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. 2021 Nov 19;27(3):1300–1309. doi: 10.1038/s41380-021-01384-8

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — FTLD has been linked to changes in several principal neurotransmitter systems such as the glutamatergic, GABAergic, dopaminergic and serotonergic systems. Due to the lack of officially validated and approved pharmacological therapies for FTLD, off-label medications targeting different neurotransmitter systems, indicated here, to alleviate the clinical symptoms are commonly used. Drugs with other modes of action are also in use. For instance, retigabine acts as a positive allosteric modulator of the neuronal potassium channels KNCQ (Kv2 to 5), carbamazepine preferentially binds to voltage-gated sodium channels in their inactive conformation, which prevents repetitive and sustained firing of an action potential, and topiramate blocks voltage-dependent sodium and calcium channels. There are several drugs (listed in the multipathway drug box) that act simultaneously on different pathways. For example, methylphenidate and quetiapine affect both dopaminergic and noradrenergic pathways. Also, antidepressants such as duloxetine and venlafaxine affect the noradrenergic system but have also other targets. Some drugs have multiple targets such as trazodone (serotonin, histamine, and α1-adrenergic receptors, serotonin reuptake) and olanzapine (dopamine, serotonin, α1-adrenergic, muscarinic receptors). The mode of action of olanzapine is not completely clear and it may possibly act through the dopaminergic, serotonergic or cholinergic pathways. Currently there are no selective serotonin-noradrenaline re-uptake inhibitors (SNRI) targeting the noradrenaline system on the market.