3 Clinical psychopharmacology3.3 Pharmacodynamics
3.3.6.2 Antiepileptics non mood stabilising
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Written by Resident Doctor Committee · Published
Why psychiatrists prescribe them
Gabapentin was developed and is classed as an antiepileptic, but psychiatrists mostly use it for its sedative and analgesic effects.
Neuropathic pain accounts for most gabapentin and pregabalin use.
Pregabalin is licensed in the UK for generalised anxiety disorder.
Mechanisms of action
Mechanism | Agents | Effect |
|---|---|---|
Sodium channel stabilisation | Phenytoin, carbamazepine, oxcarbazepine, lamotrigine | Hold voltage-gated sodium channels in the inactivated state |
Alpha-2-delta subunit binding | Gabapentin, pregabalin | Bind this subunit of presynaptic voltage-gated calcium channels, reducing calcium entry and excitatory transmitter release |
T-type calcium current reduction | Ethosuximide | Acts on thalamic relay neurones |
GAT-1 transporter blockade | Tiagabine | GABA stays longer in the synaptic cleft |
Synaptic vesicle protein 2A (SV2A) binding | Levetiracetam, brivaracetam | Regulates vesicle fusion and transmitter release |
Gabapentin and pregabalin are analogues of gamma-aminobutyric acid (GABA), but they have no action at GABA receptors, on GABA uptake or on GABA breakdown.
Carbamazepine prolongs fast inactivation in a use-dependent way, so it holds back burst firing.
Ethosuximide treats typical absence seizures but not focal or tonic-clonic seizures.
Brivaracetam binds SV2A with higher affinity than levetiracetam.
Topiramate has four actions: sodium channel blockade, GABA-A potentiation at a non-benzodiazepine site, AMPA and kainate glutamate receptor antagonism, and weak carbonic anhydrase inhibition.
Antiseizure is not mood stabilising
Drug | Bipolar effect |
|---|---|
Valproate | Antimanic, little effect in bipolar depression |
Carbamazepine | Antimanic |
Lamotrigine | Prevents depressive relapse, no efficacy in acute mania |
Topiramate, gabapentin | No efficacy in acute mania |
Levetiracetam, pregabalin | No established efficacy |
Pregabalin
Absorption is almost complete after oral dosing, with bioavailability of 90% or more that does not fall as the dose rises.
Elimination is by the kidneys, almost entirely as unchanged drug with negligible hepatic metabolism, so the dose is adjusted for renal function.
Tolerance develops to its euphoric effect with continued use.
Gabapentinoids cause dependence and withdrawal (anxiety, insomnia, autonomic symptoms) and are UK Class C controlled drugs.
Gabapentinoids can cause respiratory depression, especially with opioids, renal impairment, respiratory disease or older age.
Weight
Effect | Drugs |
|---|---|
Reduced appetite and weight loss | Topiramate |
Weight gain | Valproate, carbamazepine, pregabalin (with increased appetite) |
Weight-neutral | Lamotrigine |
Other adverse effects
Topiramate
Carbonic anhydrase inhibition lowers bicarbonate reclamation, causing paraesthesia and a normal anion gap acidosis.
The same action alkalinises the urine and lowers urinary citrate, so calcium phosphate precipitates as renal stones.
Topiramate tends to cause cognitive slowing, word-finding difficulty and low mood.
Acute angle-closure glaucoma can occur in the first month and is an ophthalmic emergency.
Carbamazepine
Neurotoxic effects are dose-related: diplopia is common, and ataxia, dizziness and somnolence are very common (at least one in ten).
Stevens-Johnson syndrome is very rare.
Carbamazepine can cause agranulocytosis, aplastic anaemia and hyponatraemia, which shows in older patients as confusion or falls.
Levetiracetam and vigabatrin
Levetiracetam has the highest rate of behavioural and aggressive adverse effects among commonly used antiepileptics.
Vigabatrin causes high rates of agitation, aggression and irritability, particularly in children, and can cause depression or psychosis.
Vigabatrin causes irreversible bilateral concentric constriction of the peripheral visual fields, painless and gradual with acuity preserved, so patients need perimetry monitoring.
All antiseizure medicines carry a suicidality warning.
Pregnancy and interactions
NICE (National Institute for Health and Care Excellence) first-line monotherapy for generalised tonic-clonic seizures in a woman or girl able to have children is lamotrigine or levetiracetam.
Valproate and topiramate are avoided because they carry malformation and neurodevelopmental risks; both have a Pregnancy Prevention Programme.
Oestrogen-containing contraception induces lamotrigine glucuronidation, roughly doubling clearance and halving the plasma level, so the dose is reviewed when contraception starts or stops.
Valproate raises the lamotrigine level.
Carbamazepine, phenytoin and phenobarbital induce enzymes, lowering levels of psychotropics such as quetiapine and aripiprazole, and of some pill and implant contraceptives.