The most widely studied herbal compound is kava, a plant containing kavapyrones, which are thought to exert anxiolytic effects through activity on sodium and calcium channels or most likely from action on GABA-A receptors like benzodiazepines A Cochrane meta-analysis of RCTs of kava in anxiety disorders, published in , reported reductions in anxiety scores and separation from placebo A more recent analysis was more conservative and noted that kava could be recommended for short-term use in anxiety but should not replace longer-term medications , while another review concluded that, given insufficient evidence, kava could not be recommended for GAD All the above reviews also noted the risk of liver toxicity, including potentially severe liver toxicity, with the use of kava.

There are no known active or upcoming studies of kava in anxiety disorders. Several systematic reviews of other herbal compounds for the treatment of anxiety and anxiety disorders have been conducted and reported including RCTs for several agents such as ashwagandha, passionflower, galphimia, echinacea, ginkgo, chamomile, lemon balm, valerian, and lavender , , A recent trial compared Galphimine-B G-B , isolated from Galphimia and found in rats to have anxiolytic effect through inhibition of dopaminergic neurons in the ventral tegmental area , to alprazolam, a benzodiazepine, as a control, in patients with GAD and reported that G-B had comparable efficacy to alprazolam with less sedation Although there have been several positive studies of natural treatments for GAD, in particular for chamomile , the agent with strongest evidence for use is kava.

Currently, there are ongoing clinical trials using lavender thought to treat anxiety by inhibiting voltage-gated calcium channels for dental NCT and pre-operative anxiety NCT and a Phase 2 randomized double-blind trial comparing galphimia to alprazolam for the treatment of anxiety NCT Although saffron Crocus sativus has been studied for depression and anxiety, due to its possible effects of inhibiting serotonin reuptake in synapses , there is only one listed study, a randomized, double-blind RCT in mild to moderate GAD, although its status is unknown NCT Since this group's last review of novel therapies for anxiety disorders in , there has been little headway made in the development or clinical evaluation of new drugs for PD, GAD, and SAD.

There have been no new medications approved by the FDA for any anxiety disorder during that time. Although there have been trials of serotonergic agents like vortioxetine and agomelatine , glutamate modulators such as riluzole and ketamine , neuropeptides, and even cannabinoids, very few have advanced to Phase III trials or have shown real promise for anxiety disorders.

Moreover, the field lacks data contrasting specific drugs or mechanisms of action with efficacy, which would be required to propose rational protocols for the selection of optimally efficacious treatments. The traditional areas of research for anxiety included serotonin, norepinephrine, and GABA, and indeed there are several drugs recently studied and under investigation targeting these neurotransmitters.

This research, however, has been built upon the previous success of SSRIs, SNRIs, and GABAergic agents like benzodiazepines, and, to a lesser extent, pregabalin and gabapentin, neither of which are approved in the United States but are prescribed off-label for anxiety.

The temptation to continue work on these pathways is due to the acknowledgment that these treatments are effective while failing to expand beyond this comfort zone. Indeed, the neurobiology of anxiety has expanded well beyond the research on fear condition, false suffocation alarms, and the neuroendocrine and HPA-axis models of panic and fear.

The early neurocircuitry models of anxiety were based on pre-clinical research and cast a wide net, including PTSD in those models.

It is now better understood how much heterogeneity exists between PTSD and other anxiety disorders and even in the class of anxiety disorders, among PD, SAD, and GAD While neuroimaging studies in the last two decades have led to a refined understanding of brain circuits involved in fear and anxiety, this knowledge has not yet translated in insights leading to novel treatments with the exception, perhaps, of attempts to use transcranial magnetic stimulation to modulate anxiety and fear circuitry This is also because in general pharmacotherapies are less clearly related to the functioning of specific brain circuits.

The pursuit of novel pharmacotherapies for anxiety disorders has been fraught with many complications. The first-line treatments, SSRIs and SNRIs, were originally approved for depressive disorders and then later for anxiety disorders. There have been very few drugs developed de novo for anxiety.

Studies of newer agents have been hampered by flawed study designs such as lack of controls or using placebos instead of comparison to established medications such as SSRIs or benzodiazepines. While this may seem like an insurmountable hurdle, there is hope in that several compounds, including neurosteroids, neuropeptides, and phytochemicals herbal compounds , have shown some potential.

It also would help to study medications specifically for how the disorder manifests clinically, such as how PH94B has been investigated for performance anxiety in SAD by being administered 15 min before the participant is to have a social interaction or give a performance Therein lies a second area of concern.

Although it has been assumed that most patients respond to SSRI or SNRI medications, benzodiazepines, psychological treatments, or some combination, about one-third of these patients have treatment-refractory anxiety.

There is still little known about treatment resistance in anxiety disorders and how to treat it effectively. It also remains unclear how many patients are being treated with effective doses or being given adequate trials or are potentially being misdiagnosed or treated with inappropriate regimens.

Anxiety disorders, in addition to their high prevalence, are a leading cause of disability, which is exacerbated by their high comorbidity with depression Naturalistic studies may be needed to understand how to treat anxiety patients with psychiatric, medical, and substance comorbidities.

Perhaps the clearest limitation of this synopsis is the intentional omission of psychotherapies for anxiety disorders.

Although their efficacy in PD, GAD, and SAD, has been documented, this review aimed to focus on pharmacotherapies. That said, it is impossible to ignore the importance of therapy-assisted medications such as DCS or potentially even psychedelic medications.

Ideally, such medications could reduce the distress related to exposure techniques and enhance the retention of information in anxiety-focused psychotherapy, ultimately increasing its overall efficacy.

Such medications are also important given the lack of access to care and how few patients are in fact being treated first by psychiatrists for medication management and can receive appropriate CBT or exposure therapies for their anxiety disorders.

This is certainly an area that needs greater investigation. Further research on augmented psychotherapies should not, however, preclude the concomitant development of novel pharmacotherapies, especially given evidence for greater efficacy of pharmacologic treatments over psychological therapies for certain anxiety disorders such as GAD Since this review did not uncover a wide range of support for promising pharmacotherapies for anxiety disorders in development, we need to reconsider what treatments currently work best, and what areas to focus on going forward.

While developing serotonergic or GABAergic agents with more favorable side effect profiles compared to SSRIs, SNRIs, and benzodiazepines, gabapentin and pregabalin may have some clinical value, there needs to be further expansion into agents targeting neuropeptide pathways, glutamate, endocannabinoids, and multi-modal medications including phytochemicals and hallucinogens.

These newer compounds may not replace the current treatments but may over time serve as adjuncts or aid in therapy, at least until the field can develop better biomarkers and incorporate brain imaging, pharmacogenomic and other neurobiochemical advances.

In terms of pharmacological development, it is time for anxiety disorders to catch up to depression, PTSD, bipolar disorder, and schizophrenia. AG, JM, RT, RF, and DI contributed to conception and design and wrote the original draft of the manuscript.

AG, JM, RF, RT, KL, FB, and DI contributed to manuscript revisions, review and analysis of the literature, and creation of the tables. All authors reviewed and approved the final draft of the manuscript and made substantial contributions to this study. JM is named on a patent pending for neuropeptide Y as a treatment for mood and anxiety disorders and on a patent pending for the use of ezogabine and other KCNQ channel openers to treat depression and related conditions.

The Icahn School of Medicine employer of JM is named on a patent and has entered into a licensing agreement and will receive payments related to the use of ketamine or esketamine for the treatment of depression.

The Icahn School of Medicine is also named on a patent related to the use of ketamine for the treatment of PTSD. JM is not named on these patents and will not receive any payments. In the last 5 years, DI has received consulting honoraria from Alkermes, Axsome, Centers for Psychiatric Excellence, Jazz, Lundbeck, Otsuka, Precision Neuroscience, Sage, Sunovion; he has received research support through his academic institution from Alkermes, Astra Zeneca, Brainsway, Litecure, Neosync, Otsuka, Roche, Shire.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of month DSM-IV disorders in the National Comorbidity Survey Replication.

Arch Gen Psychiatry. doi: CrossRef Full Text Google Scholar. Depression and Other Common Mental Disorders: Global Health Estimates. Geneva: World Health Organization Ahola K, Virtanen M, Honkonen T, Isometsä E, Aromaa A, Lönnqvist J.

Common mental disorders and subsequent work disability: a population-based health study. J Affect Disord. PubMed Abstract CrossRef Full Text Google Scholar. Smit F, Cuijpers P, Oostenbrink J, Batelaan N, de Graaf R, Beekman A.

Costs of nine common mental disorders: implications for curative and preventive psychiatry. J Ment Health Policy Econ. PubMed Abstract Google Scholar. Alonso J, Angermeyer MC, Bernert S, Bruffaerts R, Brugha TS, Bryson H, et al.

Disability and quality of life impact of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders ESEMeD project.

Acta Psychiatr Scand Suppl. CrossRef Full Text. Bystritsky A. Treatment-resistant anxiety disorders. Mol Psychiatry.

Rodriguez BF, Weisberg RB, Pagano ME, Bruce SE, Spencer MA, Culpepper L, et al. Characteristics and predictors of full and partial recovery from generalized anxiety disorder in primary care patients.

J Nerv Ment Dis. Bruce SE, Yonkers KA, Otto MW, Eisen JL, Weisberg RB, Pagano M, et al. Influence of psychiatric comorbidity on recovery and recurrence in generalized anxiety disorder, social phobia, and panic disorder: a year prospective study.

Am J Psychiatry. Roy-Byrne P. Treatment-refractory anxiety; definition, risk factors, and treatment challenges. Dialogues Clin Neurosci. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders.

Washington, DC Google Scholar. Anttila V, Bulik-Sullivan B, Finucane HK, Walters RK, Bras J, Duncan L, et al. Analysis of shared heritability in common disorders of the brain.

Sartori SB, Singewald N. Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders. Pharmacol Ther. Bandelow B, Reitt M, Röver C, Michaelis S, Görlich Y, Wedekind D.

Efficacy of treatments for anxiety disorders: a meta-analysis. Int Clin Psychopharmacol. Practice Guideline for the Treatment of Patients with Panic Disorder. National Institute for Health and Care Excellence NICE. Generalised Anxiety Disorder and Panic Disordr in Adults: Management.

Social Anxiety Disorder: Recognition, Assessment and Treatment. He H, Xiang Y, Gao F, Bai L, Gao F, Fan Y, et al. Comparative efficacy and acceptability of first-line drugs for the acute treatment of generalized anxiety disorder in adults: a network meta-analysis.

J Psychiatr Res. Dragioti E, Solmi M, Favaro A, Fusar-Poli P, Dazzan P, Thompson T, et al. Association of antidepressant use with adverse health outcomes: a systematic umbrella review.

JAMA Psychiatry. Sinclair LI, Christmas DM, Hood SD, Potokar JP, Robertson A, Isaac A, et al. Br J Psychiatry. Bakker A, Van Balkom A, Spinhoven P.

SSRIs vs. TCAs in the treatment of panic disorder: a meta-analysis. Acta Psychiatr Scand. Curtiss J, Andrews L, Davis M, Smits J, Hofmann SG. A meta-analysis of pharmacotherapy for social anxiety disorder: an examination of efficacy, moderators, and mediators.

Expert Opin Pharmacother. Chessick CA, Allen MH, Thase M, Batista Miralha da Cunha AB, Kapczinski FF, de Lima MS, et al. Azapirones for generalized anxiety disorder.

Cochrane Database Syst Rev. Imai H, Tajika A, Chen P, Pompoli A, Guaiana G, Castellazzi M, et al. Azapirones versus placebo for panic disorder in adults. Rissardo JP, Caprara ALF. Buspirone-associated movement disorder: a literature review.

Prague Med Rep. Landén M, Eriksson E, Agren H, Fahlén T. Effect of buspirone on sexual dysfunction in depressed patients treated with selective serotonin reuptake inhibitors.

J Clin Psychopharmacol. Moll JL, Brown CS. The use of monoamine pharmacological agents in the treatment of sexual dysfunction: evidence in the literature. J Sexual Med. Croom KF, Perry CM, Plosker GL. Mirtazapine: a review of its use in major depression and other psychiatric disorders. CNS Drugs.

Ribeiro L, Busnello JV, Kauer-Sant'Anna M, Madruga M, Quevedo J, Busnello EA, et al. Mirtazapine versus fluoxetine in the treatment of panic disorder. Braz J Med Biol Res. Muehlbacher M, Nickel MK, Nickel C, Kettler C, Lahmann C, Pedrosa Gil F, et al. Mirtazapine treatment of social phobia in women: a randomized, double-blind, placebo-controlled study.

Schutters SI, Van Megen HJ, Van Veen JF, Denys DA, Westenberg HG. Mirtazapine in generalized social anxiety disorder: a randomized, double-blind, placebo-controlled study. Trivedi MH, Rush AJ, Carmody TJ, Donahue RM, Bolden-Watson C, Houser TL, et al.

Do bupropion SR and sertraline differ in their effects on anxiety in depressed patients? J Clin Psychiatry. Papakostas GI, Trivedi MH, Alpert JE, Seifert CA, Krishen A, Goodale EP, et al. Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of anxiety symptoms in major depressive disorder: a meta-analysis of individual patient data from 10 double-blind, randomized clinical trials.

Papakostas GI, Stahl SM, Krishen A, Seifert CA, Tucker VL, Goodale EP, et al. Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of major depressive disorder with high levels of anxiety anxious depression : a pooled analysis of 10 studies.

Bystritsky A, Kerwin L, Feusner JD, Vapnik T. A pilot controlled trial of bupropion XL versus escitalopram in generalized anxiety disorder. Psychopharmacol Bull. Sheehan DV, Davidson J, Manschreck T, Van Wyck Fleet J. Lack of efficacy of a new antidepressant bupropion in the treatment of panic disorder with phobias.

Simon NM, Emmanuel N, Ballenger J, Worthington JJ, Kinrys G, Korbly NB, et al. Bupropion sustained release for panic disorder. Papp LA, Coplan JD, Martinez JM, de Jesus M, Gorman JM. Efficacy of open-label nefazodone treatment in patients with panic disorder. Bystritsky A, Rosen R, Suri R, Vapnik T.

Pilot open-label study of nefazodone in panic disorder. Depress Anxiety. DeMartinis NA, Schweizer E, Rickels K. An open-label trial of nefazodone in high comorbidity panic disorder.

Hedges DW, Reimherr FW, Strong RE, Halls CH, Rust C. An open trial of nefazodone in adult patients with generalized anxiety disorder. Van Ameringen M, Mancini C, Oakman J, Walker J, Kjernisted K, Chokka P, et al. Nefazodone in the treatment of generalized social phobia: a randomized, placebo-controlled trial.

Agarwal SD, Landon BE. Patterns in outpatient benzodiazepine prescribing in the United States. JAMA Netw Open.

Torres-Bondia F, de Batlle J, Galván L, Buti M, Barbé F, Piñol-Ripoll G. Trends in the consumption rates of benzodiazepines and benzodiazepine-related drugs in the health region of Lleida from to BMC Public Health.

Balon R, Starcevic V. Role of benzodiazepines in anxiety disorders. Adv Exp Med Biol. Moore N, Pariente A, Bégaud B.

Why are benzodiazepines not yet controlled substances? Gomez AF, Barthel AL, Hofmann SG. Comparing the efficacy of benzodiazepines and serotonergic anti-depressants for adults with generalized anxiety disorder: a meta-analytic review.

Offidani E, Guidi J, Tomba E, Fava GA. Efficacy and tolerability of benzodiazepines versus antidepressants in anxiety disorders: a systematic review and meta-analysis. Psychother Psychosom.

Shinfuku M, Kishimoto T, Uchida H, Suzuki T, Mimura M, Kikuchi T. Effectiveness and safety of long-term benzodiazepine use in anxiety disorders: a systematic review and meta-analysis. Osler M, Jørgensen MB. Associations of benzodiazepines, Z-drugs, and other anxiolytics with subsequent dementia in patients with affective disorders: a nationwide cohort and nested case-control study.

Lim B, Sproule BA, Zahra Z, Sunderji N, Kennedy SH, Rizvi SJ. Understanding the effects of chronic benzodiazepine use in depression: a focus on neuropharmacology. Mula M, Pini S, Cassano GB. The role of anticonvulsant drugs in anxiety disorders: a critical review of the evidence.

Generoso MB, Trevizol AP, Kasper S, Cho HJ, Cordeiro Q, Shiozawa P. Pregabalin for generalized anxiety disorder: an updated systematic review and meta-analysis. Kawalec P, Cierniak A, Pilc A, Nowak G. Pregabalin for the treatment of social anxiety disorder. Expert Opin Investig Drugs. Greist JH, Liu-Dumaw M, Schweizer E, Feltner D.

Efficacy of pregabalin in preventing relapse in patients with generalized social anxiety disorder: results of a double-blind, placebo-controlled week study. Pande AC, Feltner DE, Jefferson JW, Davidson JR, Pollack M, Stein MB, et al.

Efficacy of the novel anxiolytic pregabalin in social anxiety disorder: a placebo-controlled, multicenter study. Feltner DE, Liu-Dumaw M, Schweizer E, Bielski R. Efficacy of pregabalin in generalized social anxiety disorder: results of a double-blind, placebo-controlled, fixed-dose study.

Evoy KE, Covvey JR, Peckham AM, Ochs L, Hultgren KE. Reports of gabapentin and pregabalin abuse, misuse, dependence, or overdose: an analysis of the Food And Drug Administration Adverse Events Reporting System FAERS. Res Social Adm Pharm. Schifano F, Chiappini S.

Pregabalin: a range of misuse-related unanswered questions. CNS Neurosci Ther. Nahar LK, Murphy KG, Paterson S. Misuse and mortality related to gabapentin and pregabalin are being under-estimated: a two-year post-mortem population study.

J Anal Toxicol. Ahmed S, Stanciu CN, Kotapati PV, Ahmed R, Bhivandkar S, Khan AM, et al. Effectiveness of gabapentin in reducing cravings and withdrawal in alcohol use disorder: a meta-analytic review. Prim Care Companion CNS Disord.

Ahmed S, Bachu R, Kotapati P, Adnan M, Ahmed R, Farooq U, et al. Use of gabapentin in the treatment of substance use and psychiatric disorders: a systematic review. Front Psychiatry. Pande AC, Pollack MH, Crockatt J, Greiner M, Chouinard G, Lydiard RB, et al. Placebo-controlled study of gabapentin treatment of panic disorder.

de-Paris F, Sant'Anna MK, Vianna MR, Barichello T, Busnello JV, Kapczinski F, et al. Effects of gabapentin on anxiety induced by simulated public speaking.

J Psychopharmacol. PubMed Abstract CrossRef Full Text. Smith RV, Havens JR, Walsh SL. Gabapentin misuse, abuse and diversion: a systematic review. Schmitt U, Lüddens H, Hiemke C.

Anxiolytic-like effects of acute and chronic GABA transporter inhibition in rats. J Neural Transm. Pollack MH, Tiller J, Xie F, Trivedi MH. Tiagabine in adult patients with generalized anxiety disorder: results from 3 randomized, double-blind, placebo-controlled, parallel-group studies.

Zwanzger P, Eser D, Nothdurfter C, Baghai TC, Möller HJ, Padberg F, et al. Effects of the GABA-reuptake inhibitor tiagabine on panic and anxiety in patients with panic disorder. Urbano MR, Spiegel DR, Laguerta N, Shrader CJ, Rowe DF, Hategan LF.

Gabapentin and tiagabine for social anxiety: a randomized, double-blind, crossover study of 8 adults. Prim Care Companion J Clin Psychiatry.

Mirza NR, Bright JL, Stanhope KJ, Wyatt A, Harrington NR. Lamotrigine has an anxiolytic-like profile in the rat conditioned emotional response test of anxiety: a potential role for sodium channels? Masdrakis VG, Papadimitriou GN, Oulis P.

Lamotrigine administration in panic disorder with agoraphobia. Clin Neuropharmacol. Van Ameringen M, Mancini C, Pipe B, Bennett M. Antiepileptic drugs in the treatment of anxiety disorders: role in therapy. Aliyev NA, Aliyev ZN.

Valproate depakine-chrono in the acute treatment of outpatients with generalized anxiety disorder without psychiatric comorbidity: randomized, double-blind placebo-controlled study.

Eur Psychiatry. Kinrys G, Pollack MH, Simon NM, Worthington JJ, Nardi AE, Versiani M. Valproic acid for the treatment of social anxiety disorder. Stein MB, Ravindran LN, Simon NM, Liebowitz MR, Khan A, Brawman-Mintzer O, et al.

Levetiracetam in generalized social anxiety disorder: a double-blind, randomized controlled trial. Zhang W, Connor KM, Davidson JR. Levetiracetam in social phobia: a placebo controlled pilot study. Guaiana G, Barbui C, Cipriani A. Hydroxyzine for generalised anxiety disorder.

Steenen SA, van Wijk AJ, van der Heijden GJ, van Westrhenen R, de Lange J, de Jongh A. Propranolol for the treatment of anxiety disorders: systematic review and meta-analysis. Davidson JR. Pharmacotherapy of social anxiety disorder: what does the evidence tell us?

Charney DS, Heninger GR. Abnormal regulation of noradrenergic function in panic disorders. Effects of clonidine in healthy subjects and patients with agoraphobia and panic disorder.

Strawn JR, Compton SN, Robertson B, Albano AM, Hamdani M, Rynn MA. Extended release guanfacine in pediatric anxiety disorders: a pilot, randomized, placebo-controlled trial.

J Child Adolesc Psychopharmacol. Uhde TW, Stein MB, Vittone BJ, Siever LJ, Boulenger JP, Klein E, et al. Behavioral and physiologic effects of short-term and long-term administration of clonidine in panic disorder.

Hoehn-Saric R, Merchant AF, Keyser ML, Smith VK. Effects of clonidine on anxiety disorders. Bergendahl H, Lönnqvist PA, Eksborg S. Clonidine in paediatric anaesthesia: review of the literature and comparison with benzodiazepines for premedication.

Acta Anaesthesiol Scand. Maher AR, Maglione M, Bagley S, Suttorp M, Hu JH, Ewing B, et al. Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis.

Depping AM, Komossa K, Kissling W, Leucht S. Second-generation antipsychotics for anxiety disorders. LaLonde CD, Van Lieshout RJ. Treating generalized anxiety disorder with second generation antipsychotics: a systematic review and meta-analysis.

Katzman MA, Bleau P, Blier P, Chokka P, Kjernisted K, Van Ameringen M, et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders.

BMC Psychiatry. Perna G, Alessandra A, Raffaele B, Elisa M, Giuseppina D, Paolo C, et al. Is there room for second-generation antipsychotics in the pharmacotherapy of panic disorder? A systematic review based on PRISMA guidelines. Int J Mol Sci.

Griebel G, Holmes A. Nat Rev Drug Discov. Zareifopoulos N, Dylja I. Efficacy and tolerability of vilazodone for the acute treatment of generalized anxiety disorder: a meta-analysis. Asian J Psychiatr. Slee A, Nazareth I, Bondaronek P, Liu Y, Cheng Z, Freemantle N.

Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis. Schneier FR, Moskow DM, Choo TH, Galfalvy H, Campeas R, Sanchez-Lacay A.

A randomized controlled pilot trial of vilazodone for adult separation anxiety disorder. Careri JM, Draine AE, Hanover R, Liebowitz MR.

A week doubleblind, placebo-controlled, flexible-dose trial of vilazodone in generalized social anxiety disorder. Clayton AH, Durgam S, Tang X, Chen C, Ruth A, Gommoll C.

Characterizing sexual function in patients with generalized anxiety disorder: a pooled analysis of three vilazodone studies. Neuropsychiatr Dis Treat.

Yee A, Ng CG, Seng LH. Vortioxetine treatment for anxiety disorder: a meta-analysis study. Curr Drug Targets. Bidzan L, Mahableshwarkar AR, Jacobsen P, Yan M, Sheehan DV. Vortioxetine Lu AA in generalized anxiety disorder: results of an 8-week, multinational, randomized, double-blind, placebo-controlled clinical trial.

Eur Neuropsychopharmacol. Baldwin DS, Loft H, Florea I. Lu AA, a multimodal psychotropic agent, in the prevention of relapse in adult patients with generalized anxiety disorder. Qin B, Huang G, Yang Q, Zhao M, Chen H, Gao W, et al.

Vortioxetine treatment for generalised anxiety disorder: a meta-analysis of anxiety, quality of life and safety outcomes. BMJ Open. Shah A, Northcutt J. An open-label, flexible dose adaptive study evaluating the efficacy of vortioxetine in subjects with panic disorder.

Ann Genrl Psychiatry. Celada P, Bortolozzi A, Artigas F. Serotonin 5-HT 1A receptors as targets for agents to treat psychiatric disorders: rationale and current status of research.

Pecknold JC, Luthe L, Scott-Fleury MH, Jenkins S. Gepirone and the treatment of panic disorder: an open study. Kaur Gill A, Bansal Y, Bhandari R, Kaur S, Kaur J, Singh R, et al.

Gepirone hydrochloride: a novel antidepressant with 5-HT1A agonistic properties. Drugs Today. Fabre-Kramer Pharmaceuticals I. Nishitsuji K, To H, Murakami Y, Kodama K, Kobayashi D, Yamada T, et al.

Tandospirone in the treatment of generalised anxiety disorder and mixed anxiety-depression : results of a comparatively high dosage trial. Clin Drug Investig. Lin J, Su Y, Wang C, Yang F, Xu Y, Yuan Y, et al. Effects of tandospirone augmentation in major depressive disorder patients with high anxiety: a multicenter, randomized, parallel-controlled, open-label study.

Rickels K, Mathew S, Banov MD, Zimbroff DL, Oshana S, Parsons EC, et al. Effects of PRX, a novel, selective serotonin 1A receptor agonist on measures of anxiety and depression in generalized anxiety disorder: results of a double-blind, placebo-controlled trial.

Wesołowska A, Nikiforuk A, Stachowicz K. Anxiolytic-like and antidepressant-like effects produced by the selective 5-HT6 receptor antagonist SB after intrahippocampal administration to rats.

Behav Pharmacol. Ivachtchenko AV, Lavrovsky Y, Okun I. AVN a multi-target drug candidate for the treatment of CNS disorders. J Alzheimers Dis. Freeman AM 3rd, Westphal JR, Norris GT, Roggero BA, Webb PB, Freeman KL, et al. Efficacy of ondansetron in the treatment of generalized anxiety disorder.

Schneier FR, Garfinkel R, Kennedy B, Campeas R, Fallon B, Marshall R, et al. Ondansetron in the treatment of panic disorder. MacIsaac SE, Carvalho AF, Cha DS, Mansur RB, McIntyre RS.

The mechanism, efficacy, and tolerability profile of agomelatine. Stein DJ, Khoo JP, Ahokas A, Jarema M, Van Ameringen M, Vavrusova L, et al. Stein DJ, Ahokas AA, de Bodinat C. Efficacy of agomelatine in generalized anxiety disorder: a randomized, double-blind, placebo-controlled study.

Stein DJ, Ahokas A, Márquez MS, Höschl C, Oh KS, Jarema M, et al. Agomelatine in generalized anxiety disorder: an active comparator and placebo-controlled study. Stein DJ, Ahokas A, Jarema M, Avedisova AS, Vavrusova L, Chaban O, et al. Stein DJ, Ahokas A, Albarran C, Olivier V, Allgulander C.

Agomelatine prevents relapse in generalized anxiety disorder: a 6-month randomized, double-blind, placebo-controlled discontinuation study. Weston NM, Gibbs D, Bird CIV, Daniel A, Jelen LA, Knight G, et al.

Historic psychedelic drug trials and the treatment of anxiety disorders. Fuentes JJ, Fonseca F, Elices M, Farré M, Torrens M. Therapeutic use of LSD in psychiatry: a systematic review of randomized-controlled clinical trials. Krystal JH, Mathew SJ, D'Souza DC, Garakani A, Gunduz-Bruce H, Charney DS.

Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists. Bergink V, Westenberg HG. Metabotropic glutamate II receptor agonists in panic disorder: a double blind clinical trial with LY Dunayevich E, Erickson J, Levine L, Landbloom R, Schoepp DD, Tollefson GD.

Kent JM, Daly E, Kezic I, Lane R, Lim P, De Smedt H, et al. Prog Neuropsychopharmacol Biol Psychiatry. Wan LB, Levitch CF, Perez AM, Brallier JW, Iosifescu DV, Chang LC, et al.

Ketamine safety and tolerability in clinical trials for treatment-resistant depression. Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, et al.

Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial.

Fava M, Freeman MP, Flynn M, Judge H, Hoeppner BB, Cusin C, et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression TRD.

Singh JB, Fedgchin M, Daly EJ, De Boer P, Cooper K, Lim P, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Phillips JL, Norris S, Talbot J, Birmingham M, Hatchard T, Ortiz A, et al.

Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: a randomized controlled trial. Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, aan het Rot M, et al.

Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS, Schatzberg AF, et al.

A consensus statement on the use of ketamine in the treatment of mood disorders. Papakostas GI, Salloum NC, Hock RS, Jha MK, Murrough JW, Mathew SJ, et al.

Efficacy of esketamine augmentation in major depressive disorder: a meta-analysis. Engin E, Treit D, Dickson CT. Anxiolytic- and antidepressant-like properties of ketamine in behavioral and neurophysiological animal models.

Irwin SA, Iglewicz A, Nelesen RA, Lo JY, Carr CH, Romero SD, et al. Daily oral ketamine for the treatment of depression and anxiety in patients receiving hospice care: a day open-label proof-of-concept trial.

J Palliat Med. Glue P, Medlicott NJ, Harland S, Neehoff S, Anderson-Fahey B, Le Nedelec M, et al. Ketamine's dose-related effects on anxiety symptoms in patients with treatment refractory anxiety disorders.

Glue P, Neehoff SM, Medlicott NJ, Gray A, Kibby G, McNaughton N. Safety and efficacy of maintenance ketamine treatment in patients with treatment-refractory generalised anxiety and social anxiety disorders. Taylor JH, Landeros-Weisenberger A, Coughlin C, Mulqueen J, Johnson JA, Gabriel D, et al.

Ketamine for social anxiety disorder: a randomized, placebo-controlled crossover trial. Zarate CA Jr, Payne JL, Quiroz J, Sporn J, Denicoff KK, et al. An open-label trial of riluzole in patients with treatment-resistant major depression. Sanacora G, Kendell SF, Levin Y, Simen AA, Fenton LR, Coric V, et al.

Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Mathew SJ, Murrough JW, aan het Rot M, Collins KA, Reich DL, Charney DS.

Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial. Int J Neuropsychopharmacol. Sugiyama A, Saitoh A, Iwai T, Takahashi K, Yamada M, Sasaki-Hamada S, et al. Riluzole produces distinct anxiolytic-like effects in rats without the adverse effects associated with benzodiazepines.

Stutzmann JM, Cintrat P, Laduron PM, Blanchard JC. Riluzole antagonizes the anxiogenic properties of the beta-carboline FG in rats. Mathew SJ, Amiel JM, Coplan JD, Fitterling HA, Sackeim HA, Gorman JM.

Open-label trial of riluzole in generalized anxiety disorder. Mathew SJ, Price RB, Mao X, Smith EL, Coplan JD, Charney DS, et al. Hippocampal N-acetylaspartate concentration and response to riluzole in generalized anxiety disorder.

Abdallah CG, Coplan JD, Jackowski A, Sato JR, Mao X, Shungu DC, et al. A pilot study of hippocampal volume and N-acetylaspartate NAA as response biomarkers in riluzole-treated patients with GAD.

Myers KM, Carlezon WA Jr, Davis M. Glutamate receptors in extinction and extinction-based therapies for psychiatric illness.

Nations KR, Dogterom P, Bursi R, Schipper J, Greenwald S, Zraket D, et al. Examination of Org , an AMPA receptor positive allosteric modulator, in patients diagnosed with major depressive disorder: an exploratory, randomized, double-blind, placebo-controlled trial.

Davis M, Ressler K, Rothbaum BO, Richardson R. Effects of D-cycloserine on extinction: translation from preclinical to clinical work. Heresco-Levy U, Kremer I, Javitt DC, Goichman R, Reshef A, Blanaru M, et al.

Pilot-controlled trial of D-cycloserine for the treatment of post-traumatic stress disorder. Bailey J, Papadopoulos A, Lingford-Hughes A, Nutt D. D-Cycloserine and performance under different states of anxiety in healthy volunteers.

Onur OA, Schlaepfer TE, Kukolja J, Bauer A, Jeung H, Patin A, et al. The N-methyl-D-aspartate receptor co-agonist D-cycloserine facilitates declarative learning and hippocampal activity in humans. Nave AM, Tolin DF, Stevens MC. Exposure therapy, D-cycloserine, and functional magnetic resonance imaging in patients with snake phobia: a randomized pilot study.

Ori R, Amos T, Bergman H, Soares-Weiser K, Ipser JC, Stein DJ. Augmentation of cognitive and behavioural therapies CBT with d-cycloserine for anxiety and related disorders.

Mataix-Cols D, Fernández de la Cruz L, Monzani B, Rosenfield D, Andersson E, Pérez-Vigil A, et al. D-cycloserine augmentation of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders: a systematic review and meta-analysis of individual participant data.

Reinecke A, Nickless A, Browning M, Harmer CJ. Neurocognitive processes in d-cycloserine augmented single-session exposure therapy for anxiety: a randomized placebo-controlled trial. Behav Res Therapy. Hofmeijer-Sevink MK, Duits P, Rijkeboer MM, Hoogendoorn AW, van Megen HJ, Vulink NC, et al.

No effects of D-cycloserine enhancement in exposure with response prevention therapy in panic disorder with agoraphobia: a double-blind, randomized controlled trial. Roque AD, Rosenfield D, Smits JAJ, Simon N, Otto MW, Marques L, et al. Does d-cycloserine facilitate the effects of homework compliance on social anxiety symptom reduction?

J Anxiety Disord. Hofmann SG, Meuret AE, Smits JA, Simon NM, Pollack MH, Eisenmenger K, et al. Augmentation of exposure therapy with D-cycloserine for social anxiety disorder. Guastella AJ, Richardson R, Lovibond PF, Rapee RM, Gaston JE, Mitchell P, et al.

A randomized controlled trial of D-cycloserine enhancement of exposure therapy for social anxiety disorder. Smits JAJ, Pollack MH, Rosenfield D, Otto MW, Dowd S, Carpenter J, et al.

Dose timing of D-cycloserine to augment exposure therapy for social anxiety disorder: a randomized clinical trial. Hofmann SG, Smits JA, Rosenfield D, Simon N, Otto MW, Meuret AE, et al.

D-Cycloserine as an augmentation strategy with cognitive-behavioral therapy for social anxiety disorder. Hofmann SG, Papini S, Carpenter JK, Otto MW, Rosenfield D, Dutcher CD, et al.

Effect of d-cycloserine on fear extinction training in adults with social anxiety disorder. PLoS ONE. Tart CD, Handelsman PR, Deboer LB, Rosenfield D, Pollack MH, Hofmann SG, et al. Augmentation of exposure therapy with post-session administration of D-cycloserine. Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, et al.

Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Kappelmann N, Suesse M, Steudte-Schmiedgen S, Kaldewaij R, Browning M, Michael T, et al.

D-cycloserine as adjunct to brief computerised CBT for spider fear: effects on fear, behaviour, and cognitive biases. J Behav Ther Exp Psychiatry. Gutner CA, Weinberger J, Hofmann SG. The effect of D-cycloserine on subliminal cue exposure in spider fearful individuals. Cogn Behav Ther.

Guastella AJ, Dadds MR, Lovibond PF, Mitchell P, Richardson R. A randomized controlled trial of the effect of D-cycloserine on exposure therapy for spider fear. Sani G, Serra G, Kotzalidis GD, Romano S, Tamorri SM, Manfredi G, et al.

The role of memantine in the treatment of psychiatric disorders other than the dementias: a review of current preclinical and clinical evidence.

Feusner JD, Kerwin L, Saxena S, Bystritsky A. Differential efficacy of memantine for obsessive-compulsive disorder vs. generalized anxiety disorder: an open-label trial. Jevtović-Todorović V, Todorović SM, Mennerick S, Powell S, Dikranian K, Benshoff N, et al. Nitrous oxide laughing gas is an NMDA antagonist, neuroprotectant and neurotoxin.

Nat Med. Garakani A, Jaffe RJ, Savla D, Welch AK, Protin CA, Bryson EO, et al. Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: a systematic review of the case literature. Am J Addict. Gillman MA. Mini-review: a brief history of nitrous oxide N 2 O use in neuropsychiatry.

Curr Drug Res Rev. Nagele P, Duma A, Kopec M, Gebara MA, Parsoei A, Walker M, et al. Nitrous oxide for treatment-resistant major depression: a proof-of-concept trial. Gordon D, Heimberg RG, Tellez M, Ismail AI. A critical review of approaches to the treatment of dental anxiety in adults.

Atack JR. Preclinical and clinical pharmacology of the GABAA receptor alpha5 subtype-selective inverse agonist alpha5IA. Simen A, Whitlock M, Qiu R, Miceli J, Zumpano L, Du Metz M, et al.

An 8-week, randomized, phase 2, double-blind, sequential parallel-group comparison study of two dose levels of the GABAA positive allosteric modulator PF compared with placebo as an adjunctive treatment in outpatients with inadequate response to standard of care for generalized anxiety disorder.

Wise T, Patrick F, Meyer N, Mazibuko N, Oates AE, van der Bijl AHM, et al. Cholinergic modulation of disorder-relevant neural circuits in generalized anxiety disorder.

Prevot TD, Li G, Vidojevic A, Misquitta KA, Fee C, Santrac A, et al. Novel benzodiazepine-like ligands with various anxiolytic, antidepressant, or pro-cognitive profiles. Mol Neuropsychiatry. Hoffmann E, Nomikos GG, Kaul I, Raines S, Wald J, Bullock A, et al. SAGE, a novel GABA A receptor positive allosteric modulator: clinical pharmacology and tolerability in randomized phase i dose-finding studies.

Clin Pharmacokinet. Macdonald K, Feifel D. Helping oxytocin deliver: considerations in the development of oxytocin-based therapeutics for brain disorders. There are several types of medications used to treat anxiety disorders. Within each of these categories, there are subgroups of drugs that work differently and have their own benefits, risks, and possible side effects.

The two classes of antidepressants most commonly used to treat anxiety disorders are selective serotonin reuptake inhibitors SSRIs and serotonin-norepinephrine reuptake inhibitors SNRIs.

Buspirone BuSpar is typically used to treat generalized anxiety disorder. It is often prescribed with an antidepressant. They are really good for the physical symptoms such as heart racing, sweating, and shakiness, but they work less well for the anxious thoughts that might be causing the symptoms.

Additional reporting by Carlene Bauer. Everyday Health follows strict sourcing guidelines to ensure the accuracy of its content, outlined in our editorial policy. We use only trustworthy sources, including peer-reviewed studies, board-certified medical experts, patients with lived experience, and information from top institutions.

Health Conditions A-Z. Best Oils for Skin Complementary Approaches Emotional Wellness Fitness and Exercise Healthy Skin Online Therapy Reiki Healing Resilience Sleep Sexual Health Self Care Yoga Poses See All.

Atkins Diet DASH Diet Golo Diet Green Tea Healthy Recipes Intermittent Fasting Intuitive Eating Jackfruit Ketogenic Diet Low-Carb Diet Mediterranean Diet MIND Diet Paleo Diet Plant-Based Diet See All. Consumer's Guides: Understand Your Treatments Albuterol Inhalation Ventolin Amoxicillin Amoxil Azithromycin Zithromax CoQ10 Coenzyme Q Ibuprofen Advil Levothyroxine Synthroid Lexapro Escitalopram Lipitor Atorvastatin Lisinopril Zestril Norvasc Amlodipine Prilosec Omeprazole Vitamin D3 Xanax Alprazolam Zoloft Sertraline Drug Reviews See All.

Health Tools. Body Type Quiz Find a Doctor - EverydayHealth Care Hydration Calculator Menopause Age Calculator Symptom Checker Weight Loss Calculator. See All. DailyOM Courses. About DailyOM Most Popular Courses New Releases Trending Courses See All. Anxiety Disorders. By Lindsey Konkel. Medically Reviewed.

Allison Young, MD of American College of Lifestyle Medicine. Antidepressants Benzodiazepines Other Medications. Psychotherapy, exercise, and medication. Are antidepressants addictive?

No, antidepressants such as SSRIs are not addictive. What are the common side effects of SSRIs and SNRIs? Nausea, nervousness, dizziness, reduced sexual desire, drowsiness, insomnia, weight gain or loss, headache, dry mouth, vomiting, and diarrhea.

Are benzodiazepines addictive? Yes, benzodiazepines can cause addiction, even in a short period of time. What are some other medications prescribed for anxiety? Other medications include buspirone, beta-blockers, and hydroxyzine.

Antidepressants Benzodiazepines Buspirone Hydroxyzine Beta blockers Within each of these categories, there are subgroups of drugs that work differently and have their own benefits, risks, and possible side effects.

Antidepressants are often used as the first line of treatment. They impact a neurotransmitter that has been linked to mood. These medications often take four to six weeks, or longer, to be fully effective. Next up video playing in 10 seconds.

Examples of SSRIs include: [ 3 ]. Examples of SNRIs include: [ 3 ]. Some people respond better to some antidepressants rather than others.

If the patient does not show a robust response, we increase the SRI in one-week increments until sufficient improvement is seen or the maximum recommended or highest tolerated dose is reached.

In individuals who show gradual improvement, we continue to monitor for up to 12 weeks at the maximum tolerated dose. As an example, treatment with sertraline can be initiated at 25 mg per day. See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Dose'.

Common side effects include sexual dysfunction, gastrointestinal abnormalities nausea and diarrhea , insomnia, sedation, weight gain, dizziness, and sweating.

In individuals treated with venlafaxine , increases in blood pressure can be seen. In these cases, blood pressure should be monitored weekly table 2. See "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects" and "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects".

Thus, side effects need to be recognized and managed early in treatment. Individual medications vary in their side effect profile table 1.

Early adverse effects of SRI treatment include agitation and insomnia which can often lead to discontinuation of the medication before it has had time to effectively treat the primary anxiety associated with GAD. Our approach to addressing early SRI-induced insomnia or agitation is as follows:.

Many individuals get relief of side effects at this dose; however, when further titration is needed, we typically titrate by 1 mg every two to three days in divided doses while monitoring for further improvement of side effects. We are particularly cautious and attentive to dosing when using benzodiazepines due to their risk of dependence.

We use the lowest dose that is effective. We continue the benzodiazepine for four to six weeks or until the individual responds to the SRI and then taper the benzodiazepine by 25 percent per week eg, lorazepam 0.

We typically continue the medication for four to six weeks and then taper off if irritability and insomnia are improved. Limited role of alternatives to SRIs as initial treatment — Other medications including benzodiazepines, buspirone , pregabalin , mirtazapine , and TCAs have been studied as initial treatment for GAD [ 16,23 ].

These medications have been shown to improve symptoms of anxiety; however, we generally do not use them as first-line treatment due to prominent side effects, risk of dependence, or limited data supporting their use as initial monotherapy.

In select cases, for example in individuals with severe anxiety that precludes waiting for the SRI to begin to show clinically meaningful effect see 'Administration of SRI' above , we typically begin a different antianxiety medication concurrent with the SRI.

Most often we use either hydroxyzine in individuals with a substance use disorder or a benzodiazepine in individuals without a history of substance use disorder.

Our practice is to continue this medication for four to six weeks or until the SRI begins to show effect. In most cases, however, we reserve use of these medications for patients who have suboptimal response to an adequate trial of medication.

See 'No response to SRI treatment' below. Nonresponse refers to minimal or no change in symptoms with treatment. Symptom reduction that falls between a complete response and nonresponse is considered a partial response. Our subsequent management depends, in part, on response to initial treatment.

An algorithm of the treatment for generalized anxiety disorder GAD can be found here algorithm 1. Adjunctive CBT — For individuals with suboptimal response eg, partial or no response to initial pharmacologic management, we suggest adjunctive cognitive-behavioral therapy CBT.

CBT uses reasoning exercises or real experience to facilitate symptom reduction and improve functioning. See "Generalized anxiety disorder in adults: Cognitive-behavioral therapy and other psychotherapies".

Trials evaluation the pharmacologic augmentation of CBT show mixed results. While some studies suggest that augmentation of pharmacotherapy with CBT can lead to a greater reduction in symptoms of GAD compared with medications alone, others suggest no difference and have methodologic issues limiting their value [ 11,44,45 ].

However, in one trial, adolescents between ages 7 and 17 years old with anxiety disorders including GAD were treated with CBT, sertraline , sertraline plus CBT, or placebo [ 11 ]. The percentages of children who were rated as improved or very much improved on the Clinician Global Impression-Improvement scale were 81 percent for combined treatment, 60 percent for cognitive therapy, 55 percent for sertraline, and 24 percent for placebo.

No response to SRI treatment — For individuals who are unresponsive to the initial serotonergic reuptake inhibitor SRI agent in addition to adjunctive CBT, we suggest tapering off of the first agent and titrating another SRI.

In our clinical experience, an inadequate response to one SRI does not predict failure of a second SRI in GAD. We select the second SRI using the same factors as the first eg, side effect profile, drug-drug interactions, and patient history and preference.

Partial response to SRI treatment — For individuals with a partial response to SRI treatment, in addition to adjunctive CBT, we recommend augmentation of the SRI with buspirone. Subsequent pharmacologic management of GAD is discussed below.

See 'Adjunctive CBT' above and 'Approach for most individuals' below. Approach for most individuals — For most individuals with a partial response to SRI we augment the SRI with buspirone. In individuals who do not respond to buspirone, we use gabapentin as our next choice. With titration at this rate, buspirone is generally well tolerated.

The medication should be given a trial of four to six weeks at the maximally tolerated dose before concluding it is ineffective. A meta-analysis of eight clinical trials in patients with GAD found buspirone to reduce anxiety symptoms compared with placebo [ 46 ], offering similar efficacy to benzodiazepines without the risk of dependence.

After eight weeks, patients receiving buspirone experienced a reduction in anxiety symptoms comparable to lorazepam and greater than individuals receiving placebo. Additionally, buspirone was associated with fewer side effects than lorazepam. Pregabalin is another option; however, due to the greater potential of addiction and dependence to pregabalin, we typically use gabapentin.

Gabapentin and pregabalin have shown efficacy in the treatment of anxiety disorders however limited data are available [ ].

Dose and therapeutic range of gabapentin and pregabalin are on the provided table table 2. Individuals with mood instability — In individuals who have not fully responded to initial treatment and in whom there are clinically significant mood fluctuations eg, hypomania or irritability , we occasionally augment the SRI with agents that have mood stabilizing properties, such as valproate or lamotrigine.

Very limited data support use of these agents in the treatment of anxiety disorders [ 51,52 ]. Choice of medication — In our clinical experience, a substantial proportion of patients with GAD do not improve or have residual symptoms despite multiple trials of medications and augmenting agents [ 17,35 ].

Selection among alternative agents for such patients is influenced by patient characteristics, treatment history, medication profiles, and patient preference table 2. As an example, in an individual with prominent sleep disturbance, we might choose mirtazapine for its effects on sleep induction.

In an individual with depressed mood, we might use vortioxetine or imipramine. Due to the possibility of dependence or abuse of medications or side effects such as tardive dyskinesia TD we generally consider using benzodiazepines and antipsychotics after all other options have been ineffective or exhausted.

The interventions vary widely in supporting evidence and safety. Other antidepressants — Antidepressants other than SRIs have shown efficacy in the treatment of GAD and can be used as alternative therapy in those without response to first-line agents and augmentation.

We typically use these agents as monotherapy ie, switch patients off their ineffective regimen to one of these in order to limit polypharmacy and associated side effects. However, in patients with a partial response to their regimen, we may add one of these agents.

While clinical trials of mirtazapine in GAD are insufficient to determine its efficacy, promising findings were seen in a small, open-label trial of refractory anxiety with insomnia [ 53,54 ].

Sedation and weight gain are two prominent side effects. See "Atypical antidepressants: Pharmacology, administration, and side effects", section on 'Mirtazapine'.

Selective serotonin reuptake inhibitors SSRIs and serotonin-norepinephrine reuptake inhibitors SNRIs are generally preferred over TCAs because the latter have an increased risk of cardiotoxicity in overdose and less acceptable tolerability profiles [ 6 ]. See "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects".

Vortioxetine has shown mixed results compared with placebo in clinical trials for GAD [ 56,57 ]. See "Serotonin modulators: Pharmacology, administration, and side effects", section on 'Vilazodone' and "Serotonin modulators: Pharmacology, administration, and side effects", section on 'Vortioxetine'.

Antipsychotics — Another potential pharmacologic treatment strategy for treatment-resistant GAD is the use of the second-generation antipsychotic SGA medications.

We usually use SGAs, for example, quetiapine or aripiprazole , adjunctively as augmentation of antidepressants. However, they can be used as monotherapy in patients who have had little to no response to prior drug trials. See "Second-generation antipsychotic medications: Pharmacology, administration, and side effects".

Randomized trials support the use of SGAs, particularly quetiapine , as part of an augmentation strategy or as monotherapy in treating anxiety [ 59 ]. However, adverse effects associated with SGAs, including TD, extrapyramidal symptoms, adverse metabolic effects, and sedation have limited their use in GAD.

Additionally, they have been associated with lengthening of the QTc interval, which can lead to syncope, arrhythmia, or sudden cardiac arrest.

Our practice is to use these only after other alternatives have been exhausted. See "Schizophrenia in adults: Maintenance therapy and side effect management", section on 'Side effect management' and "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Acquired long QT syndrome: Definitions, pathophysiology, and causes".

Benzodiazepines — In select individuals with GAD who are refractory to multiple prior medication and augmentation trials, we use benzodiazepines as augmentation or monotherapy.

We avoid benzodiazepines in individuals with a history of substance use, misuse of medications, or depression because of concerns about dependence and worsening mood symptoms. Selecting and starting a benzodiazepine — The unique pharmacologic properties of individual benzodiazepines eg, rapidity of onset, persistence of active drug or metabolite in the body have clinical significance in their selection.

These differences are summarized in a table for the most widely used benzodiazepines, along with clinically important pharmacologic characteristics related to the use and abuse of benzodiazepines table 3 [ 60,61 ]. We tend to preferentially use diazepam or clonazepam as our first choice in the treatment of GAD due to their rapid onset and long half-life ie, less likely to precipitate withdrawal after repetitive use and discontinuation.

See 'Adverse effects and withdrawal considerations' below. Clinical trials and meta-analyses have shown benzodiazepines to be effective in reduction of anxiety and associated symptoms for GAD [ 16, ]. Generally they lead to a reduction of emotional and somatic symptoms within minutes to hours depending on the specific medication.

However, due to the potential for abuse and dependence of benzodiazepines we use them after other options have been ineffective or exhausted table 3 [ 62,66 ].

See 'Unresponsive to multiple agents' above. Benzodiazepines are generally started at a low dose and titrated up based on response. Meta-analyses and other trials have found benzodiazepines to be effective in the treatment of GAD while being better tolerated than antidepressants [ 16,62,67 ].

For example, in a meta-analysis of 15 trials and over individuals, benzodiazepines were found to improve symptoms of anxiety as measured by the Hamilton Rating Scale for anxiety versus placebo mean difference Additionally, in a trial comparing diazepam , venlafaxine , and placebo in patients with GAD, while response rates were similar between groups, discontinuation due to adverse effects were more frequent in individuals taking venlafaxine XR than diazepam [ 68 ].

Adverse effects and withdrawal considerations — Side effects of benzodiazepines include impairment of psychomotor performance, amnesia, dependence, withdrawal symptoms after long-term treatment, and rebound anxiety after short-term treatment [ 69 ].

Withdrawal and cognitive or learning impairment are more likely for persons taking higher doses. The onset of withdrawal in individuals who have used benzodiazepines regularly or daily for prolonged periods is driven by the elimination half-life of the medication.

Benzodiazepines with shorter elimination half-lives eg, alprazolam , lorazepam , and oxazepam are more likely to produce acute withdrawal on abrupt cessation after prolonged use. Benzodiazepines with longer elimination half-lives eg, clorazepate , diazepam , flurazepam , prazepam, and clonazepam usually produce more delayed and somewhat attenuated withdrawal symptoms.

See "Benzodiazepine use disorder", section on 'Withdrawal'. Antihistamines — We use hydroxyzine in individuals who have not responded to multiple prior medications and augmentation trials. We typically use 25 to 50 mg orally up to four times daily as monotherapy or adjunctive treatment. In a meta-analysis of five trials with patients, hydroxyzine appeared efficacious for GAD, though the analysis suggested a high risk of bias [ 43 ].

Hydroxyzine was found to be more sedating than benzodiazepines and buspirone , and thus potentially useful for treating insomnia associated with GAD. In addition to pharmacotherapy or cognitive-behavioral therapy, we suggest aerobic exercise for treatment of generalized anxiety disorder GAD in patients who are medically capable.

In particular, high-intensity exercise appears to be more effective than low-intensity as a complement to first-line therapy for GAD [ 70 ]. Mindfulness-based stress reduction and yoga may also be helpful, as they have also been shown to reduce symptoms of generalized anxiety relative to education control conditions [ 71,72 ].

The outcomes of these activities on anxiety are discussed in detail elsewhere. See "Complementary and alternative treatments for anxiety symptoms and disorders: Physical, cognitive, and spiritual interventions" and "Complementary and alternative treatments for anxiety symptoms and disorders: Herbs and medications".

Pharmacotherapy — If effective, antidepressant treatment for generalized anxiety disorder GAD should be continued for at least 12 months [ 73,74 ]. In a randomized trial, patients with GAD who experienced reduced anxiety during six months of treatment with venlafaxine extended-release XR were assigned to medication continuation treatment or placebo for an additional six months [ 74 ].

Patients continuing venlafaxine XR had a much lower rate of relapse during the second six months than patients receiving placebo 9.

Incidence rates of side effects during the second six months compared with the first six months were lower, did not differ statistically between drug and placebo patients, and included no new side effects.

If the patient experiences a relapse following termination of an effective medication, the length of treatment can be extended. After two relapses when tapering off the medication, ongoing maintenance treatment is suggested.

Cognitive-behavioral therapy — Duration of cognitive-behavioral therapy CBT depends on the severity of symptoms, presence of comorbidity, patient resistance to treatment, therapist competence, and number of components incorporated.

Typically, this ranges from 10 to 15 sessions however individuals are encouraged to continue to use CBT skills as a form of relapse prevention. There is some evidence that booster sessions monthly following CBT for anxiety disorders is associated with greater maintenance of therapeutic benefits [ 75 ], although this has not been specifically studied in the context of GAD.

See "Generalized anxiety disorder in adults: Cognitive-behavioral therapy and other psychotherapies", section on 'Relapse prevention'. SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately.

See "Society guideline links: Anxiety and anxiety disorders in adults". These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed.

These articles are written at the 10 th to 12 th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. Individuals with mild GAD that does not interfere with daily functioning may reasonably elect to forgo treatment initially.

We typically follow-up every three months to see if worsening symptoms warrant treatment. See 'Determining need for treatment' above. The choice between them is individualized and made through shared decision making. See 'Choosing between medication and CBT' above. Details on the administration of CBT for GAD are discussed in detail elsewhere.

See 'SRIs as preferred initial therapy' above. Early adverse effects of SRI treatment include agitation and insomnia which can often lead to discontinuation of the medication before it has had time to effectively treat GAD symptoms. When early adverse effects occur, we typically treat with short-term use of benzodiazepines or hydroxyzine.

See 'Adjunctive therapy for early side effects' above. Our pharmacologic approach depends on whether there was partial response or no response to initial treatment algorithm 1. See 'Subsequent management' above. See 'No response to SRI treatment' above. Gabapentin is a reasonable second choice of augmenting agent.

For individuals with significant mood instability, irritability, or hypomania, medications that have mood stabilizing effects such as lamotrigine or valproate are reasonable options. See 'Partial response to SRI treatment' above.

We occasionally use second-generation antipsychotics, such as aripiprazole or quetiapine , or benzodiazepines in the treatment of refractory GAD. However, due to their potential for abuse and dependence, we reserve long-term benzodiazepines for patients who cannot use other options or have refractory GAD.

See 'Benzodiazepines' above. For this reason, as well as the general physical and mental health benefits of exercise, we encourage aerobic exercise for patients with anxiety disorders who are able to do so.

See 'Complementary treatments' above. CBT typically ranges from 10 to 15 sessions; however, individuals with a robust response may benefit from monthly booster sessions. See 'Duration of treatment' above. SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitors.

QTc prolongation classifications are based upon US Food and Drug Administration guidance. Refer to UpToDate topics on acquired long QT syndrome and acute antidepressant poisonings. Transaminase monitoring is required. However, SNRIs can produce anticholinergic-like effects which appear to be mediated by noradrenergic stimulation such as dry mouth and constipation, and they should be used with caution in narrow angle glaucoma.

Levomilnacipran is associated with urinary hesitancy. Monitor blood pressure regularly. Withdrawn from market due to hepatotoxicity in many countries. ΔΔ Trazodone is associated rarely with priapism, which is considered a medical emergency.

Refer to UpToDate topic on serotonin modulators. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy. Why UpToDate? Product Editorial Subscription Options Subscribe Sign in. View Topic Loading Font Size Small Normal Large. Generalized anxiety disorder in adults: Management. Formulary drug information for this topic. No drug references linked in this topic.

Find in topic Formulary Print Share. Official reprint from UpToDate ® www. com © UpToDate, Inc. All Rights Reserved. Authors: Michelle Craske, PhD Alexander Bystritsky, MD, PhD Section Editor: Murray B Stein, MD, MPH Deputy Editor: Michael Friedman, MD. All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jan This topic last updated: Jul 05, Suboptimal response Adjunctive CBT — For individuals with suboptimal response eg, partial or no response to initial pharmacologic management, we suggest adjunctive cognitive-behavioral therapy CBT.

Pharmacologic management No response to SRI treatment — For individuals who are unresponsive to the initial serotonergic reuptake inhibitor SRI agent in addition to adjunctive CBT, we suggest tapering off of the first agent and titrating another SRI.

Unresponsive to multiple agents Choice of medication — In our clinical experience, a substantial proportion of patients with GAD do not improve or have residual symptoms despite multiple trials of medications and augmenting agents [ 17,35 ].

DURATION OF TREATMENT Pharmacotherapy — If effective, antidepressant treatment for generalized anxiety disorder GAD should be continued for at least 12 months [ 73,74 ].

Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition DSM-5 , American Psychiatric Association, Arlington, VA Lieb R, Becker E, Altamura C. The epidemiology of generalized anxiety disorder in Europe. Eur Neuropsychopharmacol ; Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and month prevalence of DSM-III-R psychiatric disorders in the United States.

Results from the National Comorbidity Survey. Arch Gen Psychiatry ; Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.

Bruce SE, Yonkers KA, Otto MW, et al. Influence of psychiatric comorbidity on recovery and recurrence in generalized anxiety disorder, social phobia, and panic disorder: a year prospective study. Am J Psychiatry ; Keller MB.

The long-term clinical course of generalized anxiety disorder. J Clin Psychiatry ; 63 Suppl Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, and comorbidity of month DSM-IV disorders in the National Comorbidity Survey Replication. Bereza BG, Machado M, Einarson TR.

Systematic review and quality assessment of economic evaluations and quality-of-life studies related to generalized anxiety disorder. Clin Ther ; Stein MB, Sareen J. CLINICAL PRACTICE. Generalized Anxiety Disorder.

N Engl J Med ; Weissman MM, Verdeli H, Gameroff MJ, et al. National survey of psychotherapy training in psychiatry, psychology, and social work. Walkup JT, Albano AM, Piacentini J, et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety.

Hunot V, Churchill R, Silva de Lima M, Teixeira V. Psychological therapies for generalised anxiety disorder. Cochrane Database Syst Rev ; :CD Hendriks GJ, Oude Voshaar RC, Keijsers GP, et al. Cognitive-behavioural therapy for late-life anxiety disorders: a systematic review and meta-analysis.

Acta Psychiatr Scand ; Mitte K. Meta-analysis of cognitive-behavioral treatments for generalized anxiety disorder: a comparison with pharmacotherapy. Psychol Bull ; Carl E, Witcraft SM, Kauffman BY, et al. Psychological and pharmacological treatments for generalized anxiety disorder GAD : a meta-analysis of randomized controlled trials.

Cogn Behav Ther ; Slee A, Nazareth I, Bondaronek P, et al. Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis. Lancet ; Mahe V, Balogh A. Long-term pharmacological treatment of generalized anxiety disorder. Int Clin Psychopharmacol ; Rickels K, Zaninelli R, McCafferty J, et al.

Paroxetine treatment of generalized anxiety disorder: a double-blind, placebo-controlled study. Stocchi F, Nordera G, Jokinen RH, et al. Efficacy and tolerability of paroxetine for the long-term treatment of generalized anxiety disorder. J Clin Psychiatry ; Brawman-Mintzer O, Knapp RG, Rynn M, et al.

Sertraline treatment for generalized anxiety disorder: a randomized, double-blind, placebo-controlled study. Dahl AA, Ravindran A, Allgulander C, et al. Sertraline in generalized anxiety disorder: efficacy in treating the psychic and somatic anxiety factors. Davidson JR, Bose A, Korotzer A, Zheng H.

Escitalopram in the treatment of generalized anxiety disorder: double-blind, placebo controlled, flexible-dose study. Depress Anxiety ; Kapczinski F, Lima MS, Souza JS, Schmitt R.

Antidepressants for generalized anxiety disorder. Davidson JR, Bose A, Wang Q. Safety and efficacy of escitalopram in the long-term treatment of generalized anxiety disorder.

Goodman WK, Bose A, Wang Q. Treatment of generalized anxiety disorder with escitalopram: pooled results from double-blind, placebo-controlled trials. J Affect Disord ; Norton PJ, Price EC. A meta-analytic review of adult cognitive-behavioral treatment outcome across the anxiety disorders.

J Nerv Ment Dis ; Medication and cognitive behavioral therapy CBT are the two main GAD treatments. Doctors may recommend a mixture of the two. There is no one best medication for GAD. What works for one person might not work for another. Often, people find the best medication for them through trial and error.

Learn more about GAD here. The first medication doctors will usually recommend for GAD is antidepressants. Selective serotonin reuptake inhibitors SSRI and serotonin-norepinephrine reuptake inhibitors SNRI are both types of antidepressants.

They work by increasing the level of serotonin in the brain. Serotonin is a neurotransmitter, which is a chemical that carries messages between brain cells. It plays a role in feelings of well-being and happiness.

Learn about the differences between SSRIs and SNRIs here. It can take a few weeks for antidepressants to begin working and increase the serotonin levels in the brain.

People will take antidepressants every day. Learn more about the sexual side effects of antidepressants. People should not stop taking their medication without speaking with a doctor first to avoid withdrawal symptoms. Additionally, some antidepressants can increase the effects of other medications.

These include:. A doctor may prescribe a benzodiazepine when a person requires immediate relief from the symptoms of anxiety. Mental Health America notes that they usually start working within 30 minutes to an hour and wear off within a few hours.

A person will usually only take these medications for a short time as there is a risk of dependency. Benzodiazepines strengthen a calming neurotransmitter called gamma-aminobutyric acid GABA.

Two types of benzodiazepines include diazepam and clonazepam. The National Alliance on Mental Illness notes that people can take diazepam and clonazepam at regular times, or when a person requires them.

A person should speak with a doctor about how many doses they can take in a single day. People should avoid drinking alcohol if they are taking benzodiazepines. There are also some medications that people should avoid when taking benzodiazepines.

However, which medications a person should avoid depends on the benzodiazepine they are taking. People should speak with a doctor to find out which medications they should avoid. Anxiolytic drugs, such as buspirone , are another treatment option for GAD.

As with antidepressants, anxiolytic drugs strengthen the effects of serotonin in the brain. People will take the medication every day, but it can take 2—3 weeks to start working.

People usually take drugs such as buspirone twice per day , with or without food. The exact dose will depend on how the person responds to the drug.

Sometimes it can be a case of trial and error to find the right dose. Long-term use of buspirone is safe, providing a person takes the medications as a doctor instructs. However, side effects can occur. Anyone taking buspirone should avoid doing so alongside alcohol or illegal drugs. These can decrease the benefits of the medication and increase the risk of adverse effects.

A person may experience a severe increase in blood pressure if they take buspirone alongside the following medications within 2 weeks :. People should also avoid taking buspirone alongside the following medications:. Drinking large amounts of grapefruit juice can increase the levels of buspirone in the blood.

According to a article , boxed warnings advise people about the major risks of certain drugs. The United States Food and Drug Administration FDA has placed boxed warnings on benzodiazepines and antidepressants. The FDA warns that benzodiazepines can result in slowed breathing or death when taken with other opioid medications.

In addition, there is a risk of a person becoming dependent on these medications. A person may also experience withdrawal symptoms.

They also warn that antidepressants can lead to suicidal thoughts or actions in children and adults under the age of If you or someone you know is having thoughts of suicide, a prevention hotline can help. The Suicide and Crisis Lifeline is available 24 hours a day at During a crisis, people who are hard of hearing can use their preferred relay service or dial then Click here for more links and local resources.

Mental health medication can be expensive. For some people, health insurance will cover medications for GAD.

People should check their insurance policy to determine what they are entitled to. Medicaid may be able to help some people. Doctors will often recommend people living with GAD alongside CBT. CBT is a type of therapy that helps people change the thought patterns that can lead to excessive anxiety.

The Anxiety and Depression Association of America also suggests people take regular exercise. It can help to reduce stress and anxiety. Doctors will usually prescribe antidepressants to treat GAD.

These can include escitalopram, duloxetine, venlafaxine, and paroxetine. It is important to note that the FDA has placed a boxed warning on these medications as they can lead to suicidal thoughts and tendencies in those under the age of For short-term relief of anxiety symptoms, a doctor may prescribe benzodiazepines.

Mirtazapine: a review of its use in major depression and other psychiatric disorders. CNS Drugs. Ribeiro L, Busnello JV, Kauer-Sant'Anna M, Madruga M, Quevedo J, Busnello EA, et al.

Mirtazapine versus fluoxetine in the treatment of panic disorder. Braz J Med Biol Res. Muehlbacher M, Nickel MK, Nickel C, Kettler C, Lahmann C, Pedrosa Gil F, et al. Mirtazapine treatment of social phobia in women: a randomized, double-blind, placebo-controlled study. Schutters SI, Van Megen HJ, Van Veen JF, Denys DA, Westenberg HG.

Mirtazapine in generalized social anxiety disorder: a randomized, double-blind, placebo-controlled study. Trivedi MH, Rush AJ, Carmody TJ, Donahue RM, Bolden-Watson C, Houser TL, et al.

Do bupropion SR and sertraline differ in their effects on anxiety in depressed patients? J Clin Psychiatry. Papakostas GI, Trivedi MH, Alpert JE, Seifert CA, Krishen A, Goodale EP, et al.

Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of anxiety symptoms in major depressive disorder: a meta-analysis of individual patient data from 10 double-blind, randomized clinical trials.

Papakostas GI, Stahl SM, Krishen A, Seifert CA, Tucker VL, Goodale EP, et al. Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of major depressive disorder with high levels of anxiety anxious depression : a pooled analysis of 10 studies.

Bystritsky A, Kerwin L, Feusner JD, Vapnik T. A pilot controlled trial of bupropion XL versus escitalopram in generalized anxiety disorder.

Psychopharmacol Bull. Sheehan DV, Davidson J, Manschreck T, Van Wyck Fleet J. Lack of efficacy of a new antidepressant bupropion in the treatment of panic disorder with phobias. Simon NM, Emmanuel N, Ballenger J, Worthington JJ, Kinrys G, Korbly NB, et al.

Bupropion sustained release for panic disorder. Papp LA, Coplan JD, Martinez JM, de Jesus M, Gorman JM. Efficacy of open-label nefazodone treatment in patients with panic disorder. Bystritsky A, Rosen R, Suri R, Vapnik T.

Pilot open-label study of nefazodone in panic disorder. Depress Anxiety. DeMartinis NA, Schweizer E, Rickels K. An open-label trial of nefazodone in high comorbidity panic disorder.

Hedges DW, Reimherr FW, Strong RE, Halls CH, Rust C. An open trial of nefazodone in adult patients with generalized anxiety disorder. Van Ameringen M, Mancini C, Oakman J, Walker J, Kjernisted K, Chokka P, et al. Nefazodone in the treatment of generalized social phobia: a randomized, placebo-controlled trial.

Agarwal SD, Landon BE. Patterns in outpatient benzodiazepine prescribing in the United States. JAMA Netw Open. Torres-Bondia F, de Batlle J, Galván L, Buti M, Barbé F, Piñol-Ripoll G. Trends in the consumption rates of benzodiazepines and benzodiazepine-related drugs in the health region of Lleida from to BMC Public Health.

Balon R, Starcevic V. Role of benzodiazepines in anxiety disorders. Adv Exp Med Biol. Moore N, Pariente A, Bégaud B.

Why are benzodiazepines not yet controlled substances? Gomez AF, Barthel AL, Hofmann SG. Comparing the efficacy of benzodiazepines and serotonergic anti-depressants for adults with generalized anxiety disorder: a meta-analytic review.

Offidani E, Guidi J, Tomba E, Fava GA. Efficacy and tolerability of benzodiazepines versus antidepressants in anxiety disorders: a systematic review and meta-analysis.

Psychother Psychosom. Shinfuku M, Kishimoto T, Uchida H, Suzuki T, Mimura M, Kikuchi T. Effectiveness and safety of long-term benzodiazepine use in anxiety disorders: a systematic review and meta-analysis.

Osler M, Jørgensen MB. Associations of benzodiazepines, Z-drugs, and other anxiolytics with subsequent dementia in patients with affective disorders: a nationwide cohort and nested case-control study.

Lim B, Sproule BA, Zahra Z, Sunderji N, Kennedy SH, Rizvi SJ. Understanding the effects of chronic benzodiazepine use in depression: a focus on neuropharmacology.

Mula M, Pini S, Cassano GB. The role of anticonvulsant drugs in anxiety disorders: a critical review of the evidence.

Generoso MB, Trevizol AP, Kasper S, Cho HJ, Cordeiro Q, Shiozawa P. Pregabalin for generalized anxiety disorder: an updated systematic review and meta-analysis.

Kawalec P, Cierniak A, Pilc A, Nowak G. Pregabalin for the treatment of social anxiety disorder. Expert Opin Investig Drugs. Greist JH, Liu-Dumaw M, Schweizer E, Feltner D. Efficacy of pregabalin in preventing relapse in patients with generalized social anxiety disorder: results of a double-blind, placebo-controlled week study.

Pande AC, Feltner DE, Jefferson JW, Davidson JR, Pollack M, Stein MB, et al. Efficacy of the novel anxiolytic pregabalin in social anxiety disorder: a placebo-controlled, multicenter study. Feltner DE, Liu-Dumaw M, Schweizer E, Bielski R.

Efficacy of pregabalin in generalized social anxiety disorder: results of a double-blind, placebo-controlled, fixed-dose study.

Evoy KE, Covvey JR, Peckham AM, Ochs L, Hultgren KE. Reports of gabapentin and pregabalin abuse, misuse, dependence, or overdose: an analysis of the Food And Drug Administration Adverse Events Reporting System FAERS. Res Social Adm Pharm.

Schifano F, Chiappini S. Pregabalin: a range of misuse-related unanswered questions. CNS Neurosci Ther. Nahar LK, Murphy KG, Paterson S. Misuse and mortality related to gabapentin and pregabalin are being under-estimated: a two-year post-mortem population study.

J Anal Toxicol. Ahmed S, Stanciu CN, Kotapati PV, Ahmed R, Bhivandkar S, Khan AM, et al. Effectiveness of gabapentin in reducing cravings and withdrawal in alcohol use disorder: a meta-analytic review. Prim Care Companion CNS Disord. Ahmed S, Bachu R, Kotapati P, Adnan M, Ahmed R, Farooq U, et al.

Use of gabapentin in the treatment of substance use and psychiatric disorders: a systematic review. Front Psychiatry. Pande AC, Pollack MH, Crockatt J, Greiner M, Chouinard G, Lydiard RB, et al. Placebo-controlled study of gabapentin treatment of panic disorder.

de-Paris F, Sant'Anna MK, Vianna MR, Barichello T, Busnello JV, Kapczinski F, et al. Effects of gabapentin on anxiety induced by simulated public speaking.

J Psychopharmacol. PubMed Abstract CrossRef Full Text. Smith RV, Havens JR, Walsh SL. Gabapentin misuse, abuse and diversion: a systematic review. Schmitt U, Lüddens H, Hiemke C. Anxiolytic-like effects of acute and chronic GABA transporter inhibition in rats. J Neural Transm.

Pollack MH, Tiller J, Xie F, Trivedi MH. Tiagabine in adult patients with generalized anxiety disorder: results from 3 randomized, double-blind, placebo-controlled, parallel-group studies.

Zwanzger P, Eser D, Nothdurfter C, Baghai TC, Möller HJ, Padberg F, et al. Effects of the GABA-reuptake inhibitor tiagabine on panic and anxiety in patients with panic disorder. Urbano MR, Spiegel DR, Laguerta N, Shrader CJ, Rowe DF, Hategan LF. Gabapentin and tiagabine for social anxiety: a randomized, double-blind, crossover study of 8 adults.

Prim Care Companion J Clin Psychiatry. Mirza NR, Bright JL, Stanhope KJ, Wyatt A, Harrington NR. Lamotrigine has an anxiolytic-like profile in the rat conditioned emotional response test of anxiety: a potential role for sodium channels?

Masdrakis VG, Papadimitriou GN, Oulis P. Lamotrigine administration in panic disorder with agoraphobia. Clin Neuropharmacol. Van Ameringen M, Mancini C, Pipe B, Bennett M. Antiepileptic drugs in the treatment of anxiety disorders: role in therapy. Aliyev NA, Aliyev ZN. Valproate depakine-chrono in the acute treatment of outpatients with generalized anxiety disorder without psychiatric comorbidity: randomized, double-blind placebo-controlled study.

Eur Psychiatry. Kinrys G, Pollack MH, Simon NM, Worthington JJ, Nardi AE, Versiani M. Valproic acid for the treatment of social anxiety disorder.

Stein MB, Ravindran LN, Simon NM, Liebowitz MR, Khan A, Brawman-Mintzer O, et al. Levetiracetam in generalized social anxiety disorder: a double-blind, randomized controlled trial. Zhang W, Connor KM, Davidson JR. Levetiracetam in social phobia: a placebo controlled pilot study.

Guaiana G, Barbui C, Cipriani A. Hydroxyzine for generalised anxiety disorder. Steenen SA, van Wijk AJ, van der Heijden GJ, van Westrhenen R, de Lange J, de Jongh A. Propranolol for the treatment of anxiety disorders: systematic review and meta-analysis.

Davidson JR. Pharmacotherapy of social anxiety disorder: what does the evidence tell us? Charney DS, Heninger GR. Abnormal regulation of noradrenergic function in panic disorders.

Effects of clonidine in healthy subjects and patients with agoraphobia and panic disorder. Strawn JR, Compton SN, Robertson B, Albano AM, Hamdani M, Rynn MA. Extended release guanfacine in pediatric anxiety disorders: a pilot, randomized, placebo-controlled trial. J Child Adolesc Psychopharmacol.

Uhde TW, Stein MB, Vittone BJ, Siever LJ, Boulenger JP, Klein E, et al. Behavioral and physiologic effects of short-term and long-term administration of clonidine in panic disorder. Hoehn-Saric R, Merchant AF, Keyser ML, Smith VK. Effects of clonidine on anxiety disorders.

Bergendahl H, Lönnqvist PA, Eksborg S. Clonidine in paediatric anaesthesia: review of the literature and comparison with benzodiazepines for premedication. Acta Anaesthesiol Scand.

Maher AR, Maglione M, Bagley S, Suttorp M, Hu JH, Ewing B, et al. Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis. Depping AM, Komossa K, Kissling W, Leucht S. Second-generation antipsychotics for anxiety disorders.

LaLonde CD, Van Lieshout RJ. Treating generalized anxiety disorder with second generation antipsychotics: a systematic review and meta-analysis. Katzman MA, Bleau P, Blier P, Chokka P, Kjernisted K, Van Ameringen M, et al.

Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders.

BMC Psychiatry. Perna G, Alessandra A, Raffaele B, Elisa M, Giuseppina D, Paolo C, et al. Is there room for second-generation antipsychotics in the pharmacotherapy of panic disorder?

A systematic review based on PRISMA guidelines. Int J Mol Sci. Griebel G, Holmes A. Nat Rev Drug Discov. Zareifopoulos N, Dylja I. Efficacy and tolerability of vilazodone for the acute treatment of generalized anxiety disorder: a meta-analysis.

Asian J Psychiatr. Slee A, Nazareth I, Bondaronek P, Liu Y, Cheng Z, Freemantle N. Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis. Schneier FR, Moskow DM, Choo TH, Galfalvy H, Campeas R, Sanchez-Lacay A.

A randomized controlled pilot trial of vilazodone for adult separation anxiety disorder. Careri JM, Draine AE, Hanover R, Liebowitz MR. A week doubleblind, placebo-controlled, flexible-dose trial of vilazodone in generalized social anxiety disorder. Clayton AH, Durgam S, Tang X, Chen C, Ruth A, Gommoll C.

Characterizing sexual function in patients with generalized anxiety disorder: a pooled analysis of three vilazodone studies. Neuropsychiatr Dis Treat. Yee A, Ng CG, Seng LH. Vortioxetine treatment for anxiety disorder: a meta-analysis study. Curr Drug Targets.

Bidzan L, Mahableshwarkar AR, Jacobsen P, Yan M, Sheehan DV. Vortioxetine Lu AA in generalized anxiety disorder: results of an 8-week, multinational, randomized, double-blind, placebo-controlled clinical trial.

Eur Neuropsychopharmacol. Baldwin DS, Loft H, Florea I. Lu AA, a multimodal psychotropic agent, in the prevention of relapse in adult patients with generalized anxiety disorder. Qin B, Huang G, Yang Q, Zhao M, Chen H, Gao W, et al. Vortioxetine treatment for generalised anxiety disorder: a meta-analysis of anxiety, quality of life and safety outcomes.

BMJ Open. Shah A, Northcutt J. An open-label, flexible dose adaptive study evaluating the efficacy of vortioxetine in subjects with panic disorder. Ann Genrl Psychiatry. Celada P, Bortolozzi A, Artigas F. Serotonin 5-HT 1A receptors as targets for agents to treat psychiatric disorders: rationale and current status of research.

Pecknold JC, Luthe L, Scott-Fleury MH, Jenkins S. Gepirone and the treatment of panic disorder: an open study. Kaur Gill A, Bansal Y, Bhandari R, Kaur S, Kaur J, Singh R, et al. Gepirone hydrochloride: a novel antidepressant with 5-HT1A agonistic properties. Drugs Today. Fabre-Kramer Pharmaceuticals I.

Nishitsuji K, To H, Murakami Y, Kodama K, Kobayashi D, Yamada T, et al. Tandospirone in the treatment of generalised anxiety disorder and mixed anxiety-depression : results of a comparatively high dosage trial. Clin Drug Investig. Lin J, Su Y, Wang C, Yang F, Xu Y, Yuan Y, et al.

Effects of tandospirone augmentation in major depressive disorder patients with high anxiety: a multicenter, randomized, parallel-controlled, open-label study.

Rickels K, Mathew S, Banov MD, Zimbroff DL, Oshana S, Parsons EC, et al. Effects of PRX, a novel, selective serotonin 1A receptor agonist on measures of anxiety and depression in generalized anxiety disorder: results of a double-blind, placebo-controlled trial.

Wesołowska A, Nikiforuk A, Stachowicz K. Anxiolytic-like and antidepressant-like effects produced by the selective 5-HT6 receptor antagonist SB after intrahippocampal administration to rats. Behav Pharmacol. Ivachtchenko AV, Lavrovsky Y, Okun I.

AVN a multi-target drug candidate for the treatment of CNS disorders. J Alzheimers Dis. Freeman AM 3rd, Westphal JR, Norris GT, Roggero BA, Webb PB, Freeman KL, et al. Efficacy of ondansetron in the treatment of generalized anxiety disorder. Schneier FR, Garfinkel R, Kennedy B, Campeas R, Fallon B, Marshall R, et al.

Ondansetron in the treatment of panic disorder. MacIsaac SE, Carvalho AF, Cha DS, Mansur RB, McIntyre RS. The mechanism, efficacy, and tolerability profile of agomelatine. Stein DJ, Khoo JP, Ahokas A, Jarema M, Van Ameringen M, Vavrusova L, et al.

Stein DJ, Ahokas AA, de Bodinat C. Efficacy of agomelatine in generalized anxiety disorder: a randomized, double-blind, placebo-controlled study. Stein DJ, Ahokas A, Márquez MS, Höschl C, Oh KS, Jarema M, et al. Agomelatine in generalized anxiety disorder: an active comparator and placebo-controlled study.

Stein DJ, Ahokas A, Jarema M, Avedisova AS, Vavrusova L, Chaban O, et al. Stein DJ, Ahokas A, Albarran C, Olivier V, Allgulander C. Agomelatine prevents relapse in generalized anxiety disorder: a 6-month randomized, double-blind, placebo-controlled discontinuation study.

Weston NM, Gibbs D, Bird CIV, Daniel A, Jelen LA, Knight G, et al. Historic psychedelic drug trials and the treatment of anxiety disorders. Fuentes JJ, Fonseca F, Elices M, Farré M, Torrens M. Therapeutic use of LSD in psychiatry: a systematic review of randomized-controlled clinical trials.

Krystal JH, Mathew SJ, D'Souza DC, Garakani A, Gunduz-Bruce H, Charney DS. Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists. Bergink V, Westenberg HG. Metabotropic glutamate II receptor agonists in panic disorder: a double blind clinical trial with LY Dunayevich E, Erickson J, Levine L, Landbloom R, Schoepp DD, Tollefson GD.

Kent JM, Daly E, Kezic I, Lane R, Lim P, De Smedt H, et al. Prog Neuropsychopharmacol Biol Psychiatry. Wan LB, Levitch CF, Perez AM, Brallier JW, Iosifescu DV, Chang LC, et al. Ketamine safety and tolerability in clinical trials for treatment-resistant depression. Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB.

Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial.

Fava M, Freeman MP, Flynn M, Judge H, Hoeppner BB, Cusin C, et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression TRD.

Singh JB, Fedgchin M, Daly EJ, De Boer P, Cooper K, Lim P, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression.

Phillips JL, Norris S, Talbot J, Birmingham M, Hatchard T, Ortiz A, et al. Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: a randomized controlled trial. Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, aan het Rot M, et al.

Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS, Schatzberg AF, et al. A consensus statement on the use of ketamine in the treatment of mood disorders.

Papakostas GI, Salloum NC, Hock RS, Jha MK, Murrough JW, Mathew SJ, et al. Efficacy of esketamine augmentation in major depressive disorder: a meta-analysis. Engin E, Treit D, Dickson CT. Anxiolytic- and antidepressant-like properties of ketamine in behavioral and neurophysiological animal models.

Irwin SA, Iglewicz A, Nelesen RA, Lo JY, Carr CH, Romero SD, et al. Daily oral ketamine for the treatment of depression and anxiety in patients receiving hospice care: a day open-label proof-of-concept trial. J Palliat Med.

Glue P, Medlicott NJ, Harland S, Neehoff S, Anderson-Fahey B, Le Nedelec M, et al. Ketamine's dose-related effects on anxiety symptoms in patients with treatment refractory anxiety disorders.

Glue P, Neehoff SM, Medlicott NJ, Gray A, Kibby G, McNaughton N. Safety and efficacy of maintenance ketamine treatment in patients with treatment-refractory generalised anxiety and social anxiety disorders.

Taylor JH, Landeros-Weisenberger A, Coughlin C, Mulqueen J, Johnson JA, Gabriel D, et al. Ketamine for social anxiety disorder: a randomized, placebo-controlled crossover trial. Zarate CA Jr, Payne JL, Quiroz J, Sporn J, Denicoff KK, et al.

An open-label trial of riluzole in patients with treatment-resistant major depression. Sanacora G, Kendell SF, Levin Y, Simen AA, Fenton LR, Coric V, et al. Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms.

Mathew SJ, Murrough JW, aan het Rot M, Collins KA, Reich DL, Charney DS. Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial.

Int J Neuropsychopharmacol. Sugiyama A, Saitoh A, Iwai T, Takahashi K, Yamada M, Sasaki-Hamada S, et al. Riluzole produces distinct anxiolytic-like effects in rats without the adverse effects associated with benzodiazepines.

Stutzmann JM, Cintrat P, Laduron PM, Blanchard JC. Riluzole antagonizes the anxiogenic properties of the beta-carboline FG in rats. Mathew SJ, Amiel JM, Coplan JD, Fitterling HA, Sackeim HA, Gorman JM.

Open-label trial of riluzole in generalized anxiety disorder. Mathew SJ, Price RB, Mao X, Smith EL, Coplan JD, Charney DS, et al. Hippocampal N-acetylaspartate concentration and response to riluzole in generalized anxiety disorder. Abdallah CG, Coplan JD, Jackowski A, Sato JR, Mao X, Shungu DC, et al.

A pilot study of hippocampal volume and N-acetylaspartate NAA as response biomarkers in riluzole-treated patients with GAD. Myers KM, Carlezon WA Jr, Davis M. Glutamate receptors in extinction and extinction-based therapies for psychiatric illness. Nations KR, Dogterom P, Bursi R, Schipper J, Greenwald S, Zraket D, et al.

Examination of Org , an AMPA receptor positive allosteric modulator, in patients diagnosed with major depressive disorder: an exploratory, randomized, double-blind, placebo-controlled trial.

Davis M, Ressler K, Rothbaum BO, Richardson R. Effects of D-cycloserine on extinction: translation from preclinical to clinical work. Heresco-Levy U, Kremer I, Javitt DC, Goichman R, Reshef A, Blanaru M, et al. Pilot-controlled trial of D-cycloserine for the treatment of post-traumatic stress disorder.

Bailey J, Papadopoulos A, Lingford-Hughes A, Nutt D. D-Cycloserine and performance under different states of anxiety in healthy volunteers. Onur OA, Schlaepfer TE, Kukolja J, Bauer A, Jeung H, Patin A, et al. The N-methyl-D-aspartate receptor co-agonist D-cycloserine facilitates declarative learning and hippocampal activity in humans.

Nave AM, Tolin DF, Stevens MC. Exposure therapy, D-cycloserine, and functional magnetic resonance imaging in patients with snake phobia: a randomized pilot study. Ori R, Amos T, Bergman H, Soares-Weiser K, Ipser JC, Stein DJ. Augmentation of cognitive and behavioural therapies CBT with d-cycloserine for anxiety and related disorders.

Mataix-Cols D, Fernández de la Cruz L, Monzani B, Rosenfield D, Andersson E, Pérez-Vigil A, et al. D-cycloserine augmentation of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders: a systematic review and meta-analysis of individual participant data.

Reinecke A, Nickless A, Browning M, Harmer CJ. Neurocognitive processes in d-cycloserine augmented single-session exposure therapy for anxiety: a randomized placebo-controlled trial. Behav Res Therapy.

Hofmeijer-Sevink MK, Duits P, Rijkeboer MM, Hoogendoorn AW, van Megen HJ, Vulink NC, et al. No effects of D-cycloserine enhancement in exposure with response prevention therapy in panic disorder with agoraphobia: a double-blind, randomized controlled trial.

Roque AD, Rosenfield D, Smits JAJ, Simon N, Otto MW, Marques L, et al. Does d-cycloserine facilitate the effects of homework compliance on social anxiety symptom reduction? J Anxiety Disord.

Hofmann SG, Meuret AE, Smits JA, Simon NM, Pollack MH, Eisenmenger K, et al. Augmentation of exposure therapy with D-cycloserine for social anxiety disorder. Guastella AJ, Richardson R, Lovibond PF, Rapee RM, Gaston JE, Mitchell P, et al.

A randomized controlled trial of D-cycloserine enhancement of exposure therapy for social anxiety disorder. Smits JAJ, Pollack MH, Rosenfield D, Otto MW, Dowd S, Carpenter J, et al. Dose timing of D-cycloserine to augment exposure therapy for social anxiety disorder: a randomized clinical trial.

Hofmann SG, Smits JA, Rosenfield D, Simon N, Otto MW, Meuret AE, et al. D-Cycloserine as an augmentation strategy with cognitive-behavioral therapy for social anxiety disorder. Hofmann SG, Papini S, Carpenter JK, Otto MW, Rosenfield D, Dutcher CD, et al. Effect of d-cycloserine on fear extinction training in adults with social anxiety disorder.

PLoS ONE. Tart CD, Handelsman PR, Deboer LB, Rosenfield D, Pollack MH, Hofmann SG, et al. Augmentation of exposure therapy with post-session administration of D-cycloserine. Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, et al.

Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Kappelmann N, Suesse M, Steudte-Schmiedgen S, Kaldewaij R, Browning M, Michael T, et al.

D-cycloserine as adjunct to brief computerised CBT for spider fear: effects on fear, behaviour, and cognitive biases. J Behav Ther Exp Psychiatry. Gutner CA, Weinberger J, Hofmann SG.

The effect of D-cycloserine on subliminal cue exposure in spider fearful individuals. Cogn Behav Ther. Guastella AJ, Dadds MR, Lovibond PF, Mitchell P, Richardson R. A randomized controlled trial of the effect of D-cycloserine on exposure therapy for spider fear.

Sani G, Serra G, Kotzalidis GD, Romano S, Tamorri SM, Manfredi G, et al. The role of memantine in the treatment of psychiatric disorders other than the dementias: a review of current preclinical and clinical evidence. Mindfulness-based stress reduction and yoga may also be helpful, as they have also been shown to reduce symptoms of generalized anxiety relative to education control conditions [ 71,72 ].

The outcomes of these activities on anxiety are discussed in detail elsewhere. See "Complementary and alternative treatments for anxiety symptoms and disorders: Physical, cognitive, and spiritual interventions" and "Complementary and alternative treatments for anxiety symptoms and disorders: Herbs and medications".

Pharmacotherapy — If effective, antidepressant treatment for generalized anxiety disorder GAD should be continued for at least 12 months [ 73,74 ]. In a randomized trial, patients with GAD who experienced reduced anxiety during six months of treatment with venlafaxine extended-release XR were assigned to medication continuation treatment or placebo for an additional six months [ 74 ].

Patients continuing venlafaxine XR had a much lower rate of relapse during the second six months than patients receiving placebo 9. Incidence rates of side effects during the second six months compared with the first six months were lower, did not differ statistically between drug and placebo patients, and included no new side effects.

If the patient experiences a relapse following termination of an effective medication, the length of treatment can be extended. After two relapses when tapering off the medication, ongoing maintenance treatment is suggested. Cognitive-behavioral therapy — Duration of cognitive-behavioral therapy CBT depends on the severity of symptoms, presence of comorbidity, patient resistance to treatment, therapist competence, and number of components incorporated.

Typically, this ranges from 10 to 15 sessions however individuals are encouraged to continue to use CBT skills as a form of relapse prevention. There is some evidence that booster sessions monthly following CBT for anxiety disorders is associated with greater maintenance of therapeutic benefits [ 75 ], although this has not been specifically studied in the context of GAD.

See "Generalized anxiety disorder in adults: Cognitive-behavioral therapy and other psychotherapies", section on 'Relapse prevention'. SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately.

See "Society guideline links: Anxiety and anxiety disorders in adults". These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 th to 12 th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. Individuals with mild GAD that does not interfere with daily functioning may reasonably elect to forgo treatment initially.

We typically follow-up every three months to see if worsening symptoms warrant treatment. See 'Determining need for treatment' above. The choice between them is individualized and made through shared decision making. See 'Choosing between medication and CBT' above.

Details on the administration of CBT for GAD are discussed in detail elsewhere. See 'SRIs as preferred initial therapy' above. Early adverse effects of SRI treatment include agitation and insomnia which can often lead to discontinuation of the medication before it has had time to effectively treat GAD symptoms.

When early adverse effects occur, we typically treat with short-term use of benzodiazepines or hydroxyzine. See 'Adjunctive therapy for early side effects' above. Our pharmacologic approach depends on whether there was partial response or no response to initial treatment algorithm 1.

See 'Subsequent management' above. See 'No response to SRI treatment' above. Gabapentin is a reasonable second choice of augmenting agent. For individuals with significant mood instability, irritability, or hypomania, medications that have mood stabilizing effects such as lamotrigine or valproate are reasonable options.

See 'Partial response to SRI treatment' above. We occasionally use second-generation antipsychotics, such as aripiprazole or quetiapine , or benzodiazepines in the treatment of refractory GAD.

However, due to their potential for abuse and dependence, we reserve long-term benzodiazepines for patients who cannot use other options or have refractory GAD. See 'Benzodiazepines' above. For this reason, as well as the general physical and mental health benefits of exercise, we encourage aerobic exercise for patients with anxiety disorders who are able to do so.

See 'Complementary treatments' above. CBT typically ranges from 10 to 15 sessions; however, individuals with a robust response may benefit from monthly booster sessions.

See 'Duration of treatment' above. SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitors. QTc prolongation classifications are based upon US Food and Drug Administration guidance.

Refer to UpToDate topics on acquired long QT syndrome and acute antidepressant poisonings. Transaminase monitoring is required. However, SNRIs can produce anticholinergic-like effects which appear to be mediated by noradrenergic stimulation such as dry mouth and constipation, and they should be used with caution in narrow angle glaucoma.

Levomilnacipran is associated with urinary hesitancy. Monitor blood pressure regularly. Withdrawn from market due to hepatotoxicity in many countries. ΔΔ Trazodone is associated rarely with priapism, which is considered a medical emergency. Refer to UpToDate topic on serotonin modulators.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content.

Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy. Why UpToDate? Product Editorial Subscription Options Subscribe Sign in.

View Topic Loading Font Size Small Normal Large. Generalized anxiety disorder in adults: Management. Formulary drug information for this topic. No drug references linked in this topic. Find in topic Formulary Print Share.

Official reprint from UpToDate ® www. com © UpToDate, Inc. All Rights Reserved. Authors: Michelle Craske, PhD Alexander Bystritsky, MD, PhD Section Editor: Murray B Stein, MD, MPH Deputy Editor: Michael Friedman, MD.

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jan This topic last updated: Jul 05, Suboptimal response Adjunctive CBT — For individuals with suboptimal response eg, partial or no response to initial pharmacologic management, we suggest adjunctive cognitive-behavioral therapy CBT.

Pharmacologic management No response to SRI treatment — For individuals who are unresponsive to the initial serotonergic reuptake inhibitor SRI agent in addition to adjunctive CBT, we suggest tapering off of the first agent and titrating another SRI. Unresponsive to multiple agents Choice of medication — In our clinical experience, a substantial proportion of patients with GAD do not improve or have residual symptoms despite multiple trials of medications and augmenting agents [ 17,35 ].

DURATION OF TREATMENT Pharmacotherapy — If effective, antidepressant treatment for generalized anxiety disorder GAD should be continued for at least 12 months [ 73,74 ]. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition DSM-5 , American Psychiatric Association, Arlington, VA Lieb R, Becker E, Altamura C.

The epidemiology of generalized anxiety disorder in Europe. Eur Neuropsychopharmacol ; Kessler RC, McGonagle KA, Zhao S, et al.

Lifetime and month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey.

Arch Gen Psychiatry ; Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Bruce SE, Yonkers KA, Otto MW, et al.

Influence of psychiatric comorbidity on recovery and recurrence in generalized anxiety disorder, social phobia, and panic disorder: a year prospective study. Am J Psychiatry ; Keller MB. The long-term clinical course of generalized anxiety disorder.

J Clin Psychiatry ; 63 Suppl Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, and comorbidity of month DSM-IV disorders in the National Comorbidity Survey Replication. Bereza BG, Machado M, Einarson TR. Systematic review and quality assessment of economic evaluations and quality-of-life studies related to generalized anxiety disorder.

Clin Ther ; Stein MB, Sareen J. CLINICAL PRACTICE. Generalized Anxiety Disorder. N Engl J Med ; Weissman MM, Verdeli H, Gameroff MJ, et al. National survey of psychotherapy training in psychiatry, psychology, and social work. Walkup JT, Albano AM, Piacentini J, et al.

Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. Hunot V, Churchill R, Silva de Lima M, Teixeira V. Psychological therapies for generalised anxiety disorder. Cochrane Database Syst Rev ; :CD Hendriks GJ, Oude Voshaar RC, Keijsers GP, et al.

Cognitive-behavioural therapy for late-life anxiety disorders: a systematic review and meta-analysis. Acta Psychiatr Scand ; Mitte K. Meta-analysis of cognitive-behavioral treatments for generalized anxiety disorder: a comparison with pharmacotherapy. Psychol Bull ; Carl E, Witcraft SM, Kauffman BY, et al.

Psychological and pharmacological treatments for generalized anxiety disorder GAD : a meta-analysis of randomized controlled trials.

Cogn Behav Ther ; Slee A, Nazareth I, Bondaronek P, et al. Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis.

Lancet ; Mahe V, Balogh A. Long-term pharmacological treatment of generalized anxiety disorder. Int Clin Psychopharmacol ; Rickels K, Zaninelli R, McCafferty J, et al. Paroxetine treatment of generalized anxiety disorder: a double-blind, placebo-controlled study. Stocchi F, Nordera G, Jokinen RH, et al.

Efficacy and tolerability of paroxetine for the long-term treatment of generalized anxiety disorder. J Clin Psychiatry ; Brawman-Mintzer O, Knapp RG, Rynn M, et al. Sertraline treatment for generalized anxiety disorder: a randomized, double-blind, placebo-controlled study.

Dahl AA, Ravindran A, Allgulander C, et al. Sertraline in generalized anxiety disorder: efficacy in treating the psychic and somatic anxiety factors. Davidson JR, Bose A, Korotzer A, Zheng H. Escitalopram in the treatment of generalized anxiety disorder: double-blind, placebo controlled, flexible-dose study.

Depress Anxiety ; Kapczinski F, Lima MS, Souza JS, Schmitt R. Antidepressants for generalized anxiety disorder. Davidson JR, Bose A, Wang Q. Safety and efficacy of escitalopram in the long-term treatment of generalized anxiety disorder.

Goodman WK, Bose A, Wang Q. Treatment of generalized anxiety disorder with escitalopram: pooled results from double-blind, placebo-controlled trials. J Affect Disord ; Norton PJ, Price EC.

A meta-analytic review of adult cognitive-behavioral treatment outcome across the anxiety disorders. J Nerv Ment Dis ; Hofmann SG, Smits JA. Cognitive-behavioral therapy for adult anxiety disorders: a meta-analysis of randomized placebo-controlled trials. Hall J, Kellett S, Berrios R, et al.

Efficacy of Cognitive Behavioral Therapy for Generalized Anxiety Disorder in Older Adults: Systematic Review, Meta-Analysis, and Meta-Regression. Am J Geriatr Psychiatry ; Brenes GA, Danhauer SC, Lyles MF, et al. Telephone-Delivered Cognitive Behavioral Therapy and Telephone-Delivered Nondirective Supportive Therapy for Rural Older Adults With Generalized Anxiety Disorder: A Randomized Clinical Trial.

JAMA Psychiatry ; Loerinc AG, Meuret AE, Twohig MP, et al. Response rates for CBT for anxiety disorders: Need for standardized criteria. Clin Psychol Rev ; Bielski RJ, Bose A, Chang CC. A double-blind comparison of escitalopram and paroxetine in the long-term treatment of generalized anxiety disorder.

Ann Clin Psychiatry ; Hidalgo RB, Tupler LA, Davidson JR. An effect-size analysis of pharmacologic treatments for generalized anxiety disorder. J Psychopharmacol ; Rickels K, Rynn M, Iyengar M, Duff D.

Remission of generalized anxiety disorder: a review of the paroxetine clinical trials database. Lydiard RB.

An overview of generalized anxiety disorder: disease state--appropriate therapy. If SSRIs and SNRIs aren't suitable for you, you may be offered pregabalin. This is a medication known as an anticonvulsant, which is used to treat conditions such as epilepsy , but it's also been found to be beneficial in treating anxiety.

Benzodiazepines are a type of sedative that may sometimes be used as a short-term treatment during a particularly severe period of anxiety. This is because they help ease the symptoms within 30 to 90 minutes of taking the medication.

If you're prescribed a benzodiazepine, it'll usually be diazepam. Although benzodiazepines are very effective in treating the symptoms of anxiety, they can't be used for long periods. This is because they can become addictive if used for longer than 4 weeks.

Benzodiazepines also start to lose their effectiveness after this time. For these reasons, you won't usually be prescribed benzodiazepines for any longer than 2 to 4 weeks at a time.

As drowsiness is a particularly common side effect of benzodiazepines, your ability to drive or operate machinery may be affected by taking this medication. You should also never drink alcohol or use opiate drugs when taking benzodiazepine as doing so can be dangerous.

If you have tried the treatments mentioned above and have significant symptoms of GAD, you may want to discuss with your GP whether you should be referred to a mental health specialist. A referral will work differently in different areas of the UK, but you'll usually be referred to your community mental health team.

An appropriate mental health specialist from your local team will carry out an overall reassessment of your condition. They'll ask you about your previous treatment and how effective you found it. They may also ask about things in your life that may be affecting your condition, or how much support you get from family and friends.

Your specialist will then be able to devise a treatment plan for you, which will aim to treat your symptoms. As part of this plan, you may be offered a treatment you haven't tried before, which might be psychological treatments or medication. Alternatively, you may be offered a combination of a psychological treatment with a medication, or a combination of 2 different medications.

Page last reviewed: 5 October Next review due: 5 October Home Mental health Mental health conditions Generalised anxiety disorder in adults Back to Generalised anxiety disorder in adults.