Comparisons of the latest ADHD treatment options: A full review

Methylphenidate and Lisdexamfetamine are central nervous stimulants commonly used for the treatment of hyperactivity. They are typically used as first line treatments for Attention Deficit Hyperactivity Disorder (ADHD), and they are also used to treat a number of other ailments including eating disorders and narcolepsy (1).  Methylphenidate is also regularly used off-label in the treatment of bipolar disorder and/or severe depressive disorder.

Methylphenidate was the first medication approved for treatment in the 1960s, with this an evolution of initial methylphenidate treatment options that were short-lasting and characterised by their immediate release function. Methylphenidate is characterised by a long lasting action of up to 12hrs, tripling the duration of effect when compared to immediate release formulations (2). Lisdexamfetamine was introduced to the market in 2008 as a proposed improvement to mixed amphetamine salt solutions, again increasing the effect time to a maximum of 14hrs (3). Both methylphenidate and lisdexamfetamine are psychostimulants, and the role of both drugs is to increase and maintain alertness, combat fatigue, and improve attention (4).

Mechanism of action

Lisdexamdetamine

Lisdexamdetamine is an inactive prodrug (a medication that is pharmacologically inactive and is metabolised/converted into an active form after being administered to the body). Upon oral administration, lisdexamdetamine is broken down by enzymes in red blood cells to form L-lysine and dextroamphetamine (5). The attachment of lysine (an amino acid) to dextroamphetamine slows down its relative amount in the bloodstream, increasing the length of time that the drug stimulates the release of norepinephrine, dopamine, and serotonin from their storage sites.

Methylphenidate

Methylphenidate is also taken orally and functions by inhibiting catecholamine reuptake as a dopamine reuptake inhibitor (DRI). It blocks dopamine and norepinephrine transporters, increasing their extracellular concentrations and acting as a 5HT1A receptor agonist.

Methylphenidate is exceptional in that the drug is distributed differently to most other long-acting drugs. Approximately 25% of the methylphenidate is delivered immediately, with the remaining 75% released gradually for sustained symptomatic relief (6). Methylphenidate has been involved in more investigational use than the lisdexamfetamine  – it has been used to determine its efficacy in treating a wide range of conditions such as bipolar disorder, treatment resistant depression, postural orthostatic tachycardia syndrome and lethargy (7), and it also has a significantly shorter elimination half life than lisdexamfetamine. Lisdexamfetamine has been trialled to determine its efficacy in treating excessive daytime sleepiness, treatment resistant depression, and the cognitive symptoms of schizophrenia (8).

Potential for abuse potential

Both Methylphenidate and Lisdexamfetamine are classified as Schedule 8 controlled drugs in Australia due to their abuse potential and risk of dependency (9).

It is generally considered that methylphenidate has higher abuse potential than lisdexamfetamine as it can be crushed and administered to the nasal mucosa for a faster-acting dopaminergic ‘high’. Because lisdexamfetamine is an inactive prodrug and must be swallowed in order to be metabolised, it is less amenable to abuse in this respect (however, high doses of either drug taken at the same time can still result in experienced highs as a result of high concentrations of dopamine release). Frequent abuse of either drug that produces consistently high dopamine levels can result in stimulant psychosis – a psychosis symptom common in individuals who overdose on psychostimulants or a very small number of people beginning amphetamine or methylphenidate therapy (it is thought to affect around 0.1% of individuals on these treatment regimens) (10). There is some evidence to suggest that a number of people abuse both methylphenidate and lisdexamfetamine with the intention of losing weight, with lisdexamfetamine being particularly popular for this purpose due to it being approved for binge eating disorder. Both drugs list a reduction in appetite, an accelerated metabolism, and increased energy reserves for conducting exercise in their known side effects (11).

Drug safety and side effects

The side effects resulting from methylphenidate and lisdexamfetamine are relatively predictable, with the most commonly experienced side-effects being:

• loss of appetite
• headaches
• insomnia
• nausea
• dizziness
• headache
• increased nervousness
• anxiety
• weight loss

The loss of weight and temporary stunting of growth has been well documented in both children and adolescents who use the drugs on a long term basis to treat ADHD (12), although there is no evidence to suggest at present that it affects final adult height.

Withdrawal is also a common side effect issue in long term uses of ADHD medication, with many individuals experiencing discomfort when they discontinue or begin to phase out their use of methylphenidate or lisdexamfetamine. This is as a result of the body’s increased physiological reliance on dopamine due to its role in reducing the symptoms of ADHD and the associated improved cognition.

Is the efficacy of each drug well established?

The efficacy of methylphenidate and lisdexamfetamine is well established in adolescents and the evidence suggests that neither drug should be regarded as clinically superior to the other in the treatment of ADHD (13). Which drug is prescribed is often determined by physician preference – lisdexamfetamine is less open to abuse and therefore generally tends to be prescribed more often than methylphenidate in recent times.

References

1. McElroy SL, Guerdjikova AI, Mori N, Munoz MR, Keck PE (2015) Overview of the treatment of binge disorder CNS Spectr 20(6):546-56

2. Childress A, Sallee FR (2013) The use of methylphenidate hydrochloride extended-release oral suspension for the treatment of ADHD Expert Rev Neuro 13(9):979-88

3. Weisler RH, Childress AC (2011) Treating attention-deficit/hyperactivity disorder in adults: focus on once-daily medications Prim Car Com CNS Dis 13(6)

4. Fujioka T, Takiguchi S, Yatsuga C, Hiratani M et al (2016) Advanced test of attention in children with ADHD in Japan for evaluation of methylphenidate and atomoxetine effects Clin Psych Neuro 14(1):79-87

5. Hansen MV, Darling L, Holst H (2015) Safety and Tolerability of Lisdexamfetamine: A retrospective cohort study CNS Drugs 134(4):693-703

6. Patrick KS, Straughn AB (2016) Absorption differences between immediate-release dexmethylphenidate and DI-methylphenidate Drug Meta Dispos pii: dmd.115.067975

7. Kanjwal K, Saeed B, Karabin B, Kanjwal Y, Grubb BP (2012) Use of methylphenidate in the treatment of patients suffering from postural orthostatic tachycardia sundrome Am J Ther 19(1):2-6

8. Rostain A, Jensen PS, Connor DF, Misele LM, Faraone SV (2015) Toward quality care in ADHD: defining the goals of treatment J Atten Disord 19(2):99-117

9. Cassidy TA, Varughese S, Russo L, Budman SH, Eaton TA, Butler SF (2015) Nonmedical use of and diversion of ADHD stimulants among US adults age 18-49: A National Survey J Atten Disord 19(7):630-40

10. Fassbender C, Lesh TA, Ursu S, Salo R (2015) Reaction time variability and related brain activity in methamphetamine psychosis Biol Psych 77(5):465-74

11. Lecomte T, Masse M (2014) Methamphetamine – just another stimulant or a more complex problem? Sante Ment Que 39(2):133-48

12. Jeffers AJ, Benotsch EG (2014) Non-medical use of prescription stimulants for weight loss, disordered eating, and body image J Eat Behav 15(3):414-8

13. Findling RL (2008) Evolution of the treatment of ADHD in children: a review J Clin Ther 30(5):942-57