CNS Drugs 2008; 22 (9): 761-786

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 762 1. The Pharmacological Actions of Riluzole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 763 1.1 Effects of Riluzole on Glutamatergic Neurotransmission and Homeostasis . . . . . . . . . . . . . . . . . . 763 1.1.1 Glutamate Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 763 1.1.2 Glutamate Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767 1.1.3 Trophic and Toxic Effects of Glutamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767 1.1.4 Glutamate Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768 1.1.5 Riluzole Potentiates Glial Glutamate Uptake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769 1.2 Other Neurotransmitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 770 1.3 Functional Overlap with Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 770 1.4 Summary of the Pharmacological Effects of Riluzole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 771 2. Riluzole in the Treatment of Neurological Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 771 2.1 Amyotrophic Lateral Sclerosis (ALS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 771 2.2 Other Neurodegenerative Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 771 2.3 Neuropathic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 772 2.4 Antiepileptic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 772 3. Riluzole in the Treatment of Psychiatric Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 772 3.1 Unipolar Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 772 3.2 Bipolar Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 773 3.3 Generalized Anxiety Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 775 3.4 Obsessive-Compulsive Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 775 3.5 Compulsive-Impulsive Spectrum Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 776 4. Tolerability and Adverse Effects of Riluzole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777 4.1 Common Adverse Effects in the ALS Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777 4.2 Transaminase Abnormalities in the ALS Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 778 4.3 Rare Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 778 4.4 Adverse Effects in the Psychiatric Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 778 4.5 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 779 5. Dosage Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 779 6. Cost Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 780 7. Summary and Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 780 762 Pittenger et al. Recent advances implicate amino acid neurotransmission in the pathophysioAbstract logy and treatment of mood and anxiety disorders. Riluzole, which is approved and marketed for the treatment of amyotrophic lateral sclerosis, is thought to be neuroprotective through its modulation of glutamatergic neurotransmission. Riluzole has multiple molecular actions in vitro; the two that have been documented to occur at physiologically realistic drug concentrations and are therefore most likely to be clinically relevant are inhibition of certain voltage-gated sodium channels, which can lead to reduced neurotransmitter release, and enhanced astrocytic uptake of extracellular glutamate. Although double-blind, placebo-controlled trials are lacking, several openlabel trials have suggested that riluzole, either as monotherapy or as augmentation of standard therapy, reduces symptoms of obsessive-compulsive disorder, unipolar and bipolar depression, and generalized anxiety disorder. In studies of psychiatrically ill patients conducted to date, the drug has been quite well tolerated; common adverse effects include nausea and sedation. Elevation of liver function tests is common and necessitates periodic monitoring, but has been without clinical consequence in studies conducted to date in psychiatric populations. Case reports suggest utility in other conditions, including trichotillomania and selfinjurious behaviour associated with borderline personality disorder. Riluzole may hold promise for the treatment of several psychiatric conditions, possibly through its ability to modulate pathologically dysregulated glutamate levels, and merits further investigation. Until very recently, aetiological theories of psyDysregulation of the most common excitatory neurotransmitter, glutamate, appears to be central to chiatric pathophysiology have focused on the the pathophysiology of mood and anxiety disorbrain’s modulatory monoamine systems – dopders.[4-7] This observation now motivates the investiamine, serotonin and norepinephrine.[1] With the gation of glutamate-modulating agents as novel exception of lithium, benzodiazepines and therapeutic tools in a variety of contexts. antiepileptic medications, all US FDA-approved treatments for mood and anxiety disorders target Considerable recent attention has focused on these monoaminergic neurotransmitters. However, riluzole (2-amino-6-trifluoromethoxy benzothiarecent large-scale effectiveness trials performed in zole; Rilutek® 1, Sanofi-Aventis, Paris, France; figpatients with mood and anxiety disorders have highure 1), an ‘orphan’ drug that reduces glutamatergic lighted the limitations of medications that target overstimulation by several mechanisms. Riluzole is brain monoamines. For example, the STAR*D (Seapproved by the FDA for the treatment of amyoquenced Treatment Alternatives to Relieve Deprestrophic lateral sclerosis (ALS); it remains the only sion) trial of treatments for major depressive disormedication proven to lengthen life and delay hospider found remission rates of only 37% after initial talization in this disease.[8-10] Because of its glutatreatment and an additional 31% after a first switch mate-modulating properties, a number of groups to another treatment modality.[2] The need for more have investigated the efficacy of riluzole in the effective pharmacotherapies for mood and anxiety treatment of several mood and anxiety disorders. disorders, combined with a growing appreciation of While no definitive double-blind, placebo-controlthe inadequacies of monoaminergic pathophysioled studies have been published to date, promising logical hypotheses, has led to the exploration of open-label reports provide preliminary evidence of novel pathophysiological and therapeutic mechanthe efficacy of riluzole in treatment-resistant major isms.[3] depressive disorder,[11-13] bipolar depression,[14] ob1 The use of trade names is for product identification purposes only and does not imply endorsement. © 2008 Adis Data Information BV. All rights reserved. CNS Drugs 2008; 22 (9) Riluzole in Mood and Anxiety Disorders 763 sessive-compulsive disorder (OCD)[15-18] and generALS,[28] traumatic brain and spinal cord injury,[29-34] alized anxiety disorder (GAD).[19] excitotoxicity[35,36] and cerebral ischaemia.[35,37-40] In this review, we present the evidence sugThe neuroprotective properties of riluzole likely degesting that riluzole may have utility in the treatrive from its modulation of glutamatergic neuroment of mood and anxiety disorders, and merits transmission. further investigation in controlled studies. We reGlutamate is the major excitatory neurotransmitview the various pharmacological effects of riluzole ter in the adult brain. It is present in the CNS and that have been described; because the drug has been CSF at high levels of 8–10 mmol/kg or even shown to interact with multiple aspects of glutahigher.[41-43] Glutamatergic projections participate in matergic neurotransmission and homeostasis, this virtually all circuits in the adult CNS, including discussion is embedded in a review of the cogent intracortical connections, cortical-subcortical conaspects of the use and regulation of glutamate in the nections and subcortical systems such as the basal brain. We highlight the ability of this medication to ganglia, cerebellum, thalamus and brainstem strucenhance glial glutamate uptake, which may retures.[44] Riluzole has been shown to affect several present its most unique pharmacological property. aspects of glutamatergic synaptic transmission, inWe briefly review the established and investigationcluding release, postsynaptic effects and homeostatal uses of riluzole in ALS and other neurological ic regulation (see figure 2 and the discussion in diseases. Next, we summarize the preliminary clinsections 1.1.1–1.1.5). However, many of these vaical evidence that riluzole has efficacy in depresried pharmacological actions have been demonstrasion, bipolar depression, OCD, GAD and other conted only in vitro, at riluzole concentrations that are ditions. Finally, we discuss safety considerations unlikely to be achieved in the brains of patients and other practical matters arising in the use of taking the drug. Those actions shown to occur at riluzole in various clinical populations. We suggest physiologically realistic drug concentrations are that riluzole may be a prototype for other treatments correspondingly more likely to contribute to the for mood and anxiety disorders that work by enpharmacological effects of riluzole in vivo (see table hancing glial glutamate uptake. I and sections 1.1.1–1.1.5). 1. The Pharmacological Actions 1.1.1 Glutamate Release of Riluzole Glutamate functions as a classical neurotransmitter (figure 2). Glutamate is packaged into vesicles at 1.1 Effects of Riluzole on Glutamatergic the synaptic termini of glutamatergic neurons. When Neurotransmission and Homeostasis an action potential reaches the axon terminal and depolarizes the membrane, it activates voltage-gated Riluzole was initially developed as an anticonsodium channels and voltage-gated calcium chanvulsant,[20,21] although it never received FDA apnels (VGCCs). The resulting influx of sodium furproval for this use. Riluzole is marketed for use in ther depolarizes the axon terminal, while the influx ALS; it has been approved for this indication in the of calcium activates synaptic release through interUS and, more recently, in Australia, Canada and actions with SNARE proteins which, when activatmany European countries.[10] Riluzole has been ed, trigger fusion of neurotransmitter-containing found to be neuroprotective in animal models of vesicles with the presynaptic membrane. Glutamateseveral neurodegenerative diseases, including containing synaptic vesicles fuse with the presynapParkinson’s disease,[22-25] Huntington’s disease,[26,27] tic membrane, releasing their contents into the synaptic cleft. Glutamate rapidly diffuses across the synaptic cleft, where it can bind to postsynaptic receptors. Glutamatergic neurons are frequently projection neurons whose axons extend to distant sites within the CNS.[44] N