduction of ADHD symptomatology, operationalized by personalized goals that
are important to the patient and its environment, in individuals with
late-diagnosed PKU.

Secondary Objective(s): To determine the effect of methylphenidate on emotion
dysregulation.

The N-of-1 series will consist of double-blind randomized placebo-controlled
multiple crossover trials within at least five individuals. The individual
N-of-1 trial will consist of three cycles each containing a randomized order of
4 seven-day periods: one active treatment (A), one placebo treatment (B), and
two *washouts* with placebo following A and B. The trial will start with a
baseline period of seven days without any intervention. A dose titration phase
of six days will follow with a washout period of 2-6 weeks before starting the
trial. The total duration of the trial will be up to 20 weeks with an
additional open-label extension phase. Outcome measures will be assessed during
the whole trial period at the end of interventional periods, and optionally
during the open-label extension phase three months after the last intervention
at the first follow-up measurement, and six months after the last intervention
during the second and final follow-up measurement.

Each participant receives multiple blocks consisting of an active treatment
period of twice daily methylphenidate (doses based on titration phase)
alternated with placebo and washout periods.

Blinded cross-over periods, the use of placebo and questionnaires are already
common clinical practice for regular ADHD treatment with methylphenidate. For
this study, a few clinical assessments and questionnaires are added to common
clinical practice. Furthermore, the additional washout periods extend the time
without active treatment. On the other hand, every participant is exposed to
the active treatment condition and an individual treatment decision will be
retrieved in terms of evidence-based medicine. Therefore, we expect the
benefits to substantially outweigh the burden of participation.