Anticonvulsants in psychiatry: their similarities are different; Part 1--mechanism of action.
Actions Learn the different mechanisms of action of anticonvulsants
Benefits Understanding mechanism of action of anticonvulsants (1-8) should help a prescriber match the best drug action to the specific psychiatric disorder of a given patient
Although all anticonvulsants share the common property of reducing seizures, they do so in different ways. Because of their divergent mechanisms of action, each anticonvulsant may have a unique therapeutic profile outside of epilepsy. In fact, clinical data already suggest that many anticonvulsants are effective in bipolar disorder, schizophrenia, anxiety, and chronic pain, but that not all anticonvulsants are effective in the same disorders. It is therefore important to understand the mechanism of action of each agent in order to select an anticonvulsant that can effectively treat the presenting symptoms of a given patient.
Anticonvulsants and Voltage-Sensitive Ion Channels
Neurotransmitter release from presynaptic nerve terminals is linked to both voltage-sensitive sodium channels (VSSC) and voltage-sensitive calcium channels (VSCC) (figure). Several anticonvulsants bind to VSSCs, some acting directly at a specific site within the channel itself (lamotrigine, carbamazepine, oxcarbazepine, and possibly zonisamide), and others acting at sites not yet well-characterized (valproate, topiramate), (1,5,6) Other anticonvulsants (gabapentin, pregabalin) bind to the alpha 2 delta subunit of VSCCs. (1,3,4,7)
Anticonvulsants and Other Mechanisms of Action
Benzodiazepines bind to gamma-aminobutyric acid (GABA) A receptors to enhance the inhibitory effects of GABA. (1) Tiagabine blocks the GABA reuptake pump, (1,2) while vigabatrin irreversibly blocks GABA-T, the enzyme that breaks down GABA. (2) One of the newer anticonvulsants, levetiracetam, acts directly at synaptic vesicles to modulate neurotransmitter release. (8)
Anticonvulsants in Psychiatric Disorders
Some anticonvulsants that act at VSSCs have demonstrated efficacy in bipolar disorder and as augmenting agents to atypical antipsychotics in schizophrenia, while preliminary data suggest that actions on VSSCs may also treat chronic pain, (1,5,6) Thus, other VSSC modulators may be effective in these disorders as well. Alpha 2 delta ligands are effective in both anxiety disorders and chronic pain, suggesting that other agents that modulate VSCCs may similarly treat these disorders. (1,3,4,7) Benzodiazepines are well-established as treatment options for anxiety, and it is reasonable that modulation of GABA neurotransmission through other means may likewise be anxiolytic. (1,2)
The bottom line -- Anticonvulsants that have demonstrated efficacy in a particular disorder should be used prior to anticonvulsants that have not. Nonetheless, knowing the mechanism of action of anticonvulsant agents can help guide clinicians in choosing treatment for their patients even in the absence of clinical data, because two agents that work in the same way would be expected to have the same therapeutic effects.
1. Stahl SM. J Clin Psychiatry 2004;65:149-50.
2. Stahl SM. J Clin Psychiatry 2004;65:291-2.
3. Stahl SM. J Clin Psychiatry 2004;65:460-1.
4. Stahl SM. J Clin Psychiatry 2004;65:596-7.
5. Stahl SM. J Clin Psychiatry 2004;65:738-9.
6. Stahl SM. J Clin Psychiatry 2004;65:894-5.
7. Stahl SM. J Clin Psychiatry 2004;65:1033-4.
8. Stahl SM. J Clin Psychiatry 2004;65:1162-3.
Edited by Meghan M. Grady
Senior Medical Writer, NEI