AZSTARYS for ADHD
Intro: Stimulant mnemonics
from Cafer's Psychopharmacology: Visualize to Memorize 270 Medication Mascots
Dexmethylphenidate and Serdexmethylphenidate (AZSTARYS)
Phonetic pronunciation: DEX meth uhl FEN i deyt / az STAR is
FDA-approved for: ADHD (age 6+)
Azstarys was approved in 2021 for treatment of ADHD in patients over age 6. It is a combination of two methylphenidate stimulants—30% dexmethylphenidate (available generically as Focalin) and 70% serdexmethylphenidate (SDX), which is unavailable individually.
SDX is a prodrug of dexmethylphenidate which has a delayed onset of action and a prolonged duration of effects compared to dexmethylphenidate. SDX is converted to dexmethylphenidate in the lower gastrointestinal tract by unidentified enzymes. If injected intravenously dexmethylphenidate is active but SDX is not.
The dexmethylphenidate component starts working in 30 minutes. The serdexmethylphenidate component lasts for 13 hours. The manufacturer touts Azstarys for causing less appetite suppression than alternative stimulants—"shown to have a minimal impact on childhood growth".
In 2021 the FDA granted approval for clinical trials investigating SDX (without dexmethylphenidate) for the treatment for stimulant use disorder.
General Info about Schedule II Stimulants
Psychostimulants are “sympathomimetics” that mimic the action of norepinephrine (NE) and dopamine (DA) to activate the sympathetic (fight or flight) nervous system. NE and DA directly bind to NE and DA receptors. Stimulants act indirectly by inhibiting the release or slowing reuptake of NE and DA. In general, stimulants increase energy, improve focus/concentration, and suppress appetite. Dry mouth is a common side effect.
The principal target symptoms for treatment of attention deficit hyperactivity disorder (ADHD) are inattention and impulsivity. Patients with ADHD have difficulty activating areas of the prefrontal cortex due to weak dopaminergic and noradrenergic transmission. Stimulants “wake up” these sleepy pathways by blocking reuptake of dopamine (DA) and norepinephrine (NE).
Most children with predominantly hyperactive ADHD eventually “grow out of it” as these neural pathways strengthen with age. Predominantly inattentive ADHD usually does not tend to improve throughout adulthood. Although adults with ADHD may be impaired by inattentive symptoms, ADHD is often not the focus of pharmacotherapy because of comorbid conditions. If applicable to a given patient, drug/alcohol addiction should be top priority, followed by mood disorders, then anxiety disorders, then ADHD,(and then smoking cessation).
Note that there is no such thing as adult-onset ADHD. As defined by DSM-5, symptoms must be present prior to age 12. Unfortunately, ADHD medications across the board have been found to be less efficacious and less well tolerated in adults than in children/adolescents (Cortese et al, 2018).
The first-line treatment of ADHD is a stimulant of the amphetamine or methylphenidate class. Milligram per milligram, Adderall (amphetamine) is about twice as potent as Ritalin (methylphenidate). Adderall 10 mg is approximately equivalent to Ritalin 20 mg. These medications are dramatically effective for 75% of individuals with ADHD. Some of the stimulants are approved for children as young as age 3, but most are approved for ages 6 and above. Generally, stimulants start working within 0.5–2 hours and lose all effectiveness by evening—otherwise they would interfere with sleep. They are detectable in serum at subtherapeutic levels for about 48 hours.
Prescription amphetamines and methylphenidates are all Schedule II controlled substances, the same level of restriction as opioid pain medications. Prescriptions for Schedule II substances cannot be phoned into the pharmacy or include refills.
The Schedule II stimulants (amphetamines and methylphenidates) have a Black Box Warning for risk of abuse and dependence. However, risk of addiction with prescription stimulants taken as prescribed is very low. No other boxed warnings have been applied to Schedule II stimulants.
Amphetamine can be addictive when taken at high dose and is highly addictive if injected intravenously. PO opioids are much more addictive than PO amphetamines. While withdrawal from opioids is highly distressing, withdrawal from stimulants is less severe and mostly consists of fatigue, hypersomnia, irritability, and increased appetite.
Many psychiatrists believe prescription amphetamines are overly regulated, especially in the case of lisdexamfetamine (Vyvanse) which has gradual onset of action, even if snorted or injected.
Modafinil (Provigil) is a less restricted (Schedule IV) stimulant that may have comparable efficacy for ADHD when used off-label (Wang et al, 2016). Although less addictive than amphetamine, modafinil is not necessarily safer or better tolerated. The norepinephrine reuptake inhibitor atomoxetine (Strattera) is noncontrolled and approved for ADHD but is substantially less effective than stimulants.
At doses effective for ADHD, the difference between amphetamine and methylphenidate is minimal, like Coca-Cola vs Pepsi—both inhibit reuptake of dopamine (DA) by blocking the dopamine transporter (DAT). When abused, the potential for addiction is greater with amphetamine. At high dose, amphetamine has the additional mechanism of entering neurons and displacing DA from synaptic vesicles and causing DA to be released in the reward pathway, resulting in euphoria.
Slow-release stimulant formulations do not have pleasurable effects and can be more effective for ADHD than immediate-release formulations. Blocking the dopamine transporter (DAT) causes entirely differing responses depending on how quickly and completely DAT is blocked. If DAT occupancy is rapid (e.g., taken IV or snorted), intermittent and saturated, the result is a euphoric “high”. ADHD symptoms are best relieved when DAT occupancy is gradual, non-saturated, constant and prolonged. This is best accomplished by a modestly dosed, slow-onset, long-duration stimulant formulation. For most individuals, the FDA maximum dose for a given stimulant is no more effective than a moderate dose.
On college campuses, prescription stimulants are commonly diverted for nonmedical uses such as all-night studying and countering sedation from binge drinking. Prescribers can minimize risk of diversion (i.e., patients sharing their pills) by limiting supply to one extended-release capsule daily. Vyvanse and Mydayis are suitable long-acting amphetamines. Suitable methylphenidate products include Concerta, Aptensio XR and Adhansia XR. These stimulants can also be more effective for ADHD by providing a slow-rising and constant steady-state level of stimulant.
If the dose is too high, stimulants can cause tremor, restlessness, and irritability. At even higher doses stimulants can produce paranoia, arrhythmias, and elevated body temperature. In overdose, stimulants can cause heart failure, seizure, and stroke.
Even at therapeutic doses, stimulants increase blood pressure (averaging 2 to 4 mmHg) and heart rate (averaging 3–6 bpm); some individuals have larger increases. Sudden death has been reported in association with stimulants at recommended doses in pediatric patients with structural cardiac abnormalities or other serious heart problems. Avoid prescribing stimulants to patients with known cardiac abnormalities, cardiomyopathy, serious heart arrhythmias, or coronary artery disease. Several large studies have found no evidence that stimulants increase the risk of serious cardiovascular events for individuals without known heart problems. A screening EKG is not necessary prior to starting a stimulant for an individual with no history of heart disease. Patients on stimulants who develop exertional chest pain or unexplained syncope need further evaluation.
Stimulants may worsen tic disorders in ⅓ of cases by increasing DA activation in brain areas involved in movement. For some individuals, stimulant-related tics improve when the dose is decreased. For a smaller group of individuals, stimulants may trigger tics that persist for several months after the stimulant is stopped, before eventually resolving spontaneously.
Stimulants may induce manic or psychotic episodes. Stimulants are to be avoided in patients with unstable bipolar disorder or schizophrenia. However, bipolar patients stabilized on an antipsychotic are often able to tolerate a stimulant for ADHD. While the stimulant increases DA activity in the prefrontal cortex (at D1 receptors) the antipsychotic blocks DA activity in the limbic system (at D2 receptors) sufficiently to prevent recurrence of mania or psychosis. Bipolar patients should be monitored closely for mood destabilization and the stimulant discontinued immediately if signs of mania arise.
Stimulants may increase anxiety in some individuals, but those with ADHD are more likely to experience stimulants as calming if dosed appropriately. Paradoxically, some patients with ADHD complain stimulants make them overly slowed or even “zombified”.
Stimulants decrease appetite by increasing adrenergic and dopaminergic activity in the hypothalamus. Children ages 7–10 years old taking stimulants 7 days per week throughout the year demonstrate growth retardation, averaging 2 cm, without evidence of growth rebound upon discontinuation of the stimulant. Taking periodic “drug holidays” from the stimulant can minimize stunting of growth. For children with severe ADHD, drug holidays may not be advisable.
Rarely, stimulants can cause priapism in boys and men. It is possible to develop priapism upon stopping the stimulant, e.g., for a drug holiday. Stimulants rarely cause Raynaud's phenomenon, which is expected to resolve with dose reduction or discontinuation.
Several stimulants are approved for narcolepsy. One amphetamine product is approved for short-term treatment of obesity (Evekeo), and another for long-term treatment of binge eating disorder (Vyvanse). Stimulants are used off-label for short-term treatment of depression, particularly in elderly patients. Tolerance to the antidepressant effect is expected to develop in 2 to 4 weeks. Poststroke lethargy and apathy may respond to stimulants, with potential long-term effectiveness. 70–90% of individuals with multiple sclerosis experience fatigue, which may be responsive to stimulants.
For treatment of ADHD there is no intervention nearly as effective as medication. Adjunctive interventions that may be beneficial include omega-3 fatty acids, sleep hygiene interventions, and cognitive behavioral therapy (CBT). EEG neurofeedback is time consuming, expensive, and ineffective, at least for adults (Schönenberg et al, 2017).
The main purpose of the stimulant mnemonics in Cafer's Psychopharmacology: Visualize to Memorize 270 Medication Mascots is to help you differentiate the “Adderalls” (amphetamines) from the “Ritalins” (methylphenidates). Amphetamine pictures include an amplifier, while methylphenidates are depicted as scantron sheets.