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. 2023 Nov 28;11(11):CD012729.
doi: 10.1002/14651858.CD012729.pub3.

Pharmacological treatments in panic disorder in adults: a network meta-analysis

Giuseppe Guaiana  1 , Nicholas Meader  2   3 , Corrado Barbui  4   5 , Simon Jc Davies  6 , Toshi A Furukawa  7 , Hissei Imai  7 , Sofia Dias  2 , Deborah M Caldwell  8 , Markus Koesters  9 , Aran Tajika  10 , Irene Bighelli  11 , Alessandro Pompoli  12 , Andrea Cipriani  13   14   15 , Sarah Dawson  8 , Lindsay Robertson  16
Affiliations

Pharmacological treatments in panic disorder in adults: a network meta-analysis

Giuseppe Guaiana et al. Cochrane Database Syst Rev. .

Abstract

Background: A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as racing heart, chest pain, sweating, shaking, dizziness, flushing, churning stomach, faintness and breathlessness. Other recognised panic attack symptoms involve fearful cognitions, such as the fear of collapse, going mad or dying, and derealisation (the sensation that the world is unreal). Panic disorder is common in the general population with a prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions, including antidepressants and benzodiazepines.

Objectives: To compare, via network meta-analysis, individual drugs (antidepressants and benzodiazepines) or placebo in terms of efficacy and acceptability in the acute treatment of panic disorder, with or without agoraphobia. To rank individual active drugs for panic disorder (antidepressants, benzodiazepines and placebo) according to their effectiveness and acceptability. To rank drug classes for panic disorder (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), mono-amine oxidase inhibitors (MAOIs) and benzodiazepines (BDZs) and placebo) according to their effectiveness and acceptability. To explore heterogeneity and inconsistency between direct and indirect evidence in a network meta-analysis.

Search methods: We searched the Cochrane Common Mental Disorders Specialised Register, CENTRAL, CDSR, MEDLINE, Ovid Embase and PsycINFO to 26 May 2022.

Selection criteria: We included randomised controlled trials (RCTs) of people aged 18 years or older of either sex and any ethnicity with clinically diagnosed panic disorder, with or without agoraphobia. We included trials that compared the effectiveness of antidepressants and benzodiazepines with each other or with a placebo.

Data collection and analysis: Two authors independently screened titles/abstracts and full texts, extracted data and assessed risk of bias. We analysed dichotomous data and continuous data as risk ratios (RRs), mean differences (MD) or standardised mean differences (SMD): response to treatment (i.e. substantial improvement from baseline as defined by the original investigators: dichotomous outcome), total number of dropouts due to any reason (as a proxy measure of treatment acceptability: dichotomous outcome), remission (i.e. satisfactory end state as defined by global judgement of the original investigators: dichotomous outcome), panic symptom scales and global judgement (continuous outcome), frequency of panic attacks (as recorded, for example, by a panic diary; continuous outcome), agoraphobia (dichotomous outcome). We assessed the certainty of evidence using threshold analyses.

Main results: Overall, we included 70 trials in this review. Sample sizes ranged between 5 and 445 participants in each arm, and the total sample size per study ranged from 10 to 1168. Thirty-five studies included sample sizes of over 100 participants. There is evidence from 48 RCTs (N = 10,118) that most medications are more effective in the response outcome than placebo. In particular, diazepam, alprazolam, clonazepam, paroxetine, venlafaxine, clomipramine, fluoxetine and adinazolam showed the strongest effect, with diazepam, alprazolam and clonazepam ranking as the most effective. We found heterogeneity in most of the comparisons, but our threshold analyses suggest that this is unlikely to impact the findings of the network meta-analysis. Results from 64 RCTs (N = 12,310) suggest that most medications are associated with either a reduced or similar risk of dropouts to placebo. Alprazolam and diazepam were associated with a lower dropout rate compared to placebo and were ranked as the most tolerated of all the medications examined. Thirty-two RCTs (N = 8569) were included in the remission outcome. Most medications were more effective than placebo, namely desipramine, fluoxetine, clonazepam, diazepam, fluvoxamine, imipramine, venlafaxine and paroxetine, and their effects were clinically meaningful. Amongst these medications, desipramine and alprazolam were ranked highest. Thirty-five RCTs (N = 8826) are included in the continuous outcome reduction in panic scale scores. Brofaromine, clonazepam and reboxetine had the strongest reductions in panic symptoms compared to placebo, but results were based on either one trial or very small trials. Forty-one RCTs (N = 7853) are included in the frequency of panic attack outcome. Only clonazepam and alprazolam showed a strong reduction in the frequency of panic attacks compared to placebo, and were ranked highest. Twenty-six RCTs (N = 7044) provided data for agoraphobia. The strongest reductions in agoraphobia symptoms were found for citalopram, reboxetine, escitalopram, clomipramine and diazepam, compared to placebo. For the pooled intervention classes, we examined the two primary outcomes (response and dropout). The classes of medication were: SSRIs, SNRIs, TCAs, MAOIs and BDZs. For the response outcome, all classes of medications examined were more effective than placebo. TCAs as a class ranked as the most effective, followed by BDZs and MAOIs. SSRIs as a class ranked fifth on average, while SNRIs were ranked lowest. When we compared classes of medication with each other for the response outcome, we found no difference between classes. Comparisons between MAOIs and TCAs and between BDZs and TCAs also suggested no differences between these medications, but the results were imprecise. For the dropout outcome, BDZs were the only class associated with a lower dropout compared to placebo and were ranked first in terms of tolerability. The other classes did not show any difference in dropouts compared to placebo. In terms of ranking, TCAs are on average second to BDZs, followed by SNRIs, then by SSRIs and lastly by MAOIs. BDZs were associated with lower dropout rates compared to SSRIs, SNRIs and TCAs. The quality of the studies comparing antidepressants with placebo was moderate, while the quality of the studies comparing BDZs with placebo and antidepressants was low.

Authors' conclusions: In terms of efficacy, SSRIs, SNRIs (venlafaxine), TCAs, MAOIs and BDZs may be effective, with little difference between classes. However, it is important to note that the reliability of these findings may be limited due to the overall low quality of the studies, with all having unclear or high risk of bias across multiple domains. Within classes, some differences emerged. For example, amongst the SSRIs paroxetine and fluoxetine seem to have stronger evidence of efficacy than sertraline. Benzodiazepines appear to have a small but significant advantage in terms of tolerability (incidence of dropouts) over other classes.

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Conflict of interest statement

GG: is a Cochrane Editor. He was not involved in the editorial process for the manuscript. He is a diplomate of the Academy of Cognitive Therapy.

NM: is a Cochrane Editor. He was not involved in the editorial process for the manuscript.

CB: is a Cochrane Editor. He was not involved in the editorial process for the manuscript.

SJCD: is a Cochrane Editor. He was not involved in the editorial process for the manuscript. He is a member of the European College of Neuropsychopharmacology and co‐chair of their Anxiety Disorders Research Network. He has published opinions in medical journals relevant to the interventions in this review. He is a member of the Anxiety Disorders Research Network of the European College of Neuropsychopharmacology (ECNP) and of the British Association of Psychopharmacology (BAP).

TAF: has received lecture fees from Eli Lilly, Meiji, Mochida, MSD, Otsuka, Pfizer, Shionogi and Mitsubishi‐Tanabe, and consultancy fees from Sekisui Chemicals and Takeda Science Foundation. He has received royalties from Igaku‐Shoin, Seiwa‐Shoten and Nihon Bunka Kagaku‐sha publishers. He has received grant or research support from the Japanese Ministry of Education, Science, and Technology, the Japanese Ministry of Health, Labor and Welfare, the Japan Foundation for Neuroscience and Mental Health, Mitsubishi‐Tanabe and Mochida. He is a diplomate of the Academy of Cognitive Therapy. TAF has a patent 2018‐177688 pending.

HI: received an honorarium for a lecture from Otsuka.

SD: no conflicts of interest

DC: no conflicts of interest.

MK: no conflicts of interest.

AT: received lecture fees from Sumitomo Dainippon Pharma, Eisai, Janssen Pharmaceutical, Meiji‐Seika Pharma, Mitsubishi Tanabe Pharma, Otsuka and Takeda Pharmaceutical.

IB: is Deputy Co‐ordinating Editor of Cochrane Schizophrenia. She was not involved in the editorial process for the current review.

AP: no conflicts of interest.

AC: is supported by the National Institute for Health Research (NIHR) Oxford Cognitive Health Clinical Research Facility, by an NIHR Research Professorship (grant RP‐2017‐08‐ST2‐006), by the NIHR Oxford and Thames Valley Applied Research Collaboration and by the NIHR Oxford Health Biomedical Research Centre (grant BRC‐1215‐20005). The views expressed are those of the authors and not necessarily those of the UK National Health Service, the NIHR or the UK Department of Health. He has received research, educational and travel support from INCiPiT (Italian Network for Paediatric Trials), CARIPLO Foundation, Lundbeck and Angelini Pharma. He is the CI/PI of two trials about seltorexant in depression, sponsored by Janssen.

SDn: is a Cochrane Editor. She was not involved in the editorial process for the manuscript.

LR: no conflicts of interest.

Figures

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Network plot for response outcome (node size and edge width weighted by sample size)
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Forest plot for threshold analysis on response Medications: 1 = placebo, 2 = fluoxetine, 3 = sertraline, 4 = venlafaxine, 5 = fluvoxamine, 6 = clomipramine, 7 = imipramine, 8 = paroxetine, 9 = moclobemide, 10 = citalopram, 11 = desipramine, 12 = clonazepam, 13 = adinazolam, 14 = alprazolam, 15 = escitalopram, 16 = diazepam, 17 = buspirone, 18 = reboxetine, 19 = etizolam, 20 = ritanserin
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Network plot for dropout (node size and edge width weighted by number of studies)
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Forest plot of dropout threshold analysis Medications: 1 = placebo, 2 = fluoxetine, 3 = sertraline, 4 = venlafaxine, 5 = fluvoxamine, 6 = clomipramine, 7 = imipramine, 8 = paroxetine, 9 = moclobemide, 10 = citalopram, 11 = desipramine, 12 = clonazepam, 13 = adinazolam, 14 = alprazolam, 15 = escitalopram, 16 = diazepam, 17 = buspirone, 18 = reboxetine, 19 = etizolam, 20 = ritanserin
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Network plot remission (node size and edge width weighted by sample size)
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Network plot intervention combinations for panic scales (change from baseline)
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Network plot of intervention comparisons included in network meta‐analysis of panic scales (endpoint)
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Network plot frequency of panic attacks (node size and edge width weighted by sample size)
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Network plot intervention combinations for agoraphobia (change from baseline)
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Network plot of intervention combinations for agoraphobia symptoms (endpoint)
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Network plot comparing medication classes for response (node size and edge width weighted by sample size)
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Network diagram comparing medication classes with placebo and one another for dropout (node size and edge width weighted by sample size)
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Tsutsui 1997 {published data only}
    1. Tsutsui S. Clinical evaluation of paroxetine Hcl, a selective serotonin reuptake inhibitor, in the treatment of panic disorder: late phase II double-blind, parallel group study. Japanese Pharmacology and Therapeutics 2000;28:S271-94.
Tsutsui 2000a {published data only}
    1. Tsutsui S. Clinical evaluation of paroxetine Hcl, a selective serotonin reuptake inhibitor, in the treatment of panic disorder: late phase II double-blind, parallel group study. Japanese Pharmacology and Therapeutics 2000;28:S271-94.
Tsutsui 2000b {published data only}
    1. Tsutsui S. Clinical evaluation of paroxetine Hcl, a selective serotonin reuptake inhibitor, in the treatment of panic disorder: phase III double-blind, parallel group study. Japanese Pharmacology and Therapeutics 2000;28:S295-314.
Uhlenhuth 1989 {published data only}
    1. Uhlenhuth EH, Matuzas W, Glass RM, Easton C. Response of panic disorder to fixed doses of alprazolam or imipramine. Journal of Affective Disorders 1989;17(3):261‐70. - PubMed
Valenca 2000 {published data only}
    1. Valenca AM, Nardi AE, Nascimento I, Mezzasalma MA, Lopes FL, Zin W. Double‐blind clonazepam vs placebo in panic disorder treatment. Arquivos de Neuro‐Psiquiatria 2000;58(4):1025-9. - PubMed
Van Vliet 1993 {published data only}
    1. Van Vliet IM, Westenberg HGM, Den Boer JA. MAO inhibitors in panic disorder: clinical effects of treatment with brofaromine. Psychopharmacology 1993;112:483-9. - PubMed
Van Vliet 1996 {published data only}
    1. Vliet IM, den Boer JA, Westenberg HGM, Slaap BR. A double‐blind comparative study of brofaromine and fluvoxamine in outpatients with panic disorder. Journal of Clinical Psychopharmacology 1996;16(4):299-306. - PubMed
Versiani 2002 {published data only}
    1. Versiani M, Cassano G, Perugi G, Benedetti A, Mastalli L, Nardi A, et al. Reboxetine, a selective norepinephrine reuptake inhibitor, is an effective and well-tolerated treatment for panic disorder. Journal of Clinical Psychiatry 2002;63:31-7. - PubMed
Wade 1997 {published data only}
    1. Wade AG, Lepola U, Koponen HJ, Pedersen V, Pedersen T. The effect of citalopram in panic disorder. British Journal of Psychiatry 1997;170:549-53. - PubMed
Zhang 2000 {published data only}
    1. Zhang HY, Zhao QP, Ma C. Paroxetine versus clomipramine for the treatment of panic disorders: a double‐blind randomised study. Chinese Mental Health Journal 2000;14(6):410-3.

References to studies excluded from this review

Ananth 1979 {published data only}
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Bakish 1994 {published data only}
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Baldini Rossi 2000 {published data only}
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Balon 1991 {published data only}
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Bernardi 1998 {published data only}
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Bueno 1988 {published data only}
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Bystritsky 1990 {published data only}
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Charney 1986 {published data only}
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Chen 1997 {published data only}
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Chen 1998 {published data only}
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Chen 2003 {published data only}
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Chouinard 1983 {published data only}
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Chounaird 1982 {published data only}
    1. Chouinard G, Annable L, Fontaine R, Solyom L. Alprazolam in the treatment of generalized anxiety and panic disorders: a double‐blind placebo‐controlled study. Psychopharmacology 1982;77(3):229-33. - PubMed
Cohn 1984 {published data only}
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Cooper 1990 {published data only}
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Cooper 1991 {published data only}
    1. Cooper SJ, Gilliland A, Kelly C, McGilloway S. A comparison of beta‐2‐adrenoceptor antagonist (ICI 118,551), diazepam and placebo in the treatment of acute anxiety. Journal of Psychopharmacology 1991;5(2):155-9. - PubMed
Csanalosi 1977 {published data only}
    1. Csanalosi I, Pereira Ogan J, Case G, Werblowsky J, Rickels K. Triflubazam (ORF 8063), a new benzodiazepine in anxiety neurosis. Current Therapeutic Research, Clinical and Experimental 1977;22(1):166-71.
Cunha 1988 {published data only}
    1. Cunha JM, Swicker AP. Anti‐anxiety activity of cannabidiol; double‐blind, comparative trial with diazepam and placebo [Efeito ansiolítico do canabidiol; um estudo comparativo duplo‐cego com diazepam e placebo. R. Cent. Ci.c Bioméd. Univ. Fed. Uberlândia 1988;4(1):27-34.
Dager 1992 {published data only}
    1. Dager SR, Roy‐Byrne PP, Hendrickson H, Cowley DS, Avery DH, Hall KC, et al. Long‐term outcome of panic states during double‐blind treatment and after withdrawal of alprazolam and placebo. Annals of Clinical Psychiatry 1992;4(4):251-8.
Dasberg 1974 {published data only}
    1. Dasberg H. The effect of daily oral dosage of diazepam, plasma concentrations and metabolic clearance of diazepam and demethyldiazepam on various constituents of the acute clinical anxiety syndrome. Psychotherapy and Psychosomatics 1974;24(2):113-8. - PubMed
Davis 1981 {published data only}
    1. Davis JM, Nasr S, Spira N, Vogel C. Anxiety: differential diagnosis and treatment from a biologic perspective. Journal of Clinical Psychiatry 1981;42(11 Pt 2):4-14. - PubMed
De Candia 2009 {published data only}
    1. De Candia MP, DiSciascio G, Durbano F, Mencacci C, Rubiera M, Aguglia E, et al. Effects of treatment with etizolam 0.5 mg BID on cognitive performance: a 3‐week, multicenter, randomized, double‐blind, placebo‐controlled, two‐treatment, three‐period, noninferiority crossover study in patients with anxiety disorder. Clinical Therapeutics 2009;31(12):2851-9. - PubMed
de Jonghe 1989 {published data only}
    1. Jonghe F, Swinkels J, Tuynman‐Qua H, Jonkers F. A comparative study of suriclone, lorazepam and placebo in anxiety disorder. Pharmacopsychiatry 1989;22(6):266-71. - PubMed
Dell'Erba 2006 {published data only}
    1. Dell'Erba GL, Nuzzo E. Effectiveness treatment for panic and agoraphobia in comparison between drug and specialized psychological treatment [Il trattamento efficace nella pratica del disturbo di panico e agorafobia in una valutazione comparativa tra psicofarmacologia e trattamento psicologico specifico]. Rivista di Psichiatria 2006;41(6):397-403.
den Boer 1987 {published data only}
    1. den Boer JA, Westenberg HG, Kamerbeek WD, Verhoeven WM, Kahn RS. Effect of serotonin uptake inhibitors in anxiety disorders; a double‐blind comparison of clomipramine and fluvoxamine. International Clinical Psychopharmacology 1987;2(1):21-32. - PubMed
De Rosa 1980 {published data only}
    1. De Rosa E, De Rosa G, Coppi R, Zannella F, Pepe C. Randomized double‐blind study of loxapine as compared with diazepam in therapy of patients with anxiety neuroses [Ricerca in doppio cieco randomizzata sulla loxapina in comparazione al diazepam nell'ambito di pazienti affeti da nevrosi d'ansia]. Clinica Terapeutica 1980;95(2):127-46. - PubMed
Downing 1978 {published data only}
    1. Downing RW, Rickels K. Prediction of response to chlordiazepoxide and placebo in anxious outpatients: an attempt at replication. Pharmakopsychiatr Neuropsychopharmakol 1978;11(5):207-19. - PubMed
Downing 1979 {published data only}
    1. Downing RW, Rickels K, Rickels LA, Downing D. Nonspecific factors and side effect complaints. Factors affecting the incidence of drowsiness in drug and placebo treated anxious and depressed outpatients. Acta Psychiatrica Scandinavica 1979;60(5):438-48. - PubMed
Downing 1983 {published data only}
    1. Downing RW, Rickels K. Physician prognosis in relationship to drug and placebo response in anxious and depressed psychiatric outpatients. Journal of Nervous and Mental Disease 1983;171(3):182-5. - PubMed
Dunner 1986 {published data only}
    1. Dunner DL, Ishiki D, Avery DH, Wilson LG, Hyde TS. Effect of alprazolam and diazepam on anxiety and panic attacks in panic disorder: a controlled study. Journal of Clinical Psychiatry 1986;47(9):458-60. - PubMed
Dyukova 1992 {published data only}
    1. Dyukova GM, Shepeleva IP, Vorob'eva OV. Treatment of negative crises (panic attacks). Neuroscience and Behavioral Physiology 1992;22(4):343-5. - PubMed
Dyukova 1993 {published data only}
    1. Dyukova GM, Shepeleva IP, Vorov'eva OV. Treatment of autonomic attacks (panic attacks). Journal of Russian and East European Psychiatry 1993;26(1):22-7.
Evans 1986 {published data only}
    1. Evans L, Kenardy J, Schneider P, Hoey H. Effect of a selective serotonin uptake inhibitor in agoraphobia with panic attacks. A double‐blind comparison of zimeldine, imipramine and placebo. Acta Psychiatrica Scandinavica 1986;73(1):49-53. - PubMed
Fahy 1992 {published data only}
    1. Fahy TJ, O'Rourke D, Brophy J, Schazmann W, Sciascia S. The Galway Study of Panic Disorder. I: Clomipramine and lofepramine in DSM III‐R panic disorder: a placebo controlled trial. Journal of Affective Disorders 1992;26(1):63-75. - PubMed
Fava 1989 {published data only}
    1. Fava M, Rosenbaum JF, MacLaughlin RA, Tesar GE, Pollack MH, Cohen LS, et al. Dehydroepiandrosterone‐sulfate/cortisol ratio in panic disorder. Psychiatry Research 1989;28:345-50. - PubMed
Filip 1981 {published data only}
    1. Filip V, Sladka R, Dostalova J, Haskovcova V, Jarosova M, Faltus F, et al. A double‐blind, placebo‐controlled study with tofizopam in anxiety neurosis. Agressologie 1981;22(C):27-30. - PubMed
Franulic 1989 {published data only}
    1. Franulic AM, Sanchez GV, O'Ryan FG, Gladic DM, Barahona MC, Gloger SK. Clomipramine and diazepam plasma levels in panic disorder and agoraphobia. Preliminary findings [Concentraciones plasmaticas de clomipramina y diazepam en Desorden de Panico y Agoraphobia. Un estudio preliminar]. Revista Chilena de Neuro‐Psiquiatria 1989;27:101-10.
Furukawa 2009 {published data only}
    1. Furukawa TA, Katherine Shear M, Barlow DH, Gorman JM, Woods SW, Money R, et al. Evidence‐based guidelines for interpretation of the Panic Disorder Severity Scale. Depression and Anxiety 2009;26(10):922-9. - PMC - PubMed
Greiss 1980 {published data only}
    1. Greiss KC, Fogari R. Double‐blind clinical assessment of alprazolam, a new benzodiazepine derivative, in the treatment of moderate to severe anxiety. Journal of Clinical Pharmacology 1980;20(11-12):693-9. - PubMed
Grilo 1988 {published data only}
    1. Grilo CM, Money R, Barlow DH, Goddard AW, Gorman JM, Hofmann SG, et al. Pretreatment patient factors predicting attrition from a multicenter randomized controlled treatment study for panic disorder. Comprehensive Psychiatry 1998;39(6):323-32. - PubMed
Hare 1974 {published data only}
    1. Hare MK. Treatment of anxiety and depression: a comparative trial of amitriptyline (Laroxyl) and diazepam (Valium). Clinical Trials Journal 1974;11(1):39-44.
Hofmeijer‐Sevink 2017 {published data only}
    1. Hofmeijer‐Sevink MK, Duits P, Rijkeboer MM, Hoogendoorn AW, 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. Journal of Clinical Psychopharmacology 2017;37(5):531-9. - PubMed
Hu 2002 {published data only}
    1. Hu H, Meng HQ. A comparative study in psychotherapy and drug in treatment of anxiety disorders. Chinese Journal of Nervous and Mental Diseases 2002;28(2):85-7.
Huppert 2004 {published data only}
    1. Huppert JD, Schultz LT, Foa EB, Barlow DH, Davidson JR, Gorman JM, et al. Differential response to placebo among patients with social phobia, panic disorder, and obsessive‐compulsive disorder. American Journal of Psychiatry 2004;161(8):1485-7. - PubMed
Kahn 1986 {published data only}
    1. Kahn RJ, McNair DM, Lipman RS, Covi L, Rickels K, Downing R, et al. Imipramine and chlordiazepoxide in depressive and anxiety disorders. II. Efficacy in anxious outpatients. Archives of General Psychiatry 1986;43(1):79-85. - PubMed
Kaplan 2000 {published data only}
    1. Kaplan GB, Greenblatt DJ, Ehrenberg BL, Goddard JE, Harmatz JS, Shader RI. Differences in pharmacodynamics but not pharmacokinetics between subjects with panic disorder and healthy subjects after treatment with a single dose of alprazolam. Journal of Clinical Psychopharmacology 2000;20(3):338-46. - PubMed
Keller 1993 {published data only}
    1. Keller MB, Lavori PW, Goldenberg IM, Baker LA, Pollack MH, Sachs GS, et al. Influence of depression on the treatment of panic disorder with imipramine, alprazolam and placebo. Journal of Affective Disorders 1993;28(1):27-38. - PubMed
Kerry 1983 {published data only}
    1. Kerry RJ, McDermott CM. Alprazolam in the treatment of neurotic anxiety. Pharmatherapeutica 1983;3(7):451-5. - PubMed
Klein 1988 {published data only}
    1. Klein DF. Nottingham study of neurotic disorder. Lancet 1988;2(8618):1915. - PubMed
Klerman 1990 {published data only}
    1. Klerman GL. Depression and panic anxiety: the effect of depressive co‐morbidity on response to drug treatment of patients with panic disorder and agoraphobia. Journal of Psychiatric Research 1990;24(Suppl 2):27-41. - PubMed
Knijnik 1990 {published data only}
    1. Knijnik L, D'Arrigo BE. Comparative study of cloxazolam and placebo in anxiety neurosis [Estudo comparativo sobre o emprego do cloxazolam e placebo em neurose de ansiedade]. Jornal Brasileiro de Psiquiatria 1990;39(4):209-12.
Laakmann 1980 {published data only}
    1. Laakmann G, Blaschke D, Buttermann M, Hippius H, Schewe S, Uberla K. Double blind study with the benzodiazepine derivative Ka‐2547 in outpatients with anxiety neurosis [Doppelblindstudie mit dem Benzodiazepin‐Derivat Ka‐2547 bei ambulanten Patienten mit Angstneurose]. Arzneimittelforschung 1980;30(8):1233-4.
Lapierre 1975 {published data only}
    1. Lapierre YD. Clinical and physiological assessment of chlorazepate, diazepam and placebo in anxious neurotics. International Journal of Clinical Pharmacology and Biopharmacy 1975;11(4):315-22. - PubMed
Lepola 1989 {published data only}
    1. Lepola U, Jolkkonen J, Rimón R, Riekkinen P. Long‐term effects of alprazolam and imipramine on cerebrospinal fluid monoamine metabolites and neuropeptides in panic disorder. Neuropsychobiology 1989;2(4):182-6. - PubMed
Lorch 1995 {published data only}
    1. Lorch B, Graf‐Morgenstern M, Hain C, Sandmann J, Schlegel S, Hautzinger M, et al. Treatment of panic disorder: pharmacological versus behavioral therapy? Pharmacopsychiatry 1995;28:199.
Marks 1993 {published data only}
    1. Marks IM, Swinson RP, Basoglu M, Kuch K, Noshirvani H, O'Sullivan G, et al. Alprazolam and exposure alone and combined in panic disorder with agoraphobia. A controlled study in London and Toronto. British Journal of Psychiatry 1993;162:776-87. - PubMed
Mavissakalian 1982 {published data only}
    1. Mavissakalian M, Michelson L. Agoraphobia: behavioral and pharmacological treatments, preliminary outcome, and process findings. Psychopharmacology Bulletin 1982;18(4):91-103. - PubMed
Mavissakalian 2003 {published data only}
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McCurdy 1978 {published data only}
    1. McCurdy L, Schatzberg AF. Studies with oral lorazepam in anxiety neurosis associated with depressive symptomatology. Journal of Clinical Psychiatry 1978;39(10 Pt 2):30-4. - PubMed
McEvilly 1981 {published data only}
    1. McEvilly JP, Etemad B. Double‐blind comparison in parallel groups with nightly single doses of halazepam and placebo[Comparacion dobleciega en grupos paralelos con dosis unicas nocturnas de halazepam y placebo]. Investigación Médica Internacional 1981;8(2):202-8.
McHugh 2007 {published data only}
    1. McHugh RK, Otto MW, Barlow DH, Gorman JM, Shear MK, Woods SW. Cost‐efficacy of individual and combined treatments for panic disorder. Journal of Clinical Psychiatry 2007;68(7):1038-44. - PubMed
Mellman 1986 {published data only}
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Miretzky 1992 {published data only}
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Mueller 1986 {published data only}
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Muncy 1981 {published data only}
    1. Muncy SM. Panic: a comparison of four treatment methods. Dissertation Abstracts International 1991;51(12-B Pt 1):6115.
Nair 1982 {published data only}
    1. Nair NP, Singh AN, Lapierre Y, Saxena BM, Nestoros JN, Schwartz G. Ketazolam in the treatment of anxiety: a standard and placebo controlled study. Current Therapeutic Research, Clinical & Experimental 1982;31(5):679-91.
Nanivadekar 1973 {published data only}
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Nardi 2011 {published data only}
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Ogunremi 1973 {published data only}
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Padron 1974 {published data only}
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Pareek 2014 {published data only}
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Pasini 1972 {published data only}
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Pfizer 2002 {published data only}
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Pfizer 2005 {published data only}
    1. Pfizer. Pilot study of venlafaxine extended release (XR) in the treatment of panic disorder (PD) in comparison to paroxetine. http://clinicaltrials.gov/show/NCT00195598 (first received 19 September 2005).
Piedade 1987 {published data only}
    1. Piedade RAM, Sougey EB, Almeida FJB, Knijnik L, Barros Camargo I, Del Porto JA, et al. Efficacy of cloxazolam versus placebo in the therapy of anxious status: double‐blind controlled study [Estudo da efic cia do cloxazolam versus placebo na terapia de estados ansiosos: estudo duplocego controlado]. Jornal Brasileiro de Psiquiatri 1987;36(3):189-97.
Pohl 1989a {published data only}
    1. Pohl R, Rickels K, Charney D. Clinical results on the use of lorazepam to treat panic attacks [Risultati clinici sull'uso del lorazepam nel disturbo da attacchi di panico]. Rivista di Psichiatri 1989;24(2):99-100.
Pollack 2002 {published data only}
    1. Pollack MH, Rapaport MH, Fayyad R, Otto MW, Nierenberg AA, Clary CM. Early improvement predicts endpoint remission status in sertraline and placebo treatments of panic disorder. Journal of Psychiatric Research 2002;36(4):229-36. - PubMed
Pollack 2003 {published data only}
    1. Pollack MH, Simon NM, Worthington JJ, Doyle AL, Peters P, Toshkov F, et al. Combined paroxetine and clonazepam treatment strategies compared to paroxetine monotherapy for panic disorder. Journal of Psychopharmacology 2003;17(3):276-82. - PubMed
Pols 1996 {published data only}
    1. Pols H, Verburg K, Hauzer R, Meijer J, Griez E. Alprazolam premedication and 35% carbon dioxide vulnerability in panic patients. Biological Psychiatry 1996;40(9):913-7. - PubMed
Porta 1974 {published data only}
    1. Porta V, Jann G, Delzanno GB. Comparative double‐blind clinical trial of SB 5833 and temazapam [Essai clinique compare, en double aveugle, du SB 5833 et du temazepam]. Bruxelles Medical 1974;54(11):655-8. - PubMed
Predescu 1969 {published data only}
    1. Predescu V, Ciurezu T, Romila A, Piree S, Ionescu G, Roman I, et al. The "double‐blind" procedure in study of the anxiolytic effects of the preparation Wy 3498 (Oxazepam). Evaluation of anxiety states with the Hamilton scale (HS) [Procedeul "dubluorb" in studiul efectelor anxiolitice ale preparatului Wy 3498 (Oxazepam). Evaluarea starilor de anxietate la scala Hamilton (SH)]. Neurologia, Psihiatria, Neurochirurgia 1969;14(2):153-65. - PubMed
Pyke 1989 {published data only}
    1. Pyke RE, Greenberg HS. Double‐blind comparison of alprazolam and adinazolam for panic and phobic disorders. Journal of Clinical Psychopharmacology 1989;9(1):15-21. - PubMed
Raffaele 2002 {published data only}
    1. Raffaele R, Vecchio I, Malaguarnera M, Rampello L, Ruggieri M, Nicoletti F. Therapy of panic attacks in the elderly. Archives of Gerontology and Geriatrics. Supplement 2002;8:295-301. - PubMed
Rapaport 2000 {published data only}
    1. Rapaport MH, Gladsjo J, McKinney R, Auerbach M, Hahn T, Rabin A, et al. Alprazolam‐XR and neuropsychological function in panic disorder. International Journal of Neuropsychopharmacology 2000;3(Suppl 1):272.
Rifkin 1991 {published data only}
    1. Rifkin A. The sequence of improvement of the symptoms encountered in patients with panic disorder. Comprehensive Psychiatry 1991;32(6):559-60. - PubMed
Rizley 1986 {published data only}
    1. Rizley R, Kahn RJ, McNair DM, Frankenthaler LM. A comparison of alprazolam and imipramine in the treatment of agoraphobia and panic disorder. Psychopharmacology Bulletin 1986;22(1):167-72. - PubMed
Roll 2004 {published data only}
    1. Roll D, Ray SE, Marcus SM, Passarelli V, Money R, Barlow DH, et al. Independent evaluator knowledge of treatment in a multicenter comparative treatment study of panic disorder. Neuropsychopharmacology 2004;29(3):612-8. - PubMed
Roy‐Byrne 2001 {published data only}
    1. Roy‐Byrne PP, Katon W, Cowley DS, Russo J. A randomized effectiveness trial of collaborative care for patients with panic disorder in primary care. Archives of General Psychiatry 2001;58(9):869-76. - PubMed
Rynn 2003 {published data only}
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References to other published versions of this review

Guaiana 2020
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