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Meta-Analysis
. 2019 Mar 28;3(3):CD010677.
doi: 10.1002/14651858.CD010677.pub2.

Benzodiazepines versus placebo for panic disorder in adults

Johanna Breilmann  1 , Francesca Girlanda, Giuseppe Guaiana, Corrado Barbui, Andrea Cipriani, Mariasole Castellazzi, Irene Bighelli, Simon Jc Davies, Toshi A Furukawa, Markus Koesters
Affiliations
Meta-Analysis

Benzodiazepines versus placebo for panic disorder in adults

Johanna Breilmann et al. Cochrane Database Syst Rev. .

Abstract

Background: Panic disorder is characterised by recurrent unexpected panic attacks consisting of a wave of intense fear that reaches a peak within a few minutes. Panic disorder is a common disorder, with an estimated lifetime prevalence of 1% to 5% in the general population and a 7% to 10% prevalence in primary care settings. Its aetiology is not fully understood and is probably heterogeneous.Panic disorder is treated with psychological and pharmacological interventions, often used in combination. Although benzodiazepines are frequently used in the treatment of panic disorder, guidelines recommend antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), as first-line treatment for panic disorder, particularly due to their lower incidence of dependence and withdrawal reaction when compared to benzodiazepines. Despite these recommendations, benzodiazepines are widely used in the treatment of panic disorder, probably because of their rapid onset of action.

Objectives: To assess the efficacy and acceptability of benzodiazepines versus placebo in the treatment of panic disorder with or without agoraphobia in adults.

Search methods: We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR Studies and References), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950-), Embase (1974-), and PsycINFO (1967-) up to 29 May 2018. We handsearched reference lists of relevant papers and previous systematic reviews. We contacted experts in the field for supplemental data.

Selection criteria: All double-blind (blinding of patients and personnel) controlled trials randomising adults with panic disorder with or without agoraphobia to benzodiazepine or placebo.

Data collection and analysis: Two review authors independently checked the eligibility of studies and extracted data using a standardised form. Data were then entered data into Review Manager 5 using a double-check procedure. Information extracted included study characteristics, participant characteristics, intervention details, settings, and outcome measures in terms of efficacy, acceptability, and tolerability.

Main results: We included 24 studies in the review with a total of 4233 participants, of which 2124 were randomised to benzodiazepines and 1475 to placebo. The remaining 634 participants were randomised to other active treatments in three-arm trials. We assessed the overall methodological quality of the included studies as poor. We rated all studies as at unclear risk of bias in at least three domains. In addition, we judged 20 of the 24 included studies as having a high risk of bias in at least one domain.Two primary outcomes of efficacy and acceptability showed a possible advantage of benzodiazepines over placebo. The estimated risk ratio (RR) for a response to treatment was 1.65 (95% confidence interval (CI) 1.39 to 1.96) in favour of benzodiazepines, which corresponds to an estimated number needed to treat for an additional beneficial outcome (NNTB) of 4 (95% CI 3 to 7). The dropout rate was lower among participants treated with benzodiazepines (RR 0.50, 95% CI 0.39 to 0.64); the estimated NNTB was 6 (95% CI 5 to 9). We rated the quality of the evidence as low for both primary outcomes. The possible advantage of benzodiazepine was also seen for remission (RR 1.61, 95% CI 1.38 to 1.88) and the endpoint data for social functioning (standardised mean difference (SMD) -0.53, 95% CI -0.65 to -0.42), both with low-quality evidence. We assessed the evidence for the other secondary outcomes as of very low quality. With the exception of the analyses of the change score data for depression (SMD -0.22, 95% CI -0.48 to 0.04) and social functioning (SMD -0.32, 95% CI -0.88 to 0.24), all secondary outcome analyses showed an effect in favour of benzodiazepines compared to placebo. However, the number of dropouts due to adverse effects was higher with benzodiazepines than with placebo (RR 1.58, 95% CI 1.16 to 2.15; low-quality evidence). Furthermore, our analyses of adverse events showed that a higher proportion of participants experienced at least one adverse effect when treated with benzodiazepines (RR 1.18, 95% CI 1.02 to 1.37; low-quality evidence).

Authors' conclusions: Low-quality evidence shows a possible superiority of benzodiazepine over placebo in the short-term treatment of panic disorders. The validity of the included studies is questionable due to possible unmasking of allocated treatments, high dropout rates, and probable publication bias. Moreover, the included studies were only short-term studies and did not examine the long-term efficacy nor the risks of dependency and withdrawal symptoms. Due to these limitations, our results regarding the efficacy of benzodiazepines versus placebo provide only limited guidance for clinical practice. Furthermore, the clinician's choice is not between benzodiazepines and placebo, but between benzodiazepines and other agents, notably SSRIs, both in terms of efficacy and adverse effects. The choice of treatment should therefore be guided by the patient's preference and should balance benefits and harms from treatment in a long-term perspective.

PubMed Disclaimer

Conflict of interest statement

JB: none.

FG: none.

GG: none.

CB: none.

AC: none.

MC: none.

IB: none.

SJD: none.

TAF has received lecture fees from Eli Lilly, Janssen, Meiji, Mitsubishi‐Tanabe, MSD, and Pfizer and consultancy fees from Takeda Science Foundation. He has received royalties from Igaku‐Shoin and Nihon Bunka Kagaku‐sha publishers. He has received research support from Mochida and Mitsubishi‐Tanabe. He is diplomate of the Academy of Cognitive Therapy.

MK: none.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Forest plot of comparison: 1 Benzodiazepines versus placebo, outcome: 1.1 Treatment response.
5
5
Forest plot of comparison: 1 Benzodiazepines versus placebo, outcome: 1.2 Total number of dropouts.
6
6
Funnel plot of comparison: 1 Benzodiazepines versus placebo, outcome: 1.1 Treatment response.
7
7
Funnel plot of comparison: 1 Benzodiazepines versus placebo, outcome: 1.2 Total number of dropouts.
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD010677

References

References to studies included in this review

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    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(3):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 MA, Sanchez VG, O'Ryan GF, Gladic MD, Barahona CM, Gloger KS. Clomipramine and diazepam plasma levels in panic disorder and agoraphobia: preliminary findings [Concentraciones plasm ticas de clomipramina y diazepam en desorden de p nico y agorafobia: un estudio preliminar]. Revista Chilena de Neuro‐psiquiatria 1989;27(2):101–10.
    1. Gloger KS, Gladic MD, O'Ryan GF, Barahona CM. Clomipramine and diazepam in the treatment of panic anxiety: a double‐blind comparison study. Unpublished.
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
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
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    1. Shear MK, Leon AC, Pollack MH, Rosenbaum JF, Keller MB. Pattern of placebo response in panic disorder. Psychopharmacology Bulletin 1995;31(2):273‐8. - 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):1015. - PubMed
Klerman 1990 {published data only}
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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
Lorch 1995 {published data only}
    1. Lorch B, Graf‐Morgenstern M, Hain C, Sandmann J, Schlegel S, Hautzinger M, Benkert O. Treatment of panic disorder: pharmacological versus behavioral therapy?. Pharmacopsychiatry 1995;28:199.
Marks 1993 {published data only}
    1. Bond AJ, Curran HV, Bruce MS, O'Sullivan G, Shine P. Behavioural aggression in panic disorder after 8 weeks' treatment with alprazolam. Journal of Affective Disorders 1995;35(3):117‐23. - PubMed
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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
    1. Michelson L, Mavissakalian M. Psychophysiological outcome of behavioral and pharmacological treatments of agoraphobia. Journal of Consulting and Clinical Psychology 1985;53(2):229‐36. - PubMed
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]. Invest med int 1981;8(2):202‐8.
Mellman 1986 {published data only}
    1. Mellman TA, Uhde TW. Withdrawal syndrome with gradual tapering of alprazolam. American Journal of Psychiatry 1986;143(11):1464‐6. - PubMed
Miretzky 1992 {published data only}
    1. Miretzky A, Horn R, Koehler K, Moller HJ. Combination of alprazolam, antidepressive drugs and cognitive behavior therapy in the treatment of panic disorder. Clinical Neuropharmacology 1992;15(1 Pt B):536.
Mueller 1986 {published data only}
    1. Mueller AA, Binz U, Wendt G, Stoll KD. Treatment outcomes of diazepam and oxprenolol with anxiety neurosis patients [Therapieerfolge von Diazepam und Oxprenolol bei Patienten mit Angstneurose]. Angst und Psychopharmaka: Methoden und Ergebnisse pharmakopsychologischer, pharmakopsychiatrischer und verhaltenspharmakologischer Forschung. 1986:261‐70.
Muncy 1991 {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 and Experimental 1982;31(5):679‐91.
Nanivadekar 1973 {published data only}
    1. Nanivadekar AS, Wig NN, Khorana AB, Master RS, Kulkarni SS. A multicenter investigation of lorazepam in anxiety neurosis. Current Therapeutic Research, Clinical and Experimental 1973;15(7):500‐7. - PubMed
Ogunremi 1973 {published data only}
    1. Ogunremi OO, Adamson L, Brezinová V, Hunter WM, Maclean AW, Oswald I, et al. Two anti‐anxiety drugs: a psychoneuroendocrine study. British Medical Journal 1973;2(5860):202‐5. - PMC - PubMed
Padron 1974 {published data only}
    1. Padron C. Comparative clinical evaluation of lorazepam [Essai clinique comparatif lorazepamdiazepam]. Schweizerische Rundschau fur Medizin Praxis 1974;63(16):494‐6. - PubMed
Pasini 1972 {published data only}
    1. Pasini E. Double blind study on the use of medazepam in ambulatory therapy] [Etude en doubleaveugle sur l'emploi du medazepam en therapeutique ambulatoire]. Cahiers de Médecine (Europa Medica) 1972;13(6):456‐7. - PubMed
Piedade 1987 {published data only}
    1. Piedade RAM, Sougey EB, Almeida FJB, Knijnik L, Barros Camargo I, Porto JA, Marcolin MA, Coutinho DM, Shirakawa I, Scibel S, Munhoz FEP, Almeida Lourenco LC, Nardi AE. 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 Psiquiatria 1987;36(3):189‐97.
Pollack 1998 {published data only}
    1. Pollack MH, Otto MW, Worthington JJ, Manfro GG, Wolkow R. Sertraline in the treatment of panic disorder: A flexible‐dose multicenter trial. Archives of General Psychiatry 1998;55(11):1010‐6. - PubMed
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
Pols 1996 {published data only}
    1. Pols H. Alprazolam premedication and 35% CO2 vulnerability in panic patients. 8th Congress of the Association of European Psychiatrists. London, UK, 1996.
    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
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 2002;35(Suppl 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
Rynn 2003 {published data only}
    1. Rynn M, Garcia‐Espana F, Greenblatt DJ, Mandos LA, Schweizer E, Rickels K. Imipramine and buspirone in patients with panic disorder who are discontinuing long‐term benzodiazepine therapy. Journal of Clinical Psychopharmacology 2003;23(5):505‐8. - PubMed
Saiz‐Ruiz 1992 {published data only}
    1. Saiz‐Ruiz J, Ibanez A. Personality traits and treatment response in panic disorder. Clinical Neuropharmacology 1992;15(1 Pt B):533.
Scieghi 1986 {published data only}
    1. Scieghi G, Levi‐Minzi A, Greco C. The intravenous infusion use of chlordemethyldiazepam in neurotic anxiety [Psicopatologia e psicofarmacologia dell'ansia nevrotica A proposito dell'impiego del clordemetildiazepam per infusione venosa]. Rivista Sperimentale Freniatria 1986;3:531‐42.
Sladka 1979 {published data only}
    1. Sladka R, Dostalova J, Haskovcova V, Jarosova M, Faltus F, Slanska J, et al. A placebo‐controlled clinical trial with tofizopam in the treament of anxiety neurosis. Therapia Hungarica 1979;27(4):176‐80. - PubMed
    1. Sladka R, Dostalova J, Haskovcova V, Jarosova M, Faltus F, Slanska J, et al. Placebo controlled clinical trial of tofisopam in treatment of anxiety neurosis [Placebokontrollierte klinische Untersuchung von Tofizopam in der Behandlung der Angstneurose]. Therapia Hungarica 1979;27(4):178‐83. - PubMed
Sonne 1986 {published data only}
    1. Sonne LM, Bruun Hansen J. Alprazolam (Tafil) and bromazepam (Lexotan) in the treatment of anxiety: a randomized, double‐blind comparison in psychiatric outpatients [Alprazolam (Tafil) og bromazepam (Lexotan) i angstbehandlingen En randomiseret, dobbeltblind sammenligning fra psykiatrisk specialpraksis]. Ugeskrift for Laeger 1986;148(23):1392‐5. - PubMed
Taylor 1982 {published data only}
    1. Taylor CB, Kenigsberg ML, Robinson JM. A controlled comparison of relaxation and diazepam in panic disorder. Journal of Clinical Psychiatry 1982;43(10):423‐5. - PubMed
Telch 1985 {published data only}
    1. Telch MJ, Agras WS, Taylor CB, Roth WT, Gallen CC. Combined pharmacological and behavioral treatment for agoraphobia. Behaviour Research and Therapy 1985;23(3):325‐35. - PubMed
Terra 1971 {published data only}
    1. Terra SO, Bueno JR, Pires LL. Evaluation of the anti‐anxiety activity of lorazepam in ambulatory patients [Avaliacao da atividade ansiolitica dolorazepam empacientes de ambulatorio]. Jornal Brasileiro de Psiquiatria 1971;20(3):237‐47. - PubMed
Tesar 1990 {published data only}
    1. Tesar GE. High‐potency benzodiazepines for short‐term management of panic disorder: the US experience. Journal of Clinical Psychiatry 1990;51(5 Suppl):4‐10. - PubMed
Tyrer 1984 {published data only}
    1. Tyrer P, Owen R. Anxiety in primary care: is short‐term drug treatment appropriate?. Journal of Psychiatric Research 1984;18(1):73‐8. - PubMed
Van Balkom 1996 {published data only}
    1. Balkom AJ, Beurs E, Koele P, Lange A, Dyck R. Long‐term benzodiazepine use is associated with smaller treatment gain in panic disorder with agoraphobia. Journal of Nervous and Mental Disease 1996;184(2):133‐5. - PubMed
Van Boeijen 2007 {published data only}
    1. Boeijen C, Oppen P, Boeke J, Visser S, Kempe P, Blankenstein N, et al. First‐line treatment of anxiety disorders: a randomized controlled trial [Angststoornissen in de eerste lijn vaak goed te behandelen: Een gerandomiseerd gecontroleerd onderzoek]. Huisarts en Wetenschap 2007;50(7):315‐20.
Versiani 1983 {published data only}
    1. Versiani M, Bueno JR. Evaluation of the use of cloxazolam in patients with moderate anxiety [Avaliacao do emprego do cloxazolam em portadores de ansiedade moderada]. Jornal Brasileiro de Psiquiatria 1983;32(1):27‐30.
Wiesner 1993 {published data only}
    1. Wiesner J, Grunder G, Wetzel H, Hiemke C. Bretazenil: neuroendocrinological profile of a partial benzodiazepine agonist in patients suffering from panic disorder with agoraphobia. Pharmacopsychiatry 1993;26:212.
Woods 1988 {published data only}
    1. Woods WS, Charney SD, Silver MJ, Krystal HJ, Heninger RG. Benzodiazepine receptor antagonist effects in panic disorder. 141st Annual Meeting of the American Psychiatric Association. Montreal, Quebec, 7‐12th May 1988.
Zmorski 1985 {published data only}
    1. Zmorski T, Fischer Cornelssen KA. [ Clinical experiences with the new‐generation anxiolytic agent cloxazolam: a double‐blind study. ] Klinische Erfahrungen mit dem Anxiolytikum der neuen Generation: CloxazolamEine Doppelblindstudie. Schweizerische Rundschau fur Medizin Praxis 1985;74(27):728‐34. - PubMed

References to studies awaiting assessment

Anon 1994 {published data only}
    1. Placebo‐controlled study of efficacy of imipramine, diazepam, baclofen and propranolol in patients with panic disorder [Sravnitelnoe issledovanie effektivnosti imipramina, diazepama, baklofena, propranolola i platsebo u bolnykh s panicheskim rasstroistvom]. Obozrenie Psikhiatrii Med Psikhologii Im V M Bekhtereva 1994:43–50.
Bernik 1983 {published data only}
    1. Bernik V, Katz PD, Bernik MA. Therapeutic of anxiety: a double blind clinical trial between alprazolam, oxazepam and placebo [Terapeutica da ansiedade: estudo clinico duplocego comparativo entre alprazolam, oxazepam e placebo]. RBM Psiquiatr 1983;1983:176–89.
Ciraulo 1990 {published data only}
    1. Ciraulo DA, Antal EJ, Smith RB, Olson DR, Goldberg DA, Rand EH, et al. The relationship of alprazolam dose to steady‐state plasma concentrations. Journal of Clinical Psychopharmacology 1990;10(1):27‐32. - PubMed
Coryell 1989 {published data only}
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Fisekovic 2005 {published data only}
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Gladsjo 1997 {published data only}
    1. Gladsjo JA, Rapaport MH, McKinney RA, Rabin A, Auerbach MD, Judd LL. Impact of alprazolam on neuropsychological functioning in panic disorder. 150th Annual Meeting of the American Psychiatric Association; 1997 May 17‐22; San Diego, CA. 1997.
Ipca Laboratories {published data only}
    1. Ipca Laboratories Ltd, Mumbai. Comparative evaluation of efficacy and safety of clonazepam‐CR, alprazolam‐XR and placebo in patients with panic disorder. WHO International Clinical Trials Registry Platform. [http://apps.who.int/trialsearch/Trial.aspx?TrialID=CTRI/2012/01/002315] 2012.
Picano 1971 {published data only}
    1. Picanco PE, Bacellar BB, Lobo‐Ponte HM, Fortaleza CB. Clinical trials with a new anti‐anxiety drug, lorazepam. V World Congress of Psychiatry. Mexico City, 1971 Nov 28‐Dec 4:950.
Tesar 1988 {published data only}
    1. Tesar EG, Rosenbaum FJ, Pollack HM, Sachs SG, Herman BJ, Sidari NJ. Panic disorder: clonezepam versus alprazolam and placebo. 141st Annual Meeting of the American Psychiatric Association; 1988 May 7‐12; Montreal, Quebec 1988.
Valenca 2003 {published data only}
    1. Valenca AM, Nardi AE, Mezzasalma MA, Nascimento I, Zin WA, Lopes FL, et al. Therapeutic response to benzodiazepine in panic disorder subtypes. Revista Paulista de Medicina (Sao Paulo Medical Journal) 2003;121(2):77‐80. - PMC - PubMed

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