ADHD Medications and Stuttering?

Authored by Dr. Kyle Roedersheimer

Introduction to ADHD

• ADHD is the most well-known and researched neurodevelopmental disorder of childhood
• Approximately 5-6% of children and 2-3% of adults
• Both genetic and environmental factors are implicated
• The genes that are thought to code for ADHD are involved in the heritability of autism spectrum disorders and Tourette’s disorder
• In general, there are three types of ADHD; Inattentive, Hyperactive and Combined

 
History of Amphetamines

• First synthesized in 1887 and then first marketed in 1932 as a nasal decongestant
• Both amphetamine and methamphetamine were supplied as stimulants for soldiers and prisoners of war in WW II
• In the 1970s FDA made amphetamines schedule II and use declined
• However, increased use with derivatives methamphetamines and MDMA

Amphetamines

• Phenylethylamine is any structure with an ethyl group backbone that has an aromatic group and a terminal amine
• Specific substitutions made to the Phenylethylamine backbone have led to the wide variety of novel amphetamines
• Large-group substitution at the alpha carbon reduces the stimulant and cardiovascular effects but retains the anorectic properties
• Substitution at the para position of the phenyl ring enhances the hallucinogenic or serotonergic effects

Psychostimulants

• Phenylethylamine derivatives have become popular over the past 20 years in the treatment of ADHD
• The psychostimulants methylphenidate, dexmethylphenidate, lisdexamfetamine or amphetamine salts are most effective
• Alpha 2-adrenergic agonists such as extended release preparations of guanfacine and clonidine are less effective 

Mechanism of action

• Enter the nerve cell by either passive diffusion or exchange diffusion through reuptake transporter that is dose dependent
• Low concentrations, amphetamines release dopamine from cytoplasmic pool
• Moderate concentrations, amphetamines diffuse through the presynaptic terminal membrane and interact with the neurotransmitter transporter on the vesicular membrane to cause exchange release of dopamine into the cytoplasm
• High concentrations, amphetamines diffuse through the cellular and vesicular membranes
• They also block the reuptake of catecholamines by competitive inhibition and also thought to be weak monoamine oxidase inhibitors

Action at noradrenergic nerve ending –
1,2 – activating or antagonizing postsynaptic alpha and beta adrenoceptors
3 – Amphetamines release dopamine from the cytoplasmic pool by exchange diffusion at the dopamine uptake transporter site in the membrane
4 – amphetamines diffuse through the presynaptic terminal membrane and interact with the neurotransmitter transporter on the vesicular membrane to cause exchange release of dopamine into the cytoplasm, dopamine is subsequently release into the synapse by reverse transport at the dopamine uptake site
5 – amphetamine diffuses through the cellular and vesicular membranes, alkalinizing the vesicles, and permitting dopamine release from the vesicles and delivery into the synapse by reverse transport
​6  – inhibiting monoamine oxidase

Pharmacology/Pharmacokinetics:

• Absorption/Distribution/Metabolism/Excretion
  • Absorption – all are rapidly absorbed, with bioavailability that ranges between 60% and 90% depending on the route of administration, peak serum concentrations between 3-6 hours
  • Distribution – most compartments of the body, most are relatively lipophilic and readily cross the BBB, Vd from 3-33 L/kg depending on the substance
  • Metabolism – all are metabolized in the liver, however, the pathway depends on the specific substance, most involve CYP2D6
  • Excretion – renal elimination of the parent compound is substantial, also acidification of the urine can increase elimination, but usually not recommended

 
Therapeutic levels

• Not generally obtained given lack of clinical relevance

 
Significant Drug/Drug Interactions

• MAOI use, as well as linezolid or methylene blue may cause hypertensive crisis

 
Metabolic Pathways and active metabolites

• Depending on the amphetamine, many active metabolites can be formed
• Dealkylation and demethylation are mainly performed by CYP1A2, CYP2D6 and CYP3A4, also performed by flavin monooxygenase

Toxicity/Clinical Presentation

• Doses >/= 1mg/kg have been known to cause acute toxicity
• Uncontrolled hyperadrenergic state including excess serotonin, dopamine and norepinephrine
• Things that will kill you? à dysrhythmias, seizures and hyperthermia
• Things to worry about? à myocardial ischemia and infarction, rhabdomyolysis, metabolic acidosis
• MDMA specifically you worry about hyponatremia related seizures

Diagnostic Testing and Laboratories

• Chem 8, EKG and cardiac monitoring/observation for at least 6 hours, depending on presentation
• Can obtain UDS to assess presence of amphetamines, however, clinical exam and history is key
  • Many immunoassays have high rate of false positives and false negatives
  • Many substances are similar to amphetamines and may cross-react with the immunoassay
  • False negatives may occur with MDMA and cathinones
• Can consider further testing including but not limited to CBC, UA, CPK, coagulation studies, CXR, CT scan of the head and LP depending on clinical situation

 
Treatment/Management

• As with all presentations, manage ABCs and gain IV access and place patient on monitor
• Vital signs, rapid glucose and complete physical exam, importantly quickly obtain internal temperature
• Hyperthermia requires rapid external and even potentially internal cooling
• Benzodiazepines are first line for both agitation and hypertension/tachycardia
• If hypertension persists and you have attempted to control agitation with benzos, can considering a-adrenergic antagonists like phentolamine and peripheral vasodilators like nitroprusside and nitroglycerin
• Use antipsychotics with caution, have not been shown to be as effective as benzos and may lower seizure threshold, alter temperature regulation, cause acute dystonia and precipitate cardiac dysrhythmias
• If concerned for rhabdomyolysis, maintain UOP of at least 1-2 mL/kg/h
• Need to be suspicious for body packers and stuffers with these substances, treat accordingly

 
What is Stuttering? What causes it?

• Condition in which the normal pattern, rhythm, or timing of speech is disrupted, may be characterized by repetition and prolongation of words, phrases, and sounds, as well as hesitations or pauses that interrupt speech flow
• Can be developmental, psychogenic, result of a medication effect and secondary to brain injuries

 
Multiple Case Reports Discussing Stuttering Associated with ADHD Medications

• A 1991 case report of a 3 year old with two separate trials of stimulants, each of which resulted in stuttering
  • 2.5 mg BID methylphenidate and then pemoline 9.375 mg
  • After 18 months, no recurrence of stuttering
  • They hypothesized that stuttering a result of increased dopaminergic neurotransmission
• A 2015 case report of a 7 year old trialed on methylphenidate and developed stuttering
  • previously healthy with no family or personal history of speech difficulty or stuttering
  • diagnosed with ADHD and started on 10mg daily of methylphenidate
  • 10 days later developed stuttering, decided to stop medication, and stuttering gone in 7 days
  • They noted that methylphenidate had even been used to treat stuttering in previous cases
  • Case report from 1996 reporting sertraline induced stuttering
    • Sertraline was discontinued, and stuttering stopped
    • Akathisia has been noted to be induced by sertraline and this could be potentially related to serotonergic inhibition of the dopaminergic neurons whose cell bodies are located in the ventral tegmental area versus serotonergic inhibition of the dopamine pathways in the nigrostriatum
    • Needs more research whether this is related to speech abnormalities 

Do ADHD medications cause stuttering?

• Some studies show that hyperdopaminergic status of the brain provokes stuttering
• The symptoms of stuttering are compared with basal ganglia motor disorders like Parkinson’s disease and dystonia
• It is proposed that the basal ganglia-thalamocortical motor circuits through the putamen are likely to play a key role in stuttering
• The core dysfunction in stuttering is suggested to be impaired ability of the basal ganglia to produce timing cues for the initiation of the next motor segment in speech​

• Similarities between stuttering and dystonia are indicated and can possibly be related to the dopamine system
• A study in a bird model did show a relationship to amphetamine administration and their songs
  • Amphetamine administration increased the stereotypy of syllable structure and sequencing as well as vocal motor repetition
  • Amphetamine increased the degree to which stereotyped sequences of syllables were completed before song determination
  • Dopaminergic activity in cortical and basal ganglia structures found to be elevated in stuttering

​
References

1. Alm PA. Stuttering and the basal ganglia circuits: A critical review of possible relations. Journal of communication disorders. 07/2004;37(4):325-369. doi: 10.1016/j.jcomdis.2004.03.001.
2. Alpaslan AH. Stuttering associated with the use of short-acting oral methylphenidate. Journal of clinical psychopharmacology. 12/2015;35(6):739-741. doi: 10.1097/JCP.0000000000000403.
3. Burd L. Stuttering and stimulants. Journal of clinical psychopharmacology. 02/1991;11(1):72-73.
4. Christensen RC. A case of sertraline-induced stuttering. Journal of clinical psychopharmacology. 02/1996;16(1):92-93.
5. Dopheide JA, Pliszka SR. Attention Deficit/Hyperactivity Disorder. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com.libproxy.lib.unc.edu/content.aspx?bookid=1861&sectionid=146063877. Accessed February 19, 2018.
6. Jang DH. Amphetamines. In: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. eds. Goldfrank's Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015. http://accesspharmacy.mhmedical.com.libproxy.lib.unc.edu/content.aspx?bookid=1163&sectionid=65097893. Accessed February 19, 2018.
7. Matheson LE. Catecholaminergic contributions to vocal communication signals. The European journal of neuroscience. 05/2015;41(9):1180-1194. doi: 10.1111/ejn.12885.
8. Rabaeys H. Influence of methylphenidate on the frequency of stuttering: A randomized controlled trial. The Annals of pharmacotherapy. 10/2015;49(10):1096-1104. doi: 10.1177/1060028015596415.