tiagabine

Tiagabine is approved by US Food and Drug Administration (FDA) as an adjunctive treatment for partial seizures in individuals of age 12 and up. It may also be prescribed off-label by physicians to treat anxiety disorders, such as panic disorder, as well as neuropathic pain (e.g., fibromyalgia). For anxiety and neuropathic pain, tiagabine is used primarily to augment other treatments. Tiagabine may be used alongside selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), or benzodiazepines for anxiety, and antidepressants, gabapentin, other anticonvulsants, or opioids for neuropathic pain.{{cite book | vauthors = Stahl SM |title=Stahl's essential psychopharmacology: the prescriber's guide; antipsychotics and mood stabilizers |date=2009 |publisher=Cambridge University Press |location=New York, NY |isbn=978-0-521-75900-7 |edition=3rd | pages = 523–526 }} It is effective as monotherapy and combination therapy with other anticonvulsant drugs in the treatment of partial seizure.{{Citation| title=Tiagabine |date=2012 |url=http://www.ncbi.nlm.nih.gov/books/NBK548376/|work=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury|place=Bethesda (MD)|publisher=National Institute of Diabetes and Digestive and Kidney Diseases|pmid=31643697|access-date=2021-12-24}}

The American Academy of Sleep Medicine's 2017 clinical practice guidelines recommended against the use of tiagabine in the treatment of insomnia due to poor effectiveness and very low quality of evidence.{{cite journal | vauthors = Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL | title = Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline | journal = Journal of Clinical Sleep Medicine | volume = 13 | issue = 2 | pages = 307–349 | date = February 2017 | pmid = 27998379 | pmc = 5263087 | doi = 10.5664/jcsm.6470 }}

Side effects of tiagabine are dose related. The most common side effect of tiagabine is dizziness.{{cite journal | vauthors = Leppik IE | title = Tiagabine: the safety landscape | journal = Epilepsia | volume = 36 | issue = Suppl 6 | pages = S10–S13 | year = 1995 | pmid = 8595787 | doi = 10.1111/j.1528-1157.1995.tb06009.x | s2cid = 24203401 }} Other side effects that have been observed with a rate of statistical significance relative to placebo include asthenia, somnolence, nervousness, memory impairment, tremor, headache, diarrhea, and depression.{{cite book| vauthors = Eadie MJ, Vajda F |title=Antiepileptic Drugs: Pharmacology and Therapeutics|url=https://books.google.com/books?id=8iv6CAAAQBAJ&pg=PA459|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-60072-2|pages=459–}} Adverse effects such as confusion, aphasia, stuttering, and paresthesia (a tingling sensation in the body's extremities, particularly the hands and fingers) may occur at higher dosages of the drug (e.g., over 8 mg/day). Tiagabine may induce seizures in those without epilepsy, particularly if they are taking another drug which lowers the seizure threshold. There may be an increased risk of psychosis with tiagabine treatment, although data is mixed and inconclusive.{{cite book | chapter = Antihistamines | veditors = Aronson JK |title=Meyler's Side Effects of Psychiatric Drugs| chapter-url = https://books.google.com/books?id=AmYFTSO8jCkC&pg=PA652 |year=2009 |publisher=Elsevier |isbn=978-0-444-53266-4|pages=652–}} Tiagabine can also reportedly interfere with visual color perception.

Tiagabine overdose can produce neurological symptoms such as lethargy, single or multiple seizures, status epilepticus, coma, confusion, agitation, tremors, dizziness, dystonias, abnormal posturing, and hallucinations, as well as respiratory depression, tachycardia, and hypertension or hypotension.{{cite journal | vauthors = Spiller HA, Winter ML, Ryan M, Krenzelok EP, Anderson DL, Thompson M, Kumar S | title = Retrospective evaluation of tiagabine overdose | journal = Clinical Toxicology | volume = 43 | issue = 7 | pages = 855–859 | year = 2009 | pmid = 16440513 | doi = 10.1080/15563650500357529 | s2cid = 25469390 }} Overdose may be fatal especially if the victim presents with severe respiratory depression or unresponsiveness.

Tiagabine increases the level of γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, by blocking the GABA transporter 1 (GAT-1), and hence is classified as a GABA reuptake inhibitor (GRI).{{cite journal | vauthors = Pollack MH, Roy-Byrne PP, Van Ameringen M, Snyder H, Brown C, Ondrasik J, Rickels K | title = The selective GABA reuptake inhibitor tiagabine for the treatment of generalized anxiety disorder: results of a placebo-controlled study | journal = The Journal of Clinical Psychiatry | volume = 66 | issue = 11 | pages = 1401–1408 | date = November 2005 | pmid = 16420077 | doi = 10.4088/JCP.v66n1109 }}

Tiagabine is primarily used as an anticonvulsant in the treatment of epilepsy as a supplement. Although the exact mechanism by which Tiagabine exerts its antiseizure effect is unknown, it is thought to be related to its ability to increase the activity of γ-aminobutyric acid (GABA), the central nervous system's major inhibitory neurotransmitter. Tiagabine attaches to the GABA reuptake carrier's recognition sites. Tiagabine is thought to block GABA reuptake into presynaptic neurons as a result of this action, allowing more GABA to be available for receptor binding on the surfaces of post-synaptic cells.{{Cite web|title=Gabitril (tiagabine) dosing, indications, interactions, adverse effects, and more|url=https://reference.medscape.com/drug/gabitril-tiagabine-343022#91|access-date=2021-12-24|website=reference.medscape.com}}

Tiagabine was discovered at Novo Nordisk in Denmark in 1988 by a team of medicinal chemists and pharmacologists under the general direction of Claus Bræstrup.{{cite journal |display-authors=6 |vauthors=Andersen KE, Braestrup C, Grønwald FC, Jørgensen AS, Nielsen EB, Sonnewald U, Sørensen PO, Suzdak PD, Knutsen LJ |date=June 1993 |title=The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (tiagabine) as an anticonvulsant drug candidate |journal=Journal of Medicinal Chemistry |volume=36 |issue=12 |pages=1716–1725 |doi=10.1021/jm00064a005 |pmid=8510100}} The drug was co-developed with Abbott Laboratories, in a 40/60 cost sharing deal, with Abbott paying a premium for licensing the IP from the Danish company.{{citation needed|date=October 2014}}

US patents on tiagabine listed in the Orange Book expired in April 2016.{{cite web |title=Search Results for Tiagabine |url=http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=020646&TABLE1=OB_Rx |archive-url=https://web.archive.org/web/20160422163656/http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=020646&TABLE1=OB_Rxx |archive-date=22 April 2016 |access-date=22 March 2016 |work=Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations |publisher=U.S. Food and Drug Administration}}

Tiagabine enhances the power of cortical delta (< 4 Hz) oscillations up to 1000% relative to placebo, which may result in an EEG or MEG signature resembling non-rapid eye movement sleep even while the person who has taken tiagabine is awake and conscious.{{cite journal | vauthors = Frohlich J, Mediano PA, Bavato F, Gharabaghi A | title = Paradoxical pharmacological dissociations result from drugs that enhance delta oscillations but preserve consciousness | journal = Communications Biology | volume = 6 | issue = 1 | pages = 654 | date = June 2023 | pmid = 37340024 | doi = 10.1038/s42003-023-04988-8 | pmc = 10282051 }} This demonstrates that cortical delta activity and wakeful consciousness are not mutually exclusive, i.e., high amplitude delta oscillations are not always a reliable indicator of unconsciousness.

File:MEG power change (averaged across all sources and epochs) induced by tiagabine (15 mg) in 14 healthy volunteers..png delta power in healthy volunteers.]]

• CI-966
• Deramciclane
• Nipecotic acid
• SKF-89976A

{{Reflist}}

• [https://web.archive.org/web/20060126205608/http://www.gabitril.com/physicians/home/default.asp Gabitril](manufacturer's website)

{{Anticonvulsants}}

{{Anxiolytics}}

{{GABA metabolism and transport modulators}}

Category:Drugs developed by AbbVie

Category:Anticonvulsants

Category:Anxiolytics

Category:Carboxylic acids

Category:GABA reuptake inhibitors

Category:Piperidines

Category:Thiophenes