Elizabeth Harari, MD

New research highlights the potential benefits and detriments of treatment strategies for ADHD, which include both pharmacological and nonpharmacological options (

Stimulants are the first line of treatment for ADHD and are typically well tolerated. Although there are potential adverse effects associated with stimulant administration, the most common are usually transient or dose related. One of the more serious effects is stimulant-induced psychosis.

To explore this risk, Moran and colleagues

 examined the records of 337,919 young persons aged 13 to 25 who had an ADHD diagnosis and were newly prescribed a stimulant medication. The researchers found 343 episodes of new-onset psychosis among the 221,846 study-matched population over an 11-year period. The median time from which the first stimulant was dispensed to the psychotic episode was 128 days.

The researchers concluded that the risk of new-onset psychosis was approximately doubled for individuals who received amphetamine compared with those who received methylphenidate. This supported their hypothesis, which was based on the similarities between idiopathic psychosis and the biologic effects of amphetamine. Individuals with primary psychosis have higher presynaptic dopaminergic capacity, which is an index of dopamine release.

Limitations of the study included: unmeasured confounding factors (ie, underreporting of substance use disorder), not knowing if the patients actually took the stimulant medication (there is a high rate of diversion, which is greater for amphetamine than methylphenidate), and the study findings, are not generalizable as the data were only from commercial insurance claims and did not take into account patients with no insurance or public insurance.

While the exact therapeutic mechanism of action of stimulants is unknown, they are thought to increase the availability of dopamine in the postsynaptic cleft by blocking the reuptake of dopamine. Amphetamine blocks the ability of the dopamine transporter to remove dopamine from the synapse, facilitates the reuptake of dopamine across the cell membrane, increases the release of vesicular dopamine (accumulates in the cytoplasm), and inhibits the degradative enzymes monoamine oxidase A and B. Methylphenidate binds to the dopamine transporter in the presynaptic cell membrane, blocking the reuptake of dopamine and, therefore, causing an increase in extracellular dopamine. The difference is that methylphenidate does not promote dopamine release from synaptic vesicles. Moreover, amphetamine induces the release of four times as much dopamine as methylphenidate.

 This increase of dopamine may contribute to adverse effects such as stimulant-induced psychosis.

Cases of stimulant-induced psychosis have been reported as early as 1938.

 However, the first case of a child who experienced auditory, tactile, visual hallucinations, and paranoia after treatment with a therapeutic dose of D-amphetamine for hyperactivity was not published until 1967.

 The 8-year-old child’s symptoms of psychosis resolved after the medication was discontinued. A few years later, similar cases were reported by Lucas and Weiss

 after they observed “psychotic reactions” in two children following a short-term therapeutic dose and in an adolescent after ingestion of excess medication after long-term use of a therapeutic dose of methylphenidate, which had been prescribed for hyperactivity.

It was not until 2007 that the FDA mandated a drug label warning that stimulants may cause psychosis in patients with no prior history. There remains limited data on whether the risk of psychosis differs among the two classes of stimulants.

While the incidence of new-onset psychosis with stimulant treatment for ADHD is small, this can be a frightening experience for the child as well as his or her parent and may negatively impact a parent’s decision to pursue stimulant treatment options. Thus, nonstimulant and non-pharmacological treatment options are often requested. Indeed, many parents continue to search for 

, especially for children with a newly established diagnosis.

 Until recently, there have been no viable nonpharmacological alternatives.

Trigeminal nerve stimulation may offer a nonpharmacological option

With concerns over potential adverse effects of medications, other strategies have been explored for treating ADHD. Preliminary studies using trigeminal nerve stimulation (TNS) to treat ADHD symptoms have peaked interest as a potential alternative or adjunctive treatment to stimulant and non-stimulant medications. TNS is a non-invasive, home administered, well-tolerated approach that has 

 Researchers became interested in TNS for ADHD after observing improvements in concentration and attention on mood disorder rating scales.

The stimulation device is compact and worn on clothing during sleep. Thin wires from the stimulator are attached to adhesive electrode pads that are placed on the forehead bilaterally over the ophthalmic branch (V1) of the trigeminal nerve. A current is sent through the wires to activate the trigeminal nerve, which projects to the nucleus tractus solitarius activating the locus coeruleus and the reticular formation. These play a key component in cognitive functions, particularly in sustaining attention.

The recent double-blind sham control study by 

 looked at cortical activation mechanisms using a quantitative electroencephalogram. The researchers found increased spectral power in the right frontal and frontal midline bands with active TNS, hypothesizing that activation of the frontobasal ganglia network targets hyperactivity and impulsivity. This mechanism of action helps to support the overall findings for improvement in both the inattention and hyperactivity components of ADHD.

During trials, the pattern of improvement on ADHD Rating Scale-IV (ADHD-RS) as well as on the Connor’s rating scale was comparable to that seen with non-stimulant medication.

 In this double-blind sham-controlled study by McGough and colleagues, symptomatic improvement was found to be highest after the first week of treatment; scores continued to improve over the next 3 weeks. While the sham group showed improvement over the first week, it was followed by a flattening response. One week after treatment discontinuation, rating scales were again administered in both the active and the sham groups. In both groups, scores from the ADHD-RS were found to decrease, indicating a recurrence of symptoms. This 4-week trial showed sustained improvement in both hyperactivity and inattention symptoms of ADHD with nightly active treatment.

Unfortunately, there are no long-term studies of mood or ADHD with TNS. Continued trials need to be undertaken to determine long-term outcomes as well as clear parameters for treatment.

The cost of the device used in the study, Monarch-TNS, is just over $1000; it is not currently covered by insurance. Other available TNS devices range between $250 and $450; their efficacy, however, is unknown. It is difficult to compare the cost of TNS versus stimulant and non-stimulant medications, since there is such a wide range in cost. The monthly cost ranges from approximately $8 for a generic stimulant and may exceed $288 for a branded product. Most insurance companies will cover at least some medication costs.

TNS has been well tolerated with high safety and compliance rates. A long-term follow-up study for TNS use in epilepsy demonstrated skin irritation as the main adverse effect from treatment.

 of short-term TNS include headache and eye twitches.

 Based on the 4-week double-blind sham study, the manufacturer of the Monarch-TNS treatment device also noted drowsiness, increased appetite, trouble sleeping, and fatigue as possible side effects. No withdrawal effects have been observed.

 suggest that TNS may be effective for ADHD as an alternative treatment to stimulant and non-stimulant medications given symptomatic improvement in both inattention and hyperactivity symptoms of ADHD. Although direct comparison of TNS to pharmacological treatment has not been undertaken, treatment may be considered in children with parental preference against pharmacological treatment after providing psychoeducation or in children who cannot tolerate psychotropic medications. TNS as an adjunctive therapy may also be considered; however, adjunctive use has not been studied.

Currently, several limitations remain a concern. First, clear parameters (eg, duration of treatment, number of treatments, the need for booster sessions) have not yet been identified. Second, there are no long-term studies for mood symptoms or ADHD, which limits the available data on long-term efficacy for TNS as a treatment. Third, the device itself is available but will come at a high out-of-pocket cost, thereby restricting treatment access.

Based on these limited data, TNS appears to be an effective, safe, well-tolerated option with high compliance rates. Although more studies are needed, this treatment has high potential for use in managing the symptoms associated with ADHD.

Dr Griffin is Assistant Professor of Psychiatry, the Medical Director of Outpatient Child and Adolescent Psychiatry, and the Director of the Child and Adolescent ADHD Clinic at Rush University Medical Center, Chicago, IL. Dr Harari is a first-year Child and Adolescent Psychiatry Fellow at Rush University Medical Center. The authors report no conflicts of interest concerning the subject matter of this article.

 Moran LV, Ongur D, Hsu J, et al. Psychosis with methylphenidate or amphetamine in patients with ADHD. 

 Schiffer WK, Volkow ND, Fowler JS, et al. Therapeutic doses of amphetamine or methylphenidate differentially increase synaptic and extracellular dopamine. 

 Young D, Scoville WB. Paranoid psychosis in narcolepsy and the possible danger of Benzedrine. 

 Ney PG. Psychosis in a child, associated with amphetamine administration. 

 Lucas AR, Weiss M. Methylphenidate hallucinosis. JAMA. 1971;217:1079-1081.

 dosReis S, Park A, Ng X, et al. Caregiver treatment preferences for children with a new versus existing attention-deficit/hyperactivity. 

 Barbaresi WJ, Colligan RC, Weaver AL, et al. Mortality, ADHD, and psychosocial adversity in adults with childhood ADHD: a prospective study. 

 Danielson ML, Bitsko RH, Ghandour RM et al. Prevalence of parent-reported ADHD diagnosis and associated treatment among U.S. children and adolescents. 

 McGough JJ, Sturm A, Cowen J, et al. Double-blind, sham-controlled, pilot study of trigeminal nerve stimulation for attention-deficit/hyperactivity disorder. 

 McGough JJ, Loo SK, Sturm A et al. An eight-week, open-trial, pilot feasibility study of trigeminal nerve stimulation in youth with attention-deficit/hyperactivity disorder. 

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New research highlights the potential benefits and detriments of treatment strategies for ADHD, including both pharmacological and nonpharmacological options.

Author | Elizabeth Harari, MD

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