Amitriptyline for ADHD
Amitriptyline is a tricyclic antidepressant
- Serotonergic, as a serotonin reuptake inhibitor, whereby this effect predominates1
- Antihistaminergic2
- H1 receptor antagonist Ki 0.72
- Anticholinergic2
- Weaker also noradrenergic
- Agonist for σ1, TrkA and TrkB receptors3
- Blocks various sodium, calcium and potassium channels3
- Functional inhibitor (FIASMA) of acid sphingoymelinase (ASM)
- With one of the strongest FIASMA found, strongest FIASMA among antidepressants4
Amitriptyline was introduced by Merck in 1961 for the treatment of major depressive disorders. Depression is the only existing FDA indication for amitriptyline.3
Amitryptiline has a sleep-promoting and anxiolytic effect. Like trimipramine, it does not impair REM sleep.
It is also used off-label for migraine prophylaxis, neuropathic pain disorders and fibromyalgia, nocturnal enuresis and irritable bowel syndrome.3
The antidepressant effect of amitriptyline is largely due to its action as FIASMA. Amitriptyline caused5
- reduced ASM activity and ceramide levels in the hippocampus
- increased neuronal proliferation, maturation and survival rate
- improved behavior in mouse models of stress-induced depression
- Effect lost in genetic ASM deficiency
Mice showed increased ceramide levels, and thus lower rates of neuronal proliferation, maturation and survival, as well as depression-like behavior even without stress, when5
- ASM was overexpressed
- which increases the degradation of sphingomyelin to ceramide
- they were heterozygous for acid ceramidase
- lysosomal enzyme that converts ceramide to sphingosine
- they have been treated with ceramide metabolism blockers
- which inhibits the breakdown of ceramide
- they were injected with C16 ceramide directly into the hippocampus
- which directly increases the ceramide level
The reduction of ceramide concentration by the antidepressant-mediated inhibition of ASM normalized these effects.
High ASM levels also correlated with sleep problems.6 Therefore, the sleep-promoting effect of amitriptyline could also be based on its property as a strong FIASMA.
The metabolite of amitryptiline is nortriptyline, which inhibits the reuptake of noradrenaline in particular. For more information, see ⇒ Nortriptyline in AD(H)S.
Häßler (2009): substanzgebundene Alternativen in der Therapie von ADHS, Seite 174, in: Häßler (Hrsg), Das ADHS Kaleidoskop – State of the Art und bisher nicht beachtete Aspekte von hoher Relevanz; medizinisch wissenschaftliche Verlagsgesellschaft ↥
Owens MJ, Morgan WN, Plott SJ, Nemeroff CB (1997): Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther. 1997 Dec;283(3):1305-22. PMID: 9400006. ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥
Beckmann N, Sharma D, Gulbins E, Becker KA, Edelmann B (2014): Inhibition of acid sphingomyelinase by tricyclic antidepressants and analogons. Front Physiol. 2014 Sep 2;5:331. doi: 10.3389/fphys.2014.00331. PMID: 25228885; PMCID: PMC4151525. REVIEW ↥ ↥ ↥ ↥
Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer TW, Spitzer GM, Liedl KR, Gulbins E, Tripal P (2011): Identification of novel functional inhibitors of acid sphingomyelinase. PLoS One. 2011;6(8):e23852. doi: 10.1371/journal.pone.0023852. PMID: 21909365; PMCID: PMC3166082. ↥
Gulbins E, Palmada M, Reichel M, Lüth A, Böhmer C, Amato D, Müller CP, Tischbirek CH, Groemer TW, Tabatabai G, Becker KA, Tripal P, Staedtler S, Ackermann TF, van Brederode J, Alzheimer C, Weller M, Lang UE, Kleuser B, Grassmé H, Kornhuber J (2013): Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs. Nat Med. 2013 Jul;19(7):934-8. doi: 10.1038/nm.3214. PMID: 23770692. ↥ ↥
Bartak (2022): ADHS im Erwachsenenalter. Klinische Charakterisierung und die Rolle der Sauren Sphingomyelinase. Dissertation. n = 55 ↥