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B R A I N S T O R M S Clinical Neuroscience Update Anticonvulsants as Anxiolytics, Part 2 Pregabalin and Gabapentin as α2δ Ligands at Voltage-Gated Calcium Channels Stephen M. Stahl, M.D., Ph.D. α δ Issue: Anticonvulsants that act as ligands at 2 subunits of voltage- gated calcium channels may also prove to be novel anxiolytics. ctivation of fear circuits tion of neurotransmitter release.5–10 If increased during neurotransmission, is a leading hypothesis this reduction happens in amygdala- neurotransmitter release is thus en- A for explaining symptoms centered fear circuits, it might have hanced. On the other hand, when the 1–3 α δ in anxiety disorders, and returning anxiolytic actions. 2 ligands pregabalin and gabapen- neurotransmission in these circuits to tin bind to these channels and thereby a more normal pattern may reduce KNOW YOUR CALCIUM CHANNELS: decrease calcium flow through them, certain symptoms.4 For example, anti- VOLTAGE-SENSITIVE OR the release of several neurotrans- convulsants may theoretically reduce LIGAND-GATED? mitters from presynaptic neurons is seizures by decreasing excessive out- decreased.5–10 put from epileptic neurons, and could, Most clinicians have heard of cal- Another subtype of voltage-gated by analogy, reduce symptoms of anxi- cium channels, but only recently has it calcium channels is an L channel, ety if these agents were also able to become clear that there are multiple which resides in membranes of vascu- decrease neuronal activation within subtypes of calcium channels, some lar smooth muscle and is blocked by fear circuits.1–4 A newly discovered regulated directly by voltage and antihypertensives commonly known mechanism of reducing neurotrans- others regulated directly by neuro- as “calcium channel blockers.”11 Such mission is employed by the anticon- transmitters, with each having unique drugs lower blood pressure but have vulsants pregabalin and gabapentin: physiologic functions as well as differ- neither anticonvulsant nor anxiolytic they bind to a specific subunit of one ential selectivity for specific drugs.11 actions. type of calcium channel—namely, the For example, calcium channels regu- α δ 2 subunit of voltage-sensitive cal- lated by the charge across the mem- Ligand-Gated Channels cium channels—which leads to reduc- brane where they reside are called An example of a ligand-gated “voltage sensitive” or “voltage gated” calcium channel is the NMDA (or whereas calcium channels regulated N-methyl-D-aspartate) glutamate re- by neurotransmitters are called “ligand ceptor complex, one of the key BRAINSTORMS is a monthly section of The gated.” mediators of excitatory postsynaptic Journal of Clinical Psychiatry aimed at neurotransmission.12 A novel drug providing updates of novel concepts emerging from the neurosciences that have relevance to Voltage-Sensitive Channels for the treatment of Alzheimer’s dis- the practicing psychiatrist. Two subtypes of calcium channels ease, memantine, binds loosely to From the Neuroscience Education Institute in the voltage-sensitive family— the NMDA receptor complex, and in Carlsbad, Calif., and the Department of Psychiatry at the University of California San known as N and P/Q channels— the hallucinogen phencyclidine binds Diego. regulate neurotransmitter release dur- tightly to the NMDA receptor com- 11 α δ Reprint requests to: Stephen M. Stahl, M.D., ing synaptic neurotransmission. On plex, but 2 ligands do not bind Ph.D., Editor, BRAINSTORMS, Neuroscience Education Institute, 5857 Owens Street, Ste. 102, the one hand, when calcium flow to the NMDA receptor complex. Carlsbad, CA 92009. through these presynaptic channels is Thus, postsynaptic ligand-gated cal- 460 © COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. © COPYRIGHT 2004 PHYSICIANSJ Clin P OSTGRADUATEPsychiatry 65:4, P AprilRESS ,2004 INC. B R A I N S T O R M S Clinical Neuroscience Update cium channels may cooperate with presynaptic voltage-gated calcium Take-Home Points channels during neurotransmission, ◆ but their functions and pharmacology Activation of neurotransmission in fear circuits may underlie are quite unique. symptoms in anxiety disorders. ◆ α δ Agents such as pregabalin and gabapentin that target the 2 COULD α2δ LIGANDS BE NOVEL ANXIOLYTICS? subunits of voltage-gated calcium channels can reduce neurotransmission in activated neuronal circuits by reducing the Preclinical studies have estab- release of neurotransmitters. α δ lished the anxiolytic actions of the 2 ◆ Reducing neurotransmission in fear circuits could hypothetically 13 ligand pregabalin. Some preliminary reduce symptoms in anxiety disorders. clinical data have suggested that the α δ 2 ligand gabapentin may have anxi- olytic properties after a case series re- ported marked clinical improvement Compared with studies for gaba- ine,20 and these findings have been with gabapentin as adjunctive therapy pentin, much better designed studies filed with the U.S. FDA for marketing in patients with treatment-refractory of anxiety have been conducted for approval in this indication. Prelimi- anxiety disorders.14 Also, a placebo- pregabalin, a higher-potency analog nary findings with pregabalin in so- controlled study15 in social phobia to gabapentin with better bioavail- cial phobia are also promising, and has shown that gabapentin reduced ability and potentially more con- studies in other anxiety disorders, in- anxiety symptoms. Another study16 sistent clinical effects. Multicenter, cluding panic disorder, are ongoing. in panic disorder found no overall placebo-controlled comparator trials Thus, it appears that the high-potency α δ gabapentin/placebo differences, only of pregabalin in generalized anxiety 2 ligand pregabalin is promising to improvement in the more severely ill disorder suggest comparable efficacy become a new anxiolytic with a novel patients. to benzodiazepines17–19 and venlafax- mechanism of action. REFERENCES 1. Stahl SM. Symptoms and circuits, pt 2: anxiety slices. Synapse 2002;45:171–190 15. Pande AC, Davidson JR, Jefferson JW. Treat- disorders [BRAINSTORMS]. J Clin Psychiatry 8. Maneuf YP, Hughes J, McKnight AT. Gabapen- ment of social phobia with gabapentin: a pla- 2003;64:1408–1409 tin inhibits the substance-P–facilitated K+- cebo-controlled study. J Clin Psychopharmacol 2. Stahl SM. Independent actions on fear circuits evoked release of 3H-flutamate from rat caudal 1999;19:341–348 may lead to therapeutic synergy for anxiety trigeminal nucleus slices. Pain 2001;93: 16. Pande AC, Pollack MH, Crockatt J, et al. when combining serotonergic and GABAergic 191–193 Placebo-controlled study of gabapentin treat- agents [BRAINSTORMS]. J Clin Psychiatry 2002; 9. Dooley DJ, Donovan CM, Pugsley TA. Stimu- ment of panic disorder. J Clin Psychopharmacol 63:854–855 lus dependent modulation of 3H-norepineph- 2000;20:467–471 3. Coplan JD, Lydiard RB. Brain circuits in panic rine release from rat neocortical slices by gaba- 17. Pande AC, Crockatt JG, Feltner DE, et al. disorder. Biol Psychiatry 1998;44:1264–1276 pentin and pregabalin. J Pharmacol Exp Ther Pregabalin in generalized anxiety disorder: 4.Stahl SM. Deconstructing psychiatric dis- 2000;295:1086–1093 a placebo-controlled trial. Am J Psychiatry orders, pt 2: an emerging, neurobiologically 10. Fehenbacher JC, Taylor CP, Vasko MR. 2003;160:533–540 based therapeutic treatment strategy for the Pregabalin and gabapentin reduce release of 18. Feltner DE, Crockatt JG, Dubovsky SJ, et al. A modern psychopharmacologist [BRAINSTORMS]. substance P and CGRP from rat spinal tissues randomized, double-blind, placebo-controlled J Clin Psychiatry 2003;64:1145–1146 only after inflammation or activation of protein fixed-dose, multicenter study of pregabalin in 5. Fink K, Dooley DJ, Meder WP, et al. Inhibition kinase C. Pain 2003;105:133–141 patients with generalized anxiety disorder. of neuronal Ca2+ influx by gabapentin and 11.McDonough SI, ed. Calcium Channel Pharma- J Clin Psychopharmacol 2003;23:240–249 pregabalin in the human neocortex. Neuro- cology. New York, NY: Kluwer Academic/ 19. Rickels K, Rynn M. Efficacy and safety of pharmacology 2002;42:229–236 Plenum; 2004 pregabalin and alprazolam in generalized anxi- 6. Gee NS, Brown JP, Dissanayake VUK, et al. 12. Stahl SM. Essential Psychopharmacology. ety disorder [poster]. Presented at the 24th The novel anticonvulsant drug gabapentin 2nd ed. New York, NY: Cambridge University annual meeting of the Collegium Internationale (Neurontin) binds to the alpha 2 delta subunit Press; 2000 Neuro-Psychopharmacologium; June 23–27, of a calcium channel. J Biol Chem 1996;271: 13. Field MJ, Oles RJ, Singh L. Pregabalin may 2002; Montreal, Quebec, Canada 5768–5776 represent a novel class of anxiolytic agents with 20. Kasper S, Blagden M, Seghers S, et al. A 7. Dooley DJ, Donovan CM, Meder WP, et al. a broad spectrum of activity. Br J Pharmacol placebo-controlled study of pregabalin and ven- Preferential action of gabapentin and 2001;132:1–4 lafaxine treatment of GAD [poster]. Presented pregabalin at P/Q-type voltage-sensitive cal- 14. Pollack MH, Matthews J, Scott EL. Gabapentin at the 24th annual meeting of the Collegium cium channels: inhibition of K+-evoked [3H]- as a potential treatment for anxiety disorders. Internationale Neuro-Psychopharmacologium; norepinephrine release from rat neocortical Am J Psychiatry 1998;155:992–993 June 23–27, 2002; Montreal, Quebec, Canada J© Clin COPYRIGHT Psychiatry 2004 65:4, P HYSICIANSApril 2004 POSTGRADUATE PRESS, INC. © COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. 461.
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