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2005 13: 371Australas PsychiatryVladan Starcevic

Issues in the Pharmacological Treatment of Anxiety Disorders  

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Vladan StarcevicAssociate Professor, Discipline of Psychological Medicine,University of Sydney, and Nepean Hospital, Sydney, NSW,Australia.

Correspondence: Assoc Professor Vladan Starcevic,Department of Psychological Medicine, Nepean Hospital,PO Box 63, Penrith, NSW 2751, Australia.Email: starcev@wahs.nsw.gov.au

CLINICAL PSYCHIATRY Issues in the pharmacologicaltreatment of anxiety disorders

Vladan Starcevic

Objective: To review the most salient issues in the pharmacotherapy of anxi-ety disorders. These pertain to means of achieving greater efficacy, acceleratingthe onset of therapeutic action, improving side-effect profile and tolerability,decreasing the propensity to induce therapeutic dependence and achieving betterlong-term outcome.

Conclusions: By and large, pharmacological agents with greater efficacy inanxiety disorders have yet to be developed. Several strategies have been usedwith some success to make medications for anxiety disorders work faster and tolessen their side-effect burden. The field of psychopharmacology has yet to findways of lessening or eliminating the problem of therapeutic drug dependenceand, even more so, of minimizing the risk of relapse following the cessation ofmedication.

Key words: anxiety disorders, dependence, efficacy, pharmacotherapy, relapse.

A lthough significant advances have been made in the pharmacologicaltreatment of anxiety disorders, there is still much room for improve-ment. However, the specific goals of such improvement may vary

from one disorder to another, they generally include the following: (i) greaterefficacy; (ii) faster onset of therapeutic action; (iii) fewer side-effects andbetter tolerability; (iv) decreased propensity of the medications to inducetherapeutic dependence; and (v) better long-term outcome.

The purpose of this paper is to review developments contributing to theachievement of better results in the pharmacotherapy of anxiety disorders.

EFFICACYPharmacotherapy has not shown equal efficacy across all the anxiety dis-orders. Medications have been most effective in treating panic disorder,while showing lesser efficacy in the treatment of generalized anxiety disor-der (GAD) and social anxiety disorder (SAD). Pharmacological treatment hasbeen performing in the range of ‘marginal to good’ in post-traumatic stressdisorder (PTSD) and obsessive–compulsive disorder (OCD). Because they lackefficacy, medications are rarely used in the treatment of specific phobias.

In recent years, the efficacy of many pharmacological agents has been inves-tigated in anxiety disorders, with the goal of improving treatment outcome.Examples include use of escitalopram in panic disorder, GAD and SAD, use ofvenlafaxine in SAD and OCD, testing enhancers of gamma-aminobutyric acid(GABA) neurotransmission (tiagabine and vigabatrin) and agents that bindto the α2δ subunit of the voltage-gated calcium channels (pregabalin andgabapentin), and augmentation with second-generation antipsychotics ofthe selective serotonin re-uptake inhibitor (SSRI) treatment or clomipraminetreatment of OCD. The results of these studies, some of which involveddouble-blind, placebo-controlled trials or double-blind comparisons withother medications, did not reveal significant differences in the efficacy be-tween the novel agents and the standard, previously established drugs foranxiety disorders. Studies of augmentation strategies for treatment-resistantOCD produced conflicting results for olanzapine, but more consistent andfavourable results for risperidone.1−4

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ONSET OF THERAPEUTIC ACTIONOne of the main drawbacks of the antidepressant treat-ment of anxiety disorders in comparison to benzodi-azepines has been a slow onset of therapeutic action.This issue has been particularly salient for panic disorder,because of the high level of acute distress experienced bypanic patients. A delay in the onset of therapeutic actionoften means that patients have to endure the distress forrelatively long periods, while potentially experiencingsome of the side-effects of the antidepressants. This maylead to premature discontinuation of pharmacotherapy.

There have been two approaches to this problem. Thefirst involved combining an antidepressant and a ben-zodiazepine. In case of panic disorder, this strategy seemsto be beneficial, as the controlled studies demonstrated afaster onset of antipanic efficacy for the combinations ofimipramine and alprazolam, sertraline and clonazepamand paroxetine and clonazepam in comparison withimipramine, sertraline and paroxetine, respectively.5−7

In contrast, this advantage was not reported for the com-bination of paroxetine and clonazepam in the treatmentof SAD.8 Therefore, it is unclear whether antidepressant–benzodiazepine combinations might be associated withfaster onset of efficacy in anxiety disorders other thanpanic disorder.

The second approach has been the use of certain non-benzodiazepine agents. Several medications – mirtaza-pine in panic disorder and pregabalin in GAD andSAD – have been associated in a very preliminary waywith faster response, comparable to the speed of re-sponse to benzodiazepines.9−12 Likewise, in patientswith SAD, venlafaxine extended-release showed efficacyearlier than paroxetine.13 These findings obviously needto be replicated before any conclusion can be madeabout the potentially faster onset of therapeutic actionof these medications.

SIDE-EFFECTS AND TOLERABILITYApart from efficacy, the area of side-effects and toler-ability is the one where most claims are made aboutthe superiority of one drug over another. Agents usedfor anxiety disorders are no exception to this rule. Theside-effect profile becomes particularly important whenthere are no significant differences in efficacy, becausemedication choice is then often based on expected side-effects. Therefore, it is not a surprise that much researchhas focused on the side-effects of drugs, their tolerabilityand dropouts related to side-effects.

Of the antidepressants used for anxiety disorders, SSRIstend to be favoured over tricyclic antidepressants, be-cause the former are presumably associated with fewerside-effects and better tolerability. This view has beenchallenged by one study,14 which did not find a dif-ference in tolerability between SSRIs and imipramineamong patients with panic disorder. As for benzodi-azepines, panic patients seem to tolerate them better

than imipramine and SSRIs.15,16 This may be an im-portant reason for continued use of benzodiazepines inpanic disorder and even for their preference to SSRIs insome settings.17 Certain side-effects of the SSRIs, such aspropensity to cause insomnia and to worsen anxiety andinduce agitation in the initial treatment of panic disor-der and PTSD, have been particularly troublesome; thishas led some clinicians to prefer to use tricyclic antide-pressants or benzodiazepines.

There have been few comparisons between differentSSRIs, and their results are inconclusive. Thus, in onestudy comparing sertraline and paroxetine in the treat-ment of panic disorder, sertraline was significantly lessassociated with weight gain and worsening during taper,and it was significantly better tolerated.18 In contrast,no significant differences were found in terms of side-effects and tolerability when sertraline and paroxetinewere compared in the treatment of GAD.19

A recent approach to addressing the issue of side-effects and tolerability has involved development ofthe controlled-release formulation of some SSRIs. Thecontrolled-release technology aims to slow the rate atwhich drug plasma concentration increases and to de-crease fluctuations in drug plasma concentration; bothof these mechanisms are believed to be associated withside-effects, especially at the beginning of treatment.Studies with controlled-release paroxetine in panic disor-der and SAD have largely confirmed the expectations offewer side-effects, better tolerability and fewer dropoutsfrom side-effects in the first weeks of treatment.20,21

Concerns about sexual side-effects of SSRIs have beenaddressed by investigating medications that might of-fer specific advantages in this area. In two recent stud-ies of controlled-release fuvoxamine in the treatmentof SAD, significantly fewer patients reported sexual side-effects when compared with other SSRIs.22,23 Also, sexualside-effects among patients treated with pregabalin forGAD and SAD were significantly less frequent in com-parison with sexual side-effects among SSRI-treated pa-tients.10,12

THERAPEUTIC DEPENDENCEBenzodiazepines used in the treatment of anxiety dis-orders are very often associated with therapeutic de-pendence. Therapeutic drug dependence is frequentlyequated with dependence on alcohol and certain illicitdrugs (‘addiction’), although emergence of the with-drawal symptoms upon abrupt cessation of the drug isthe only feature that they have in common. Unlike ‘ad-diction’, therapeutic dependence on benzodiazepines isnot associated with tolerance (escalating the dosage toproduce the same initial anxiolytic effect or the ini-tial dosage producing a decreased effect), craving forthe medication, and adverse health and/or social con-sequences (e.g. an all-encompassing preoccupation withbenzodiazepines).

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Despite these differences and despite the fact that thereis no evidence that patients with anxiety disorders aremore likely to abuse benzodiazepines in the absence ofcurrent or past substance abuse and dependence,24,25

it is difficult to alter common perception that benzo-diazepines are ‘addictive’ to these people. Therefore,introducing anxiolytic medications that would not beassociated with therapeutic dependence has been oneof the priorities in the pharmacotherapy of anxietydisorders.

By and large, efforts to find such drugs have not beenfruitful. Medications such as antidepressants may also beassociated with therapeutic dependence, although thisassociation appears to be weaker than that with ben-zodiazepines. Abrupt cessation of the antidepressantsmost commonly used for anxiety disorders – SSRIs andvenlafaxine – may also lead to withdrawal symptoms,although these tend to be milder in comparison withthe benzodiazepine withdrawal syndrome and do notoccur with the consistency seen after abrupt benzodi-azepine cessation. As a result, the dosage of antidepres-sants should be carefully tapered before their cessation,which is similar to the tapering of benzodiazepines, butthe taper can proceed at a faster rate.

Withdrawal symptoms have not been reported afterdiscontinuation of some novel pharmacological agentsused in anxiety disorders. For example, withdrawal wasnot seen with pregabalin in the treatment of GAD; thesignificance of this finding is lessened by the fact thatpatients took pregabalin only for 4 weeks.10,11 Furtherstudies and more clinical experience with such agentsare needed to clarify their association, if any, with ther-apeutic drug dependence.

LONG-TERM OUTCOMEThere is growing awareness that most anxiety disor-ders have a chronic course, often with remissions andrecurrences. In view of that, short-term treatment ap-proaches to anxiety disorders are usually not adequate,although they may produce substantial relief. These ap-proaches typically involve pharmacotherapy, becausemedications tend to work faster and to alleviate symp-toms of anxiety more obviously and more reliably. It iscurrently recommended to treat anxiety disorders withmedications for extended periods of time – at least for6 months, and usually for one or more years after achiev-ing remission. The duration of pharmacotherapy shouldnot be predetermined; treatment may end only when pa-tients are ready for it, when they feel comfortable aboutmedication cessation, and after they have been in sta-ble remission for at least 6 months, having achieved asatisfactory level of functioning.

The efficacy of pharmacological treatment of anxietydisorders tends to be maintained in the long run.26,27

In other words, medications usually remain effectivefor as long as they are taken. Various parameters of ef-ficacy may also demonstrate improvement with long-

term pharmacological treatment.28 However, high ratesof relapse following medication discontinuation were re-ported for all anxiety disorders. This problem has beenaddressed by prolonging pharmacological treatment andby combining it with psychological treatments, espe-cially cognitive–behaviour therapy (CBT). There is verylittle or no support for the former strategy as a means ofpreventing relapse or reducing relapse rates.29

Opinion is divided about the usefulness of combiningpharmacotherapy with CBT in anxiety disorders. Thereseems to be a discrepancy between some research find-ings30 and clinical practice,31 with the former generallysuggesting a negative impact of combining pharma-cotherapy with CBT (especially in the long run) and thelatter favouring such a combination. One significant ad-vantage of CBT is the longer persistence of its therapeuticeffects after its cessation, which is mainly due to teach-ing patients how to cope with anxiety more effectively.Hence, it is not surprising that in comparison with phar-macotherapy alone, the combination of pharmacother-apy and CBT in panic disorder and OCD was found tobe associated with a lower likelihood of relapse.32,33

Despite the problems inherent in combining medica-tions with CBT in the treatment of anxiety disorders(reviewed elsewhere34), when clinicians combine thesetwo treatment modalities, they should do so in a waythat maximizes rather than minimizes the likelihood ofthe benefit of such a combination. A better long-termoutcome – that is, both the maintenance of treatmentgains over long periods of time and decreased probabil-ity of relapse after cessation of treatment – may be morelikely if CBT is added to treatment initiated with medi-cation. This is of practical importance as many patientswith anxiety disorders commence treatment with med-ication. They do so for various reasons: some initiallycontact general practitioners or other therapists who aremore familiar with pharmacotherapy, others commencepharmacotherapy because CBT is not immediatelyavailable, while some patients cannot engage in CBTinitially because of the severity of their anxiety or de-pressive symptoms, prompting them to start treatmentwith medication.

CONCLUSIONThis review has summarized the main issues in the phar-macological treatment of anxiety disorders. It is disap-pointing that there have been no breakthroughs thatwould improve the efficacy of pharmacotherapy, espe-cially for conditions like OCD and PTSD. Although thesearch for more effective medications does continue, thegreatest challenge to the pharmacotherapy of anxietydisorders is to develop agents that can be discontinuedeasily and safely, and with minimal risk of relapse.

DISCLOSUREDr Vladan Starcevic has received fees from Organon andWyeth for speaking at educational meetings.

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REFERENCES

1. Shapira NA, Ward HE, Mandoki M et al. A double-blind, placebo-controlled trial ofolanzapine addition in fluoxetine-refractory obsessive–compulsive disorder. BiologicalPsychiatry 2004; 55: 553–555.

2. Bystritsky A, Ackerman DL, Rosen RM et al. Augmentation of serotonin reuptake inhibitorsin refractory obsessive–compulsive disorder using adjunctive olanzapine: a placebo-controlled trial. Journal of Clinical Psychiatry 2004; 65: 565–568.

3. McDougle CJ, Epperson CN, Pelton GH et al. A double-blind, placebo-controlled studyof risperidone addition in serotonin reuptake inhibitor-refractory obsessive–compulsivedisorder. Archives of General Psychiatry 2000; 57: 794–801.

4. Hollander E, Rossi NB, Sood E et al. Risperidone augmentation in SRI-resistant obsessivecompulsive disorder: a preliminary double-blind, placebo-controlled study. InternationalJournal of Neuropsychopharmacology 2003; 6: 397–401.

5. Woods SW, Nagy LM, Kolesar AS et al. Controlled trial of alprazolam supplementationduring imipramine treatment of panic disorder. Journal of Clinical Psychopharmacology1992; 12: 32–38.

6. Goddard AW, Brouette T, Almai A et al. Early coadministration of clonazepam withsertraline for panic disorder. Archives of General Psychiatry 2001; 58: 681–686.

7. Pollack MH, Simon NM, Worthington JJ et al. Combined paroxetine and clonazepamtreatment strategies compared to paroxetine monotherapy for panic disorder. Journal ofPsychopharmacology 2003; 17: 276–282.

8. Seedat S, Stein MB. Double-blind, placebo-controlled assessment of combined clon-azepam with paroxetine compared with paroxetine monotherapy for generalized socialanxiety disorder. Journal of Clinical Psychiatry 2004; 65: 244–248.

9. Carli V, Sarchiapone M, Camardese G et al. Mirtazapine in the treatment of panic disorder.Archives of General Psychiatry 2002; 59: 661–662.

10. Feltner DE, Crockatt JG, Dubovsky SJ et al. A randomized, double-blind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxietydisorder. Journal of Clinical Psychopharmacology 2003; 23: 240–249.

11. Pande AC, Crockatt JG, Feltner DE et al. Pregabalin in generalized anxiety disorder: aplacebo-controlled trial. American Journal of Psychiatry 2003; 160: 533–540.

12. Pande AC, Feltner DE, Jefferson JW et al. Efficacy of the novel anxiolytic pregabalinin social anxiety disorder: a placebo-controlled, multicenter study. Journal of ClinicalPsychopharmacology 2004; 24: 141–149.

13. Liebowitz MR, Gelenberg AJ, Munjack D. Venlafaxine extended release vs placebo andparoxetine in social anxiety disorder. Archives of General Psychiatry 2005; 62: 190–198.

14. Otto MW, Tuby KS, Gould RA et al. An effect-size analysis of the relative efficacy andtolerability of serotonin selective reuptake inhibitors for panic disorder. American Journalof Psychiatry 2001; 158: 1989–1992.

15. Schweizer E, Rickels K, Weiss S et al. Maintenance drug treatment of panic disorder: I.Results of a prospective, placebo-controlled comparison of alprazolam and imipramine.Archives of General Psychiatry 1993; 50: 51–60.

16. Cowley DS, Ha EH, Roy-Byrne PP. Determinants of pharmacologic treatment failure inpanic disorder. Journal of Clinical Psychiatry 1997; 58: 555–561.

17. Bruce SE, Vasile RG, Goisman RM et al. Are benzodiazepines still the medication ofchoice for patients with panic disorder with or without agoraphobia? American Journalof Psychiatry 2003; 160: 1432–1438.

18. Bandelow B, Behnke K, Lenoir S et al. Sertraline versus paroxetine in the treatmentof panic disorder: an acute, double-blind noninferiority comparison. Journal of ClinicalPsychiatry 2004; 65: 405–413.

19. Ball SG, Kuhn A, Wall D et al. Selective serotonin reuptake inhibitor treatment forgeneralized anxiety disorder: a double-blind, prospective comparison between paroxetineand sertraline. Journal of Clinical Psychiatry 2005; 66: 94–99.

20. Sheehan DV, Burnham DB, Iyengar MK et al. Efficacy and tolerability of controlled-releaseparoxetine in the treatment of panic disorder. Journal of Clinical Psychiatry 2005; 66:34–40.

21. Lepola U, Bergtholdt B, Lambert JS et al. Controlled-release paroxetine in the treatmentof patients with social anxiety disorder. Journal of Clinical Psychiatry 2004; 65: 222–229.

22. Davidson J, Yaryura-Tobias J, DuPont R et al. Fluvoxamine-controlled release formulationfor the treatment of generalized social anxiety disorder. Journal of Clinical Psychophar-macology 2004; 24: 118–125.

23. Westenberg HGM, Stein DJ, Yang H et al. A double-blind placebo-controlled study ofcontrolled release fluvoxamine for the treatment of generalized social anxiety disorder.Journal of Clinical Psychopharmacology 2004; 24: 49–55.

24. Worthington JW, Pollack MH, Otto MW et al. Long-term experience with clonazepam inpatients with a primary diagnosis of panic disorder. Psychopharmacology Bulletin 1998;34: 199–205.

25. Andersch S, Hetta J. A 15-year follow-up study of patients with panic disorder. EuropeanPsychiatry 2003; 18: 401–408.

26. Stein DJ, Versiani M, Hair T et al. Efficacy of paroxetine for relapse prevention in socialanxiety disorder: a 24-week study. Archives of General Psychiatry 2002; 59: 1111–1118.

27. Stocchi F, Nordera G, Jokinen RH et al. Efficacy and tolerability of paroxetine for thelong-term treatment of generalized anxiety disorder. Journal of Clinical Psychiatry 2003;64: 250–258.

28. Ballenger JC. Remission rates in patients with anxiety disorders treated with paroxetine.Journal of Clinical Psychiatry 2004; 65: 1696–1707.

29. Mavissakalian MR, Perel JM. Duration of imipramine therapy and relapse in panicdisorder with agoraphobia. Journal of Clinical Psychopharmacology 2002; 22: 294–299.

30. Barlow DH, Gorman JM, Shear MK et al. Cognitive–behavioral therapy, imipramine, ortheir combination for panic disorder: a randomized controlled trial. JAMA 2000; 283:2529–2536.

31. Starcevic V, Linden M, Uhlenhuth EH et al. Treatment of panic disorder with agoraphobia inan anxiety disorders clinic: factors influencing psychiatrists’ treatment choices. PsychiatryResearch 2004; 125: 41–52.

32. Biondi M, Picardi A. Increased probability of remaining in remission from panic disorderwith agoraphobia after drug treatment in patients who received concurrent cognitive–behavioural therapy: a follow-up study. Psychotherapy and Psychosomatics 2003; 72:34–42.

33. Simpson HB, Liebowitz MR, Foa EB et al. Post-treatment effects of exposure therapyand clomipramine in obsessive–compulsive disorder. Depression and Anxiety 2004; 19:225–233.

34. Starcevic V. Anxiety Disorders in Adults: A Clinical Guide. New York: Oxford UniversityPress, 2005.

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