What are possible adverse effects of magnesium pemoline (Cylert) in the treatment of attention deficit hyperactivity disorder (ADHD)?

Medical Care

Stimulants

Regarding medication for ADHD, stimulants are the first-line therapy and probably the most effective treatment. Examples of stimulants for treatment of ADHD include methylphenidate, dextroamphetamine, dexmethylphenidate, lisdexamfetamine, serdexmethylphenidate, and amphetamine.

All stimulants have similar efficacy but differ by dosing, duration of action, and adverse effect profiles in individual patients. Care should be made to start at the lowest dose and titrate up for clinical efficacy or to intolerance.

Targeted symptoms include impulsivity, distractibility, poor task adherence, hyperactivity, and lack of attention.

Some stimulants come in sustained-release preparations, which may decrease the number of total daily doses. Otherwise, dosing should be spaced every 4–6 hours.

Generally, stimulants are taken in the morning and not at bedtime owing to significant insomnia. An exception is the methylphenidate product Jornay PM, which is designed as a delayed- and extended-release product to optimize tolerability and efficacy the next morning and throughout the following day.

Other common adverse effects include appetite suppression and weight loss, headaches, and mood effects (depression, irritability).

Stimulants may exacerbate tics in children with underlying tic disorders.

Whether growth might be affected while a child is taking stimulants remains unclear. Drug holidays (during summer or on weekends) may or may not be recommended to allow periods of normal growth. The decision is based on the child’s growth rate chart and behavior and cognition off medication.

Psychosis with stimulant treatment

There has always been a concern about the possibility of psychosis with the use of the stimulants amphetamine and methylphenidate (MPH) to treat persons with AHDH. Moran et al. assessed 337,919 adolescents and young adults who received a prescription for a stimulant for ADHD. They looked at data from two commercial insurance claims databases to assess patients 13 to 25 years of age who had received a diagnosis of ADHD and who started taking MPH or amphetamine between January 1, 2004 and September 30, 2015. They found there were 343 episodes of psychosis: 106 episodes (0.10%) in the MPH group and 237 episodes (0.21%) in the amphetamine group. The researchers concluded that among adolescents and young adults with ADHD who were receiving prescription stimulants, new-onset psychosis occurred in approximately 1 in 660 patients. Amphetamine use was associated with a greater risk of psychosis than MPH. Furthermore, in the databases used for this study, 2 million patients received a prescription for amphetamine. Results suggest that a difference of 1 per 1000 person-years potentially confers additional risk of psychosis with amphetamine in thousands of patients. [34]

Substance abuse with stimulant treatment

There has long been concern that the use of stimulant therapy leads to substance abuse. However, several studies have demonstrated that stimulant therapy does not increase the risk of future substance use or abuse. [35] In one study, 112 people with ADHD were observed for a period of 10 years. At the time of the follow-up assessment, 82 (73%) had been treated previously with stimulants and 25 (22%) were undergoing stimulant treatment. No statistically significant associations were noticed between stimulant treatment and alcohol, drug, or nicotine use disorders. The findings revealed no evidence that stimulant treatment increases or decreases the risk for subsequent substance use disorders in children and adolescents with ADHD when they reach young adulthood. [36]

Stimulant medications do enhance mental executive functions for those with ADHD. [37]  A groundbreaking trial, the first to study ADHD with sluggish cognitive tempo (SCT) in adults, demonstrated effectiveness of the stimulant lisdexamfetamine for comorbid symptoms. Results showed that the stimulant reduced self-reported symptoms of SCT by 30%, in addition to lowering ADHD symptoms by more than 40%. Lisdexamfetamine also corrected deficits in executive brain function, and patients exhibited fewer episodes of procrastination with better ability to prioritize. [38]

Other medications

The selective norepinephrine reuptake inhibitor (SNRI), atomoxetine (Strattera) has become a second-line and, in some cases, first-line treatment in children and adults with ADHD because of its efficacy and classification as a nonstimulant. However, studies have reported that the overall effect of atomoxetine has not been as extensive as that reported of stimulants. Another SNRI, viloxazine (Qelbree) was approved by the FDA in 2021 for children aged 6-17 years with ADHD.

Data suggest that bupropion or venlafaxine may be effective. Dosages are similar to those used to treat depression.

Tricyclic antidepressants (imipramine, desipramine, nortriptyline) have been found effective in numerous studies in children with ADHD; however, because of potential adverse effects, they are rarely used for this purpose. If these agents are used, obtain a baseline ECG because these agents can affect cardiac conduction. A few reports have described sudden death in boys taking desipramine, but the exact cause of death was unclear and may have been unrelated to desipramine use.

Clonidine and guanfacine have been used with mixed reports of efficacy. Sudden deaths have been reported in children taking clonidine with methylphenidate at bedtime. Again, the etiology of these deaths is unclear, and this remains a controversial topic. In September 2010, the FDA approved clonidine extended-release (Kapvay) for ADHD as adjunctive therapy to stimulants or as monotherapy.

Modafinil (Provigil) has recent placebo-controlled data supporting its efficacy in children with ADHD. This medication may currently be used as a third- or fourth-line treatment.

Magnesium pemoline (Cylert) had been used in the 1990s, but concerns of rare, potentially fatal hepatotoxicity have made it a rarely used medication.

Blader et al evaluated the ability of divalproex to reduce aggressive behavior in children with ADHD and a disruptive disorder. Children with persistent aggressive behavior that was underresponsive to psychostimulant therapy were randomly assigned to receive divalproex or placebo in addition to stimulant therapy for 8 weeks. A higher proportion of improved behavior was observed in the divalproex group (8 of 14 [57%]) compared with placebo (2 of 13 [15%]). A larger trial is needed to further study the use of divalproex to ameliorate aggressive behavior in patients with ADHD. [39]

Behavioral psychotherapy

Behavioral psychotherapy often is effective when used in combination with an effective medication regimen. Behavioral therapy or modification programs can help diminish uncertain expectations and increase organization.

Working with parents and schools to ensure environments conducive to focus and attention is necessary.

For adults with ADHD, working to establish ways of decreasing distractions and improving organizational skills may be helpful.

Cognitive therapy for adults with ADHD

Metacognitive therapy involves the principles and techniques of cognitive and behavioral therapies to enhance time management. In doing so, these have made adult patients with ADHD better able to counter the anxiety and depressive symptoms they experience in task performance. Metacognitive therapy has proven to be more effective than supportive interventions and represents a viable therapeutic approach. [40]

Psychosocial interventions

A number of psychosocial treatments are effective. These include behavioral parent training (BPT) and behavioral classroom management (BCM). [41] These are best used in conjunction with psychopharmacological approaches.

Emerging evidence shows that nonpharmacological treatments should be considered the first treatment for children with ADHD. For preschoolers, intervention is best with parental training. For school-aged children, interventions of group training for parents and classroom behavioral approaches might be enough. Severe cases benefit from medication and behavioral interventions. [42]

Nonpharmacological interventions

Concern about medications to treat ADHD has increased interest in alternative treatments. Researchers conducted a systematic review and meta-analysis of randomized controlled trials of dietary and psychological treatments for ADHD and found that free fatty acid supplementation produced small but significant reductions in symptoms. A larger effect was observed with artificial food color exclusion, but this was seen in individuals selected for food sensitivities. Further studies are needed to assess behavioral interventions, neurofeedback, cognitive training, and restricted elimination diets. [43]

In April 2019, the FDA approved the first medical device to treat childhood ADHD. The prescription-only device is indicated for patients ages 7 to 12 years old who are not currently taking prescription ADHD medication. The trigeminal nerve stimulation (TNS) system is the size of a cell phone and generates a low-level electrical pulse to the branches of the trigeminal nerve. Approval was based on a clinical trial of 62 children that showed that subjects using the device had statistically significant improvement in their ADHD symptoms compared with the placebo group. [44]