lisdexamfetamine

File:30mg Vyvanse capsules.JPG

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Lisdexamfetamine is used primarily as a treatment for attention deficit hyperactivity disorder (ADHD) and binge eating disorder. It has similar {{nowrap|off-label}} uses as those of other pharmaceutical amphetamines, such as the treatment of narcolepsy.{{cite journal | vauthors = Aguilar AC, Frange C, Pimentel Filho LH, Reis MJ, Tufik S, Coelho FM | title = Lisdexamfetamine to improve excessive daytime sleepiness and weight management in narcolepsy: a case series | journal = Brazilian Journal of Psychiatry | volume = 43 | issue = 3 | pages = 314–316 | date = 2020 | pmid = 31859793 | pmc = 7236164 | doi = 10.1590/1516-4446-2019-0544 }} Individuals over the age of 65 were not commonly tested in clinical trials of lisdexamfetamine for ADHD. According to a 2019 systematic review, lisdexamfetamine was the most effective treatment for adult ADHD.{{cite journal | vauthors = Stuhec M, Lukić P, Locatelli I | title = Efficacy, Acceptability, and Tolerability of Lisdexamfetamine, Mixed Amphetamine Salts, Methylphenidate, and Modafinil in the Treatment of Attention-Deficit Hyperactivity Disorder in Adults: A Systematic Review and Meta-analysis | journal = The Annals of Pharmacotherapy | volume = 53 | issue = 2 | pages = 121–133 | date = February 2019 | pmid = 30117329 | doi = 10.1177/1060028018795703 | s2cid = 52019992 }}

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Lisdexamfetamine is available as the dimesylate salt in the form of both oral capsules and chewable tablets. A dose of 50 mg of lisdexamfetamine dimesylate is approximately equimolar to a 20 mg dose of dextroamphetamine sulfate or to 15 mg dextroamphetamine free-base in terms of the amount of dextroamphetamine contained.{{cite journal | vauthors = Ermer JC, Pennick M, Frick G | title = Lisdexamfetamine Dimesylate: Prodrug Delivery, Amphetamine Exposure and Duration of Efficacy | journal = Clinical Drug Investigation | volume = 36 | issue = 5 | pages = 341–356 | date = May 2016 | pmid = 27021968 | pmc = 4823324 | doi = 10.1007/s40261-015-0354-y }}{{cite web | title = Elvanse Adult 30mg Hard Capsules | url = https://www.medicines.org.uk/emc/product/6828/smpc | access-date = 26 February 2022 | quote = 2. Qualitative and quantitative composition. 30 mg Capsules: Each capsule contains 30 mg lisdexamfetamine dimesylate, equivalent to 8.9 mg of dexamfetamine. 50 mg Capsules: Each capsule contains 50 mg lisdexamfetamine dimesylate, equivalent to 14.8 mg of dexamfetamine. 70 mg Capsules: Each capsule contains 70 mg lisdexamfetamine dimesylate, equivalent to 20.8 mg of dexamfetamine.}} Lisdexamfetamine capsules can be swallowed intact, or they can be opened and mixed into water, yogurt, or applesauce and consumed in that manner.{{cite journal | vauthors = Ermer J, Corcoran M, Lasseter K, Martin PT | title = Relative Bioavailabilities of Lisdexamfetamine Dimesylate and D-Amphetamine in Healthy Adults in an Open-Label, Randomized, Crossover Study After Mixing Lisdexamfetamine Dimesylate With Food or Drink | journal = Ther Drug Monit | volume = 38 | issue = 6 | pages = 769–776 | date = December 2016 | pmid = 27661399 | pmc = 5158093 | doi = 10.1097/FTD.0000000000000343 }}

Pharmaceutical lisdexamfetamine is contraindicated in people with hypersensitivity to amphetamine products or any of the formulation's inactive ingredients. It is also contraindicated in patients who have used a monoamine oxidase inhibitor (MAOI) within the last 14 days.{{cite web | vauthors = Heedes G, Ailakis J | title=Amphetamine (PIM 934) | url=http://www.inchem.org/documents/pims/pharm/pim934.htm | website=INCHEM | publisher=International Programme on Chemical Safety | access-date=24 June 2014 }} Amphetamine products are contraindicated by the United States Food and Drug Administration (USFDA) in people with a history of drug abuse, heart disease, or severe agitation or anxiety, or in those currently experiencing arteriosclerosis, glaucoma, hyperthyroidism, or severe hypertension. However, a European consensus statement on adult ADHD noted that stimulants do not worsen substance misuse in adults with ADHD and comorbid substance use disorder and should not be avoided in these individuals.{{cite journal | vauthors = Kooij JJ, Bijlenga D, Salerno L, Jaeschke R, Bitter I, Balázs J, Thome J, Dom G, Kasper S, Nunes Filipe C, Stes S, Mohr P, Leppämäki S, Casas M, Bobes J, Mccarthy JM, Richarte V, Kjems Philipsen A, Pehlivanidis A, Niemela A, Styr B, Semerci B, Bolea-Alamanac B, Edvinsson D, Baeyens D, Wynchank D, Sobanski E, Philipsen A, McNicholas F, Caci H, Mihailescu I, Manor I, Dobrescu I, Saito T, Krause J, Fayyad J, Ramos-Quiroga JA, Foeken K, Rad F, Adamou M, Ohlmeier M, Fitzgerald M, Gill M, Lensing M, Motavalli Mukaddes N, Brudkiewicz P, Gustafsson P, Tani P, Oswald P, Carpentier PJ, De Rossi P, Delorme R, Markovska Simoska S, Pallanti S, Young S, Bejerot S, Lehtonen T, Kustow J, Müller-Sedgwick U, Hirvikoski T, Pironti V, Ginsberg Y, Félegyházy Z, Garcia-Portilla MP, Asherson P | title = Updated European Consensus Statement on diagnosis and treatment of adult ADHD | journal = European Psychiatry | volume = 56 | issue = | pages = 14–34 | date = February 2019 | pmid = 30453134 | doi = 10.1016/j.eurpsy.2018.11.001 | s2cid = 53714228 | doi-access = free | hdl = 10067/1564410151162165141 | hdl-access = free }} In any case, the statement noted that immediate-release stimulants should be avoided in those with both ADHD and substance use disorder and that slower-release stimulant formulations like {{Abbrlink|OROS|osmotic-controlled release oral delivery system}} methylphenidate (Concerta) and lisdexamfetamine should be preferred due to their lower misuse potential. Prescribing information approved by the Australian Therapeutic Goods Administration further contraindicates anorexia.{{cite web|title=Dexamphetamine tablets|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI-00828-3|website=Therapeutic Goods Administration|access-date=12 April 2014}}

Products containing lisdexamfetamine have a comparable drug safety profile to those containing amphetamine. The major side effects of lisdexamfetamine in short-term clinical trials (≥5% incidence) have included decreased appetite, insomnia, dry mouth, weight loss, irritability, upper abdominal pain, nausea, vomiting, diarrhea, constipation, increased heart rate, anxiety, dizziness, and feeling jittery. Rates of side effects may vary in adults, adolescents, and children. Rare but serious side effects of lisdexamfetamine may include mania, sudden cardiac death in those with underlying heart problems, stimulant psychosis, and serotonin syndrome.

• Acidifying agents: Drugs or foods that acidify the urine, such as ascorbic acid, increase urinary excretion of dextroamphetamine, thus decreasing the half-life and effectiveness of dextroamphetamine in the body.
• Alkalinizing agents: Drugs or foods that alkalinize the urine, such as sodium bicarbonate, decrease urinary excretion of dextroamphetamine, thus increasing the half-life and effectiveness of dextroamphetamine in the body.
• CYP2D6 inhibitors: Hydroxylation via the cytochrome P450 enzyme CYP2D6 is the major pathway of metabolism of dextroamphetamine.{{cite journal | vauthors = Schoretsanitis G, de Leon J, Eap CB, Kane JM, Paulzen M | title = Clinically Significant Drug-Drug Interactions with Agents for Attention-Deficit/Hyperactivity Disorder | journal = CNS Drugs | volume = 33 | issue = 12 | pages = 1201–1222 | date = December 2019 | pmid = 31776871 | doi = 10.1007/s40263-019-00683-7 | s2cid = 208330108 }} Potent CYP2D6 inhibitors, such as paroxetine, fluoxetine, bupropion, and duloxetine, among others, may inhibit the metabolism of dextroamphetamine and thereby increase exposure to it. Studies characterizing this potential interaction are currently lacking. Concomitant use of lisdexamfetamine with CYP2D6 inhibitors may increase the risk of serotonin syndrome due to greater drug exposure.
• Monoamine oxidase inhibitors: Concomitant use of MAOIs and central nervous system stimulants such as lisdexamfetamine can cause a hypertensive crisis.
• Norepinephrine reuptake inhibitors (NRIs) like atomoxetine prevent norepinephrine release induced by amphetamines and have been found to reduce the stimulant, euphoriant, and sympathomimetic effects of dextroamphetamine in humans.{{cite journal | vauthors = Treuer T, Gau SS, Méndez L, Montgomery W, Monk JA, Altin M, Wu S, Lin CC, Dueñas HJ | title = A systematic review of combination therapy with stimulants and atomoxetine for attention-deficit/hyperactivity disorder, including patient characteristics, treatment strategies, effectiveness, and tolerability | journal = J Child Adolesc Psychopharmacol | volume = 23 | issue = 3 | pages = 179–193 | date = April 2013 | pmid = 23560600 | pmc = 3696926 | doi = 10.1089/cap.2012.0093 | url = }}{{cite book | vauthors = Heal DJ, Smith SL, Findling RL | title = Behavioral Neuroscience of Attention Deficit Hyperactivity Disorder and Its Treatment | chapter = ADHD: current and future therapeutics | series = Current Topics in Behavioral Neurosciences | volume = 9 | pages = 361–390 | date = 2012 | pmid = 21487953 | doi = 10.1007/7854_2011_125 | isbn = 978-3-642-24611-1 | chapter-url = | quote = Adjunctive therapy with DL-methylphenidate in atomoxetine partial responders has been successful (Wilens et al. 2009), but this also increases the rates of insomnia, irritability and loss of appetite (Hammerness et al. 2009). This combination therapy has not included amphetamine because blockade of NET by atomoxetine prevents entry of amphetamine into presynaptic noradrenergic terminals (Sofuoglu et al. 2009). }}{{cite journal | vauthors = Sofuoglu M, Poling J, Hill K, Kosten T | title = Atomoxetine attenuates dextroamphetamine effects in humans | journal = Am J Drug Alcohol Abuse | volume = 35 | issue = 6 | pages = 412–416 | date = 2009 | pmid = 20014909 | pmc = 2796580 | doi = 10.3109/00952990903383961 | url = }}

{{hatnote|Main section: {{section link|Amphetamine|Pharmacodynamics}}}}

{{amphetamine pharmacodynamics}}

Lisdexamfetamine is an inactive prodrug that is converted in the body to dextroamphetamine, a pharmacologically active compound that is responsible for the drug's activity. After oral ingestion, lisdexamfetamine is broken down by enzymes in red blood cells to form L-lysine, a naturally occurring essential amino acid, and dextroamphetamine. The half-life of this conversion is roughly 1 hour. The conversion of lisdexamfetamine to dextroamphetamine is not affected by gastrointestinal pH and is unlikely to be affected by alterations in normal gastrointestinal transit times. Studies show a linear relationship between peak plasma concentration of dextroamphetamine and lisdexamfetamine dose up to lisdexamfetamine doses of 250 mg.{{cite journal | vauthors = Ermer J, Homolka R, Martin P, Buckwalter M, Purkayastha J, Roesch B | title = Lisdexamfetamine dimesylate: linear dose-proportionality, low intersubject and intrasubject variability, and safety in an open-label single-dose pharmacokinetic study in healthy adult volunteers | journal = Journal of Clinical Pharmacology | volume = 50 | issue = 9 | pages = 1001–1010 | date = September 2010 | pmid = 20173084 | doi = 10.1177/0091270009357346 }}

The optical isomers of amphetamine, i.e., dextroamphetamine and levoamphetamine, are TAAR1 agonists and vesicular monoamine transporter 2 inhibitors that can enter monoamine neurons;{{cite journal | vauthors = Miller GM | title = The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity | journal = Journal of Neurochemistry | volume = 116 | issue = 2 | pages = 164–176 | date = January 2011 | pmid = 21073468 | pmc = 3005101 | doi = 10.1111/j.1471-4159.2010.07109.x }}{{cite journal | vauthors = Eiden LE, Weihe E | title = VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse | journal = Annals of the New York Academy of Sciences | volume = 1216 | issue = 1 | pages = 86–98 | date = January 2011 | pmid = 21272013 | pmc = 4183197 | doi = 10.1111/j.1749-6632.2010.05906.x | quote = VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR) ... [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC). | bibcode = 2011NYASA1216...86E }} this allows them to release monoamine neurotransmitters (dopamine, norepinephrine, and serotonin, among others) from their storage sites in the presynaptic neuron, as well as prevent the reuptake of these neurotransmitters from the synaptic cleft.

Lisdexamfetamine was developed to provide a long-duration effect that is consistent throughout the day, with reduced potential for abuse. The attachment of the amino acid lysine slows down the relative amount of dextroamphetamine available in the bloodstream. Because no free dextroamphetamine is present in lisdexamfetamine capsules, dextroamphetamine does not become available through mechanical manipulation, such as crushing or simple extraction. A relatively sophisticated biochemical process is needed to produce dextroamphetamine from lisdexamfetamine. As opposed to Adderall, which contains amphetamine salts in a 3:1 dextro:levo ratio, lisdexamfetamine is a single-enantiomer dextroamphetamine formula.{{cite DrugBank|id= DB01255|drug=Lisdexamfetamine}}{{cite web | title=Adderall XR- dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate and amphetamine aspartate capsule, extended release | website=DailyMed | date=25 October 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aff45863-ffe1-4d4f-8acf-c7081512a6c0 | access-date=18 March 2024}} Studies conducted show that lisdexamfetamine dimesylate may have less abuse potential than dextroamphetamine and an abuse profile similar to diethylpropion at dosages that are FDA-approved for treatment of ADHD, but still has a high abuse potential when this dosage is exceeded by over 100%.{{cite journal | vauthors = Jasinski DR, Krishnan S | title = Abuse liability and safety of oral lisdexamfetamine dimesylate in individuals with a history of stimulant abuse | journal = Journal of Psychopharmacology | volume = 23 | issue = 4 | pages = 419–427 | date = June 2009 | pmid = 19329547 | doi = 10.1177/0269881109103113 | s2cid = 6138292 }}

File:Dextroamphetamine concentration-time curves after oral administration of equimolar doses of dextroamphetamine and lisdexamfetamine in adults.png, t_1/2, and AUC_∞ were all similar between the two drugs, while t_lag (1.5 hours vs. 0.8 hours) and t_max (4.6 hours vs. 3.3 hours) were longer for lisdexamfetamine than with dextroamphetamine.]]

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{{trim|{{#section-h:Amphetamine|Pharmacokinetics}}}}

Lisdexamfetamine is a substituted amphetamine with an amide linkage formed by the condensation of dextroamphetamine with the carboxylate group of the essential amino acid L-lysine. The reaction occurs with retention of stereochemistry, so the product lisdexamfetamine exists as a single stereoisomer. There are many possible names for lisdexamfetamine based on IUPAC nomenclature, but it is usually named as {{nowrap|N-[(2S)-1-phenyl-2-propanyl]-L-lysinamide}} or {{nowrap|(2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide}}.{{cite web|year = 2015|title = Lisdexamfetamine|url = http://www.chemspider.com/Chemical-Structure.9772458.html|website = ChemSpider|publisher = Royal Society of Chemistry|access-date = 22 April 2019}} The condensation reaction occurs with loss of water:

:dextroamphetamine   +   lysine   →   (S,S)-{{chem|PhCH|2|CH(CH|3|)NHC(O)CH(NH|2|)CH|2|CH|2|CH|2|CH|2|NH|2}}   +   {{chem|H|2|O}}

Amine functional groups are vulnerable to oxidation in air and so pharmaceuticals containing them are usually formulated as salts where this moiety has been protonated. This increases stability, water solubility, and, by converting a molecular compound to an ionic compound, increases the melting point and thereby ensures a solid product.{{cite book| veditors = Stahl PH, Wermuth DG |editor-link2 = Camille G. Wermuth |title = Pharmaceutical Salts: Properties, Selection, and Use|edition = 2nd|publisher = John Wiley & Sons|year = 2011|isbn = 978-3-906390-51-2}} In the case of lisdexamfetamine, this is achieved by reacting with two equivalents of methanesulfonic acid to produce the dimesylate salt, a water-soluble (792 mg mL⁻¹) powder with a white to off-white color.

:{{chem|PhCH|2|CH(CH|3|)NHC(O)CH(NH|2|)CH|2|CH|2|CH|2|CH|2|NH|2}}   +   2 methanesulfonic acid   →   {{chem|[PhCH|2|CH(CH|3|)NHC(O)CH(NH|3|+|)CH|2|CH|2|CH|2|CH|2|NH|3|+|]}}{{chem|[CH|3|SO|3|-|]|2}}

Lisdexamfetamine dimesylate is one marketed formulation delivering dextroamphetamine. The following table compares the drug to other amphetamine pharmaceuticals.

{{Amphetamine base in marketed amphetamine medications}}

{{See also|History and culture of substituted amphetamines}}

Lisdexamfetamine was developed by Robert Oberlender at New River Pharmaceuticals, under the name NRP104, before being bought by Takeda Pharmaceuticals through its acquisition of Shire Pharmaceuticals, prior to market release.{{Cite web |title=Robert A. Oberlender, PhD |url=https://www.michaeljfox.org/researcher/robert-oberlender-phd |access-date=2025-02-17 |website=Michael J. Fox Foundation |language=en}} It was developed to create a longer-lasting and less-easily abused version of dextroamphetamine, as the requirement of conversion into dextroamphetamine via enzymes in the red blood cells delays its onset of action, regardless of the route of administration.{{cite journal | vauthors = Mattingly G | title = Lisdexamfetamine dimesylate: a prodrug stimulant for the treatment of ADHD in children and adults | journal = CNS Spectrums | volume = 15 | issue = 5 | pages = 315–325 | date = May 2010 | pmid = 20448522 | doi = 10.1017/S1092852900027541 | s2cid = 46435024 | url = https://digitalcommons.wustl.edu/open_access_pubs/3506 }}

In February 2007, the US Food and Drug Administration (FDA) approved lisdexamfetamine for the treatment of ADHD.{{cite web | title=Drug Approval Package: Vyvanse (Lisdexamfetamine Dimesylate) NDA #021977 | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021977s000TOC.cfm | access-date=18 March 2024}} In August 2009, Health Canada approved the marketing of lisdexamfetamine for prescription use.{{cite web | title=Summary Basis of Decision (SBD) for Vyvanse | website=Health Canada | date=10 June 2010 | url=https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailOne.php?linkID=SBD00311 | access-date=18 March 2024}}

In January 2015, lisdexamfetamine was approved by the FDA for the treatment of binge eating disorder in adults.{{cite press release | title=FDA expands uses of Vyvanse to treat binge-eating disorder | website=U.S. Food and Drug Administration (FDA) | date=30 January 2015 | url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm432543.htm | archive-url=https://web.archive.org/web/20180126103215/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm432543.htm | archive-date=26 January 2018 | url-status=dead | access-date=19 March 2023}}

The FDA gave tentative approval to generic formulations of lisdexamfetamine in 2015.{{Cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/202802Orig1s000TAltr.pdf|title=Tentative approval|date=3 March 2023|access-date=24 April 2022|archive-date=3 March 2023|archive-url=https://web.archive.org/web/20230303055201/https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/202802Orig1s000TAltr.pdf|url-status=live}} The expiration date for patent protection of lisdexamfetamine in the US was 24 February 2023. The Canadian patent expired 20 years from the filing date of 1 June 2004.{{Cite web |title=Canadian Patent Database / Base de données sur les brevets canadiens |url=https://www.ic.gc.ca/opic-cipo/cpd/eng/patent/2527646/summary.html |access-date=4 May 2023 |website=www.ic.gc.ca }}

Production quotas for 2016 in the United States were 29,750 kg.{{cite web |title=DEA Office of Diversion Control |url=http://www.deadiversion.usdoj.gov/quotas/quota_history.pdf |url-status=dead |archive-url=https://web.archive.org/web/20160527045141/http://www.deadiversion.usdoj.gov/quotas/quota_history.pdf |archive-date=27 May 2016 |access-date=7 November 2023 |publisher=DEA}}

Image:Elvanse.jpg

Lisdexamfetamine is the International Nonproprietary Name (INN) and is a contraction of L-lysine-dextroamphetamine.{{cite journal | vauthors = Buoli M, Serati M, Cahn W | title = Alternative pharmacological strategies for adult ADHD treatment: a systematic review | journal = Expert Review of Neurotherapeutics | volume = 16 | issue = 2 | pages = 131–144 | date = 2016 | pmid = 26693882 | doi = 10.1586/14737175.2016.1135735 | s2cid = 33004517 }}

As of November 2020, lisdexamfetamine is sold under the following brand names: Aduvanz, Elvanse, Juneve, Samexid, Tyvense, Venvanse, and Vyvanse.{{cite web |title=Lisdexamfetamine international brands |url=https://www.drugs.com/international/lisdexamfetamine.html |publisher=Drugs.com |access-date=11 November 2020 |archive-url=https://web.archive.org/web/20201111173315/https://www.drugs.com/international/lisdexamfetamine.html |archive-date=11 November 2020 |url-status=dead}}

Amphetamine was used to treat depression starting in the 1930s and has been described as the first antidepressant.{{cite journal | vauthors = Rasmussen N | title = Making the first anti-depressant: amphetamine in American medicine, 1929-1950 | journal = J Hist Med Allied Sci | volume = 61 | issue = 3 | pages = 288–323 | date = July 2006 | pmid = 16492800 | doi = 10.1093/jhmas/jrj039 | url = }} In clinical studies in the 1970s and 1980s, psychostimulants, including amphetamine and methylphenidate, were found to transiently improve mood in a majority of people with depression and to increase psychomotor activation in almost all individuals.{{cite journal | vauthors = Brown AS, Gershon S | title = Dopamine and depression | journal = J Neural Transm Gen Sect | volume = 91 | issue = 2–3 | pages = 75–109 | date = 1993 | pmid = 8099801 | doi = 10.1007/BF01245227 | url = }}

Some clinical trials that used lisdexamfetamine as an add-on therapy with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) for treatment-resistant depression indicated that this is no more effective than the use of an SSRI or SNRI alone.{{cite journal | vauthors = Dale E, Bang-Andersen B, Sánchez C | title = Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs | journal = Biochemical Pharmacology | volume = 95 | issue = 2 | pages = 81–97 | date = May 2015 | pmid = 25813654 | doi = 10.1016/j.bcp.2015.03.011 | doi-access = free }} Other studies indicated that psychostimulants potentiated antidepressants, and were under-prescribed for treatment-resistant depression. In those studies, patients showed significant improvement in energy, mood, and psychomotor activity.{{cite journal | vauthors = Stotz G, Woggon B, Angst J | title = Psychostimulants in the therapy of treatment-resistant depression Review of the literature and findings from a retrospective study in 65 depressed patients | journal = Dialogues in Clinical Neuroscience | volume = 1 | issue = 3 | pages = 165–174 | date = December 1999 | doi = 10.31887/DCNS.1999.1.3/gstotz | pmid = 22034135 | pmc = 3181580 }} Clinical guidelines advise caution in the use of stimulants for depression and advise them only as second- or third-line adjunctive agents.

In February 2014, Shire announced that two late-stage clinical trials had found that Vyvanse was not an effective treatment for depression, and development for this indication was discontinued.{{cite news|url=http://uk.reuters.com/article/shire-vyvanse-idUKL2N0LB28F20140207 |archive-url=https://web.archive.org/web/20160310201117/http://uk.reuters.com/article/shire-vyvanse-idUKL2N0LB28F20140207 |url-status=dead |archive-date=10 March 2016 | vauthors = Hirschler B |title=UPDATE 2-Shire scraps Vyvanse for depression after failed trials|publisher=Reuters |date=7 February 2014 |access-date=13 February 2014}}{{Cite web|url=https://adisinsight.springer.com/drugs/800020876|title=Lisdexamfetamine - Shionogi/Takeda |website=Adisinsight.springer.com|access-date=12 March 2022|quote=Clinical development is underway in the US, for mood disorders in children and adolescents for binge eating disorder and ADHD.}} A 2018 meta-analysis of randomized controlled trials of lisdexamfetamine for antidepressant augmentation in people with major depressive disorder—the first to be conducted—found that lisdexamfetamine was not significantly better than placebo in improving Montgomery–Åsberg Depression Rating Scale scores, response rates, or remission rates.{{cite journal | vauthors = Giacobbe P, Rakita U, Lam R, Milev R, Kennedy SH, McIntyre RS | title = Efficacy and tolerability of lisdexamfetamine as an antidepressant augmentation strategy: A meta-analysis of randomized controlled trials | journal = Journal of Affective Disorders | volume = 226 | issue = | pages = 294–300 | date = January 2018 | pmid = 29028590 | doi = 10.1016/j.jad.2017.09.041 }} However, there was indication of a small effect in improving depressive symptoms that approached trend-level significance. Lisdexamfetamine was well-tolerated in the meta-analysis. The quantity of evidence was limited, with only four trials included. In a subsequent 2022 network meta-analysis, lisdexamfetamine was significantly effective as an antidepressant augmentation for treatment-resistant depression.{{cite journal | vauthors = Nuñez NA, Joseph B, Pahwa M, Kumar R, Resendez MG, Prokop LJ, Veldic M, Seshadri A, Biernacka JM, Frye MA, Wang Z, Singh B | title = Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis | journal = Journal of Affective Disorders | volume = 302 | issue = | pages = 385–400 | date = April 2022 | pmid = 34986373 | doi = 10.1016/j.jad.2021.12.134 | pmc = 9328668 | s2cid = 245657964 }}

Although lisdexamfetamine has shown limited effectiveness in the treatment of depression in clinical trials, a phase II clinical study found that the addition of lisdexamfetamine to an antidepressant improved executive dysfunction in people with mild major depressive disorder but persisting executive dysfunction.{{cite book | title = Translational Medicine in CNS Drug Development | vauthors = Pan Z, Grovu RC, McIntyre RS | chapter = Translational Medicine Strategies in Drug Development for Mood Disorders | series = Handbook of Behavioral Neuroscience | date = 2019 | volume = 29 | pages = 333–347 | publisher = Elsevier | issn = 1569-7339 | doi = 10.1016/B978-0-12-803161-2.00023-0 | isbn = 978-0-12-803161-2 | s2cid = 196561249 }}{{cite journal | vauthors = Madhoo M, Keefe RS, Roth RM, Sambunaris A, Wu J, Trivedi MH, Anderson CS, Lasser R | title = Lisdexamfetamine dimesylate augmentation in adults with persistent executive dysfunction after partial or full remission of major depressive disorder | journal = Neuropsychopharmacology | volume = 39 | issue = 6 | pages = 1388–1398 | date = May 2014 | pmid = 24309905 | pmc = 3988542 | doi = 10.1038/npp.2013.334 }}

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