Gamma-aminobutyric acid reuptake inhibitors

Generic and Brand Names

• Tiagabine — Gabitril

• (Investigational/legacy research examples, not marketed): NNC-711, SKF-89976A (tool compounds)

Class

• Antiseizure medication; selective GABA transporter (GAT-1) inhibitor

• Functional result: ↑ synaptic/extrasynaptic GABA concentrations → enhanced inhibitory neurotransmission

Mechanism of Action

• High-affinity, reversible inhibition of GAT-1 (SLC6A1)

  • ↓ Neuronal and astrocytic GABA reuptake

  • Prolongs GABA action at GABA_A receptors (no direct receptor agonism)

• No meaningful sodium channel block; no carbonic anhydrase or GABA-T inhibition

Indications

• Adjunctive treatment of partial-onset (focal) seizures with/without secondary generalization in patients ≥12 years

• Not recommended:

  • As monotherapy for epilepsy (higher risk of status epilepticus during rapid up-titration)

  • In absence/myoclonic/generalized epilepsies (may aggravate seizures)

  • For non-epilepsy conditions (e.g., anxiety, pain): risk of new-onset seizures

Dosage and Administration (Adults/Adolescents ≥12 y)

• Start: 4 mg once daily with food (evening preferred)

• Titrate: ↑ by 4–8 mg/day at weekly intervals based on response/tolerability

• Target daily dose (in 2–4 divided doses)

  • With enzyme-inducing AEDs (e.g., carbamazepine, phenytoin, phenobarbital, primidone): 32–56 mg/day

  • With non-inducing regimens (e.g., valproate-based): 16–48 mg/day (often lower total dose)

• Max commonly 56 mg/day (clinical practice range 32–56 mg/day)

• Hepatic impairment/elderly: slower titration; consider lower targets

• Missed dose: take when remembered unless near next dose (no doubling)

Pharmacokinetics

• Absorption: high oral bioavailability; slower with food (often improves tolerability)

• Distribution: highly protein-bound (~96%)

• Metabolism: hepatic CYP3A-mediated; minimal active metabolites

• Half-life: ~7–9 h (shorter with enzyme inducers; longer without)

• Drug transporters: not a P-gp substrate of clinical concern

Monitoring

• Efficacy: seizure diary; caregiver observations

• Safety: neuropsychiatric status (confusion, attention, mood), suicidal ideation screening; watch for non-convulsive status (prolonged confusion)

• When co-prescribed with inducers/inhibitors: reassess dose after changes

• Pregnancy: enroll in AED pregnancy registry where available; monitor levels clinically (no standardized TDM)

Contraindications

• Known hypersensitivity to tiagabine or components

Precautions

• Seizures in non-epileptic patients (off-label use): avoid

• Worsening generalized epilepsies (absence/myoclonic): avoid/use extreme caution

• Status epilepticus risk with rapid titration or overdose

• CNS depression: additive effects with alcohol, sedatives

• Hepatic dysfunction: exposure ↑; titrate conservatively

• Suicidality: class warning for antiepileptic drugs

Adverse Effects

• Common: dizziness, somnolence, tremor, nervousness, difficulty concentrating, speech disturbance, nausea, abdominal pain

• Dose-related/CNS: confusion, slowed thinking, ataxia, paresthesias

• Seizure-related: new/worsened seizures (esp. generalized/absence), non-convulsive status

• Psychiatric: irritability, mood change; rare psychosis

• Less common: rash, weight loss, visual disturbance

Drug Interactions

• CYP3A inducers (carbamazepine, phenytoin, phenobarbital, primidone, rifampin, St John’s wort) → ↓ tiagabine levels; may require higher doses

• CYP3A inhibitors (ketoconazole, macrolides, some protease inhibitors) → ↑ levels; consider dose reduction

• Highly protein-bound drugs: theoretical displacement (rarely clinically relevant)

• Additive CNS effects: benzodiazepines, opioids, alcohol

Overdose

• Presentation: marked somnolence, confusion, agitation, seizures/status epilepticus, tachycardia

• Management: airway/ventilation, benzodiazepines for seizures, supportive care, consider continuous EEG for persistent altered mental status

Patient Counselling (Concise Points)

• Take with food, same times daily; do not stop abruptly

• Report new/worsening seizures, prolonged confusion, mood changes, rash

• Avoid alcohol/sedatives when possible

• Not a general “calming” medicine; do not use for anxiety/sleep

• If pregnancy occurs, do not discontinue suddenly; contact prescriber promptly

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Comparison Table 1 — GABAergic Antiseizure Strategies

Attribute	Tiagabine	Vigabatrin	Benzodiazepines (e.g., clonazepam, diazepam)	Barbiturates (phenobarbital)	Stiripentol
Primary mechanism	GABA reuptake (GAT-1) inhibition	Irreversible GABA-T inhibition (↑ GABA synthesis pool)	GABA_A PAM (↑ channel opening frequency)	GABA_A PAM (↑ channel open duration)	Mixed: GABA_A modulation, CYP inhibition; evidence of ↑ extracellular GABA
Indications (core)	Adjunct for focal seizures	Infantile spasms; refractory focal seizures (limited by safety)	Acute seizures, status adjunct; some chronic	Focal/tonic-clonic; neonatal	Dravet syndrome (with clobazam/valproate)
Worsens generalized epilepsies	Possible (absence/myoclonic)	Possible field-dependent	Possible myoclonic worsening	Possible cognitive sedation	Neutral/variable
Key safety issue	Non-epileptic seizure risk off-label; CNS effects	Irreversible visual field constriction (boxed)	Sedation, tolerance, dependence	Sedation, cognitive slowing	Drug interactions (CYP), sedation
Titration speed	Slow (weekly)	Moderate	Rapid (as needed)	Slow–moderate	Slow; interaction-aware
Role in status epilepticus	No	No	Yes (IV lorazepam/diazepam)	Yes (second-line)	No

Comparison Table 2 — GABA Transporter Targets (Conceptual, Clinical Relevance)

Transporter	Gene	Major Location	Functional Role	Tiagabine Inhibition
GAT-1	SLC6A1	Neurons > astrocytes (forebrain, cortex, hippocampus)	Primary synaptic GABA reuptake	Potent
GAT-2	SLC6A13	Liver, meninges; limited brain	Osmolyte/β-alanine transport; minor CNS role	Minimal
GAT-3	SLC6A11	Astrocytes (perisynaptic)	Extrasyanptic GABA clearance	Weak
BGT-1	SLC6A12	Brain (low), kidney	Osmolyte transport; minor CNS GABA role	Minimal

Practical Positioning (Focal Epilepsy)

• Consider tiagabine after first-line options (e.g., levetiracetam, lamotrigine, lacosamide) when additional GABAergic augmentation is desired and generalized epilepsy is unlikely.

• Avoid off-label psychiatric/analgesic use due to seizure induction risk.

• Reassess dose when enzyme-inducing co-therapy is started/stopped.