Abstract
Benzodiazepines have been used as anxiolytics for many years, despite well described withdrawal effects and drug interactions. Serotonergic antidepressants, which benefit from a favourable adverse effect profile and do not cause dependence, are now established first-line treatments for anxiety disorders. It is apparent, however, that current treatments are not ideal, particularly as they do not always produce a complete recovery. Our growing knowledge of the neurobiology of anxiety disorders, aided by advances in neuroimaging and pharmacological challenges, has led to the development of other potential anxiolytics.
Agents with increased specificity for serotonin receptor subtypes have been developed, with the aim of maximising therapeutic efficacy while minimising adverse effects. Novel anxiolytics, such as neuropeptide agonists and antagonists, γ-aminobutyric acid (GABA)A receptor partial agonists, N-methyl-D-aspartate (NMDA) receptor antagonists, neurosteroids and others, are currently in development and may eventually offer alternatives to currently available agents.
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References
American Psychiatric Association. Diagnostic and statisticalmanual of mental disorders. 3rd ed. Washington, DC: American Psychiatric Association, 1980
Regier DA, Boyd JH, Rae DS, et al. One-month prevalenceof mental disorders in the US: based on five epidemiologiccatchment area (ECA) sites. Arch Gen Psychiatry 1988; 45: 977–86
Lecrubier Y. The impact of comorbidity on the treatment of panic disorder. J Clin Psychiatry 1998; 59 Suppl. 8: 11–6
Candilis PJ, McLean RY, Otto MW, et al. Quality of life in patients with panic disorder. J Nerv Ment Dis 1999 Jul; 187(7): 429–34
Ballenger JC. Selective serotonin reuptake inhibitors (SSRIs) in panic disorder. Nutt DJ, Ballenger JC, Lepine J-P, editors. Panic disorder. Clinical diagnosis, management and mechanisms. London: Martin Dunitz, 1999: 159–78
Graeff FG, Silveira MC, Nogueira RL, et al. Role of the amygdala and periaqueductal gray in anxiety and panic. Behav Brain Res 1993; 58(1–2): 123–31
Graeff FG, Viana MB, Mora PO. Dual role of 5-HT in defense and anxiety. Neurosci Biobehav Rev 1997; 21(6): 791–9
Coplan JD, Lydiard RB. Brain circuits in panic disorder. Biol Psychiatry 1998; 44(12): 1264–76
Reilly JG, McTavish SFB, Young AH. Rapid depletion of plasma tryptophan: a review of studies and experimental methodology. J Psychopharmacology 1997; 11: 381–92
Åberg-Wisted A, Hasselmark L, Stain-Malmgren R, et al. Serotonergic ‘vulnerability’ in affective disorder: a study of the tryptophan depletion test and relationships between peripheral and central serotonin indexes in citalopram-responders. Acta Psychiatr Scand 1998; 97: 374–80
Bremner JD, Innis RB, Salomon RM, et al. Positron emission tomography measurement of cerebral metabolic correlates of tryptophan depletion-induced depressive relapse. Arch Gen Psychiatry 1997; 54, 364–74
Delgado PL, Charney DS, Price LH, et al. Serotonin function and the mechanism of antidepressant action: reversal of anti-depressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry 1990; 45, 2323–32
Delgado PL, Price LH, Miller HL, et al. Rapid serotonin depletion as a provocative challenge for patients with major depression: relevance to antidepessant action and the neurobiology of depression. Psychopharmacol Bull 1991; 29: 389–96
Delgado PL, Miller HL, Salomon RM, et al. Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role in the mechanism of antidepressant action. Biol Psychiatry 1999; 46: 212–20
Barr LC, Goodman WK, McDougle CJ, et al. Tryptophan depletionin patients with obsessive-compulsive disorder whorespond to serotonin reuptake inhibitors. Arch Gen Psychiatry 1994; 51, 309–17
Smeraldi E, Diaferia G, Erzegovesi S, et al. Tryptophan depletion in obsessive-compulsive patients. Biol Psychiatry 1996; 40: 398–402
Rasmusson AM, Anderson GM, Lynch KA, et al. Apreliminary study of tryptophan depletion on tics, obsessive-compulsive symptoms, and mood in Tourette’s syndrome. Biol Psychiatry 1997; 41, 117–21
Nutt D, Forshall S, Bell C, et al. Mechanisms of action of selective serotonin reuptake inhibitors in the treatment of psychiatric disorders. Eur Neuropsychopharmacol 1999; 9 Suppl. 3: S81–6
Pecknold JC. Serotonin abnormalities in panic disorder. In: Ballenger JC, editor. Neurobiology of panic disorder. New York (NY): Wiley-Liss, 1990: 121–42
File SE, Hyde JRG. The effects of p-chlorophenylalanine and ethanolamine-O-sulphate in an animal test of anxiety. J Pharmacol 1977; 29: 735–8
Graeff NG, Filho NGS. Behavioural inhibition induced by electricalstimulation of the median raphe nucleus of the rat. Physiol Behav 1978; 21: 477–84
Charney DS, Heninger GR. Abnormal regulation of noradrenergicfunction in panic disorders: effects of clonidine in healthysubjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry 1986; 43(11): 1042–54
Kahn RS, Westenberg HG, Verhoeven WM, et al. Effect of aserotonin precursor and uptake inhibitor in anxiety disorders;a double-blind comparison of 5-hydroxytryptophan, clomipramineand placebo. Int Clin Psychopharmacol 1987; 2(1): 33–45
Charney DS, Woods SW, Goodman WK, et al. Serotonin functionin anxiety: II. Effects of the serotonin agonist MCPP inpanic disorder patients and healthy subjects. PsychopharmacologyBerl 1987; 92(1): 14–24
Hollander E, DeCaria CM, Nitescu A, et al. Serotonergic functionin obsessive-compulsive disorder: Behavioral and neuroendocrineresponses to oral m-chlorophenylpiperazine andfenfluramine in patients and healthy volunteers. Arch GenPsychiatry 1992 Jan; 49(1): 21–8
Eriksson E, Engberg G, Bing O, et al. Effects of mCPP on theextracellular concentrations of serotonin and dopamine in ratbrain. Neuropsychopharmacology 1999; 20(3): 287–96
Germine M, Goddard AW, Sholomskas DE, et al. Response tometa-chlorophenylpiperazine in panic disorder patients andhealthy subjects: influence of reduction in intravenous dosage. Psychiatry Res 1994; 54(2): 115–33
Greist JH, Jefferson JW. Pharmacotherapy for obsessive-compulsive disorder. Br J Psychiatry 1998; 173 Suppl. 35: 64–70
Cartwright C, Hollander E. SSRIs in the treatment of obsessive-compulsivedisorder. Depress Anxiety 1998; 8 Suppl. 1: 105–13
Blier P, de Montigny C. Possible serotonergic mechanisms underlyingthe antidepressant and anti-obsessive-compulsive disorderresponses. Biol Psychiatry 1998 Sep 1; 44(5): 313–23
Rickels K, Schweizer E, De Martinis M, et al. Gepirone anddiazepam in generalised anxiety disorders: a placebo-controlledtrial. J Clin Psychopharmacol 1997; 17: 272–7
Pecknold JC, Luthe L, Scott Fleury MH, et al. Gepirone and thetreatment of panic disorder: an open study. J Clin Psychopharmacol 1993; 13(2): 145–9
Berenyi E, Blasko G, Fekete M, et al. EGYT-3886. Drugs Future 1990 Dec; 15: 1174–5
Detari L, Szentgyorgyi V, Hajnik T, et al. Differential EEGeffects of the anxiolytic drugs, deramciclane (EGIS-3886),ritanserin and chlordiazepoxide in rats. PsychopharmacologyBerl 1999 Mar; 142(3): 318–26
Freeman AM, Westphal JR, Norris GT, et al. The efficacy of ondansetron in the treatment of generalised anxiety disorder. Depress Anxiety 1997; 5: 140–1
Depot M, Merani S, Bradwejn J, et al. Effect of oral ondansetronon total cholecystokinin plasma levels following CCK-4panic challenge procedure in healthy men. J Psychiatry Neurosci 1998; 23(5): 298–304
Schneier FR, Garfinkel R, Kennedy B, et al. Ondansetron in thetreatment of panic disorder. Anxiety 1996; 2(4): 199–202
Bell J, DeVeaugh-Geiss J. Multicenter trial of a 5-HT3 antagonist,ondansetron in social phobia [poster]. Presented at the33rd Annual Meeting of the American College of Neuropsychopharmacology; 1994 Dec 12–16; San Juan, Puerto Rico
Smith WT, Londborg PD, Blomgren SL, et al. Pilot study ofzotosetron (LY277359) maleate, a 5-hydroxytryptamine-3antagonist, in the treatment of anxiety. J Clin Psychopharmacol 1999 Apr; 19: 125–31
Hamner M, Ulmer H, Horne D. Buspirone potentiation of antidepressantsin the treatment of PTSD. Depress Anxiety 1997;5: 137–9
van Vliet IM, Westenberg HGM, den Boer JA. Effects of the5-HT1A receptor agonist flesinoxan in panic disorder. Psychopharmacology 1996 Sep; 127: 174–80
Deren-Wesolek A, Tatarcznska E, Chojnacka-Wojcik E. Thenovel buspirone analogue, 8- [4- [2- (1,2,3,4-tetrahydroisoquinolinyl)[butyl] -8-azaspiro [4.5] decane-7,9-dione, withanxiolytic-like and antidepressant-like effects in rats. J Psychopharmacol 1998; 12(4): 380–4
Hanes KR. Serotonin, psilocybin, and body dysmorphic disorder:a case report. J Clin Psychopharmacol 1996; 16: 188–9
Baumgarten HG, Grozdanovic Z. Role of serotonin in obsessive-compulsivedisorder. Br J Psychiatry Suppl 1998; 35: 13–20
McDougle CJ, Goodman WK, Price LH. Dopamine antagonistsin tic related and psychotic spectrum obsessive compulsivedisorder. J Clin Psychiatry 1994; 55 Suppl. 3: 24–31
Koran L, Ringold A, Elliott M. Olanzapine added to fluoxetinein unresponsive obsessive-compulsive disorder [abstract 3.020].Eur Neuropsychopharmacol 1999; 9 Suppl. 5: S305
O’Hanlon JF, Robbe HW, Verneeren A, et al. Venlafaxine’s effectson healthy volunteers’ driving, psychomotor, and vigilanceperformance during 15-day fixed and incrementaldosing regimens. J Clin Psychopharmacol 1998 Jun; 18(3): 221–21
American Home Products Corporation. American Home Products announces Effexor (R) XR receives FDA approval for the treatment of generalized anxiety disorder. Media Release. 1999 Mar 12; 3 pages
Wyeth-Ayerst Laboratories. New studies demonstrate long-termeffectiveness of Effexor (R) XR in treating symptoms of generalisedanxiety disorder. Media Release. 1999 Mar 26; 2 pages
Hackett D, Haudiquet V, Salinas E. A dose-response, 6 monthevaluation of venlafaxine extended-release in outpatients withgeneralized anxiety disorder [abstract]. The Summer Meetingof the British Association for Psychopharmacology; 1999 Jul25; J Psychopharmacol 1999; 13(3): A44
Kelsey JE. Venlafaxine in social phobia. Psychopharmacol Bull 1995; 31(4): 767–71
Altamura AC, Pioli R, Vitto M, et al. Venlafaxine in social phobia:a study in selective serotonin reuptake inhibitor non-responders. Int Clin Psychopharmacol 1999 Jul; 14(4): 239–45
Koran L, Quirk T, Lorberbaum J. Mirtazepine treatment ofobsessive-compulsive disorder [abstract P.3.022]. Eur Neuropsychopharmacol1999; 9 Suppl. 5: S305–S306
Longhurst JG, Carpenter LL, Epperson CN, et al. Effects ofcatecholamine depletion with AMPT (alpha-methyl-paratyrosine)in obsessive-compulsive disorder. Biol Psychiatry 1999 Aug 15; 46(4): 573–6
Braestrup C, Squires RF. Brain specific benzodiazepine receptors. Br J Psychiatry 1978 Sep; 133: 249–60
Mehta AK, Ticku MK. An update on GABAA receptors. Brain Res Brain Res Rev 1999 Apr; 29(2–3): 196–217
Rudolph U, Crestani F, Benke D, et al. Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes. Nature 1999 Oct 21; 401: 796–800
Pincock C, Jensen NO, Oliver S, et al. Cognitive effects of multiple doses of ME3127, a novel anxiolytic, in volunteers[abstract P71]. J Psychopharmacol 1999; 13(3 Suppl. A): A27
Jones S, Jensen NO, Oliver S, et al. Cognitive effects of singledoses of ME3127, a novel anxiolytic, in volunteers [abstractP70]. J Psychopharmacol 1999; 13(3 Suppl. A): A27
Linden M, Hadler D, Hofmann S. Randomised, double-blind, placebo-controlled trial of the efficacy and tolerability of anew isoindoline derivative (DN-2327) in generalized anxiety. Hum Psychopharmacol Clin Exper 1997 Sep; 12: 445–52
Evans SM, Fukuda N, Levin FR, et al. Behavioral and subjectiveeffects of DN-2327 (pazinaclone) and alprazolam in normalvolunteers. Behav Pharmacol 1995 Mar; 6: 176–86
Suzuki M, Uchiumi M, Murasaki M. Acomparative study of thepsychological effects of DN-2327, a partial benzodiazepineagonist, and alprazolam. Psychopharmacology 1995 Oct; 121(4): 442–50
Interneuron Pharmaceuticals Inc. Interneuron’s pagoclone significantlyreduces panic attacks in phase 2/3 clinical trial.Media Release. 1998 Aug 17; 2 pages
Interneuron Pharmaceuticals Inc. Interneuron’s announces positivephase 2 data on pagoclone in panic disorders. Media Release. 1997 Nov 20; 2 pages
Tang AH, Franklin SR, Carter DB, et al. Anxiolytic-like effects of PNU-101017, a partial agonist at the benzodiazepine receptor.Psychopharmacology 1997 Jun; 131: 255–63
Mumford GK, Rush CR, Griffiths RR. Abecarnil and alprazolam in humans: behavioral, subjective and reinforcing effects. J Pharmacol Exper Ther 1995 Feb; 272: 570–80
Aufdembrinke B. Abecarnil, a new beta-carboline, in the treatment of anxiety disorders. Br J Psychiatry 1998 Jul; 173 Suppl. 34: 63
Argyropoulos S, Nutt D. Peptide receptors as targets for anxiolyticdrugs. In: Briley M, Nutt D, editors. Milestones in drug therapy: anxiolytics. Basel: Birkhauser Verlag, 2000. In press
Kramer MS, Cutler N, Feighner J, et al. Distinct mechanism forantidepressant activity by blockade of central substance P receptors[see comments]. Science 1998 Sep 11; 281(5383):1640–5
Adams JB, Pyke RE, Costa J, et al. A double-blind, placebo-controlledstudy of a CCK-B receptor antagonist, CI-988, inpatients with generalized anxiety disorder. J Clin Psychopharmacol 1995 Dec; 15(6): 428–34
Goddard AW, Woods SW, Money R, et al. Effects of the CCK(B)antagonist CI-988 on responses to mCPP in generalized anxietydisorder. Psychiatry Res 1999 Mar 22; 85(3): 225–40
van Megen HJ, Westenberg HG, den Boer JA, et al. The cholecystokinin-Breceptor antagonist CI-988 failed to affect CCK-4induced symptoms in panic disorder patients. PsychopharmacolBerl 1997 Feb; 129(3): 243–8
Hasenohrl RU, Jentjens O, De Souza-Silva MA, et al. Anxiolytic-likeaction of neurokinin substance P administered systemically or into the nucleus basalis magnocellularis region.Eur J Pharmacol 1998 Aug 7; 354(2–3): 123–33
Nutt D. Substance-P antagonists: a new treatment for depression?Lancet 1998 Nov 21; 352: 1644–5
Griebel G. Is there a future for neuropeptide receptor ligands in the treatment of anxiety disorders? Pharmacol Ther 1999 Apr;82(1): 1–61
de Montigny C. Cholecystokinin tetrapeptide induces panic-like attacks in healthy volunteers: preliminary findings [see comments]. Arch Gen Psychiatry 1989 Jun; 46(6): 511–7
van Megen HJ, Westenberg HG, den Boer JA, et al. The panic-inducing properties of the cholecystokinin tetrapeptide CCK4in patients with panic disorder. Eur Neuropsychopharmacol 1996; 6(3): 187–94
Brawman Mintzer O, Lydiard RB, Bradwejn J, et al. Effects ofthe cholecystokinin agonist pentagastrin in patients with generalizedanxiety disorder. Am J Psychiatry 1997; 154(5): 700–2
De Leeuw AS, den Boer JA, Slaap BR, et al. Pentagastrin haspanic-inducing properties in obsessive compulsive disorder. Psychopharmacol Berl 1996; 126(4): 339–44
van Vliet IM, Westenberg HG, Slaap BR, et al. Anxiogeniceffects of pentagastrin in patients with social phobia and healthycontrols. Biol Psychiatry 1997; 42(1): 76–8
van Megen HJ, Westenberg HG, den Boer JA, et al. Effect ofthe selective serotonin reuptake inhibitor fluvoxamine on CCK-4induced panic attacks. Psychopharmacol Berl 1997; 129(4):357–64
van Megen HJ, Westenberg HG, den Boer JA, et al. Cholecystokininin anxiety. Eur Neuropsychopharmacol 1996; 6(4):263–80
Becker C, Hamon M, Benoliel JJ. Prevention by 5-HT1A receptoragonists of restraint stress- and yohimbine-induced releaseof cholecystokinin in the frontal cortex of the freelymoving rat. Neuropharmacology 1999 Apr; 38(4): 525–32
Gewirtz JC, Davis M. Beyond attention: the role of amygdalaNMDA receptors in fear conditioning [commentary]. BehavBrain Sci 1997 Dec; 20(4): 618
Lensi P, Cassano GB, Correddu G, et al. Obsessive-compulsivedisorder: familial-developmental history, symptomatology, comorbidityand course with special reference to gender-relateddifferences. Br J Psychiatry 1996; 169(1): 101–7
Kunovac JL, Stahl SM. Future directions in anxiolytic pharmacotherapy. Psychiatr Clin North Am 1995 Dec; 18(4): 895–909
Liebsch G, Landgraf R, Engelmann M, et al. Differential behaviouraleffects of chronic infusion of CRH 1 and CRH 2receptor antisense oligonucleotides into the rat brain. J PsychiatrRes 1999 Mar; 33(2): 153–63
Rasmusson AM, Southwick SM, Hauger RL, et al. Plasma neuropeptideY (NPY) increases in humans in response to thealpha 2 antagonist yohimbine. Neuropsychopharmacology 1998; 19(1): 95–8
Grundemar L, Håkanson R. Neuropeptide Y effector systems:perspectives for drug development. Trends Pharmacol Sci 1994May; 15(5): 153–9
Stein MB, Hauger RL, Dhalla KS, et al. Plasma neuropeptideY in anxiety disorders: findings in panic disorder and socialphobia. Psychiatry Res 1996; 59(3): 183–8
Boulenger JP, Jerabek I, Jolicoeur FB, et al. Elevated plasmalevels of neuropeptide Y in patients with panic disorder. AmJ Psychiatry 1996; 53(1): 114–6
Adamec RE, Burton P, Shallow T, et al. Unilateral block ofNMDA receptors in the amygdala prevents predator stress-inducedlasting increases in anxiety-like behavior and unconditionedstartle: effective hemisphere depends on the behavior.Physiol Behav 1999 Jan 1; 65(4–5): 739–51
Cratty MS, Birkle DL. N-methyl-D-aspartate (NMDA)-mediatedcorticotropin-releasing factor (CRF) release in culturedrat amygdala neurons. Peptides 1999; 20(1): 93–100
Adamec RE, Burton P, Shallow T, et al. NMDA receptors mediatelasting increases in anxiety-like behavior produced bythe stress of predator exposure: implications for anxiety associatedwith posttraumatic stress disorder. Physiol Behav1999 Jan 1; 65(4–5): 723–37
Parsons CG, Danysz W, Quack G. Memantine is a clinicallywell tolerated N-methyl-D-aspartate (NMDA) receptor antagonist:a review of preclinical data. Neuropharmacology 1999 Jun; 38(6): 735–67
Gasior M, Carter RB, Witkin JM. Neuroactive steroids: potentialtherapeutic use in neurological and psychiatric disorders.Trends Pharmacol Sci 1999 Mar; 20(3): 107–12
Rupprecht R, Holsboer F. Neuropsychopharmacological propertiesof neuroactive steroids. Steroids 1999 Jan; 64(1–2):83–91
Frye CA, Lacey EH. The neurosteroids DHEA and DHEASmay influence cognitive performance by altering affectivestate. Physiol Behav 1999 Mar; 66(1): 85–92
Pande AC, Davidson JRT, Jefferson JW, et al. Treatment ofsocial phobia with gabapentin: a placebo-controlled study. JClin Psychopharmacol 1999; 19(4): 341–8
Benjamin J, Levine J, Fux M, et al. Inositol treatment for panicdisorder: a double-blind placebo-controlled crossover trial. Am J Psychiatry 1995; 152: 1084–6
Fux M, Levin FR, Aviv A, et al. Inositol treatment of obsessive-compulsivedisorder. Am J Psychiatry 1996; 153: 1219–21
de Paris F, Busnello JV, Vianna MRM, et al. Gabapentin presentsanxiolytic but not amnestic effects in rats [abstract P105].J Psychopharmacol 1999; 13(3 Suppl. A): A36
Kaplan Z, Amir M, Swartz M, et al. Inositol treatment of posttraumaticstress disorder. Anxiety 1996; 2: 51–2
Walkup J, Reeve E, Yaruyura-Tobias J, et al. Fluvoxamine inchildhood OCD: long-term treatment [abstract P.3.025]. EurNeuropsychopharmacol 1999; 9 Suppl. 5: S307
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Hood, S.D., Argyropoulos, S.V. & Nutt, D.J. Agents in Development for Anxiety Disorders. Mol Diag Ther 13, 421–431 (2000). https://doi.org/10.2165/00023210-200013060-00004
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DOI: https://doi.org/10.2165/00023210-200013060-00004