The Efficacy of Paxil (Paroxetine) for Panic Disorder Journal: The Current Practice of Medicine Authors: Dr Sean D. Hood, Dr Spilios Argyropoulos, Prof David J. Nutt Corresponding Author: Sean Hood ([email protected])

Introduction Substantial advances into the pharmacological treatment of Panic Disorder (PD) have been made in the last two decades. Although tricyclic antidepressants (TCADs), benzodiazepines and monoamine oxidase inhibitors (MAOIs) have proven efficacy in this condition, their use is complicated by anticholinergic effects, possible dependence, and dietary restrictions respectively. Specific serotonin reuptake inhibitors (SSRIs) are increasingly used in PD and the current consensus is that pharmacotherapy should usually begin with an SSRI [1, 2]. Paroxetine (Paxil), the first SSRI to obtain a licence for PD by the US Food & Drug Administration, is generally well tolerated, safe, and has proven efficacy in treating conditions such as depression and obsessive compulsive disorder (OCD). This article reviews the efficacy of Paroxetine in the treatment of panic disorder.

Short Term Efficacy

Paroxetine vs (Placebo + CBT) A pivotal study of the efficacy of Paroxetine in PD, conducted by Oehrberg et al. in 1995 [3], was a randomised, double-blind study of Paroxetine vs. Placebo with both groups receiving standardised Cognitive & Behavioral Therapy (CBT). Seven centres in Denmark tested 120 DSM-IIIR defined PD +/Agoraphobia subjects in a flexible dose protocol (10 – 60 mg /day). Three weeks of single-blind placebo preceded 12 weeks of double-blind treatment, and then two weeks of single-blind placebo. The principle outcome measure was the frequency of panic attacks assessed using the Panic Inventory. Comparisons were made using consecutive 3-week intervals.

Table 1. Outcomes in Oehrberg et al. 1995 Outcome

Result (p 50% reduction in full panic attacks

PAR > P at week 6+

Zero full panic attacks

PAR > P at week 12

Number of full panic attacks.

PAR = P

Anxiety reduction (HAM-A, CGI-S)

PAR > P at week 6+

Dropouts

PAR = P

Note: PAR=Paroxetine, P=Placebo, HAM-A=Hamilton Anxiety rating, CGI-S= Clinical Global Impression Severity subscale

Paroxetine was well tolerated, with 92% completing the trial. In two of the three primary outcome variables (viz: zero panic attacks and > 50% reduction in frequency of full panic atttacks) Paroxetine was significantly more efficacious than placebo, and the average dose tested was 40-60 mg / day.

Paroxetine vs TCAD Meta-analyses of placebo-controlled double blind studies of TCAs support the view that Imipramine and especially Clomipramine [4, 5] are efficacious in the short-term treatment of PD. So far there have been few direct comparisons between TCADs and SSRIs in panic disorder. In a large (n=367) placebo controlled study, Lecrubier et al. [6] compared Paroxetine with Clomipramine over a 12 week period. The majority (80%) of patients had significant agoraphobic avoidance. After 3 weeks of single blind placebo washout patients were randomly assigned to treatment groups. A flexible dosing regimen starting at 10 mg / day minimised initial side effects whilst allowing clinically effective doses to be used. Most (70%) patients remained in the trial until weeks 7-9.

Table 2. Outcomes in Lecrubier et al. 1997 Outcome

Result (p P at week 6+ CLO > P at week 12

> 50% reduction in full panic attacks

PAR > P = CLO at week 9+

Zero full panic attacks

PAR > P = CLO at week 6+

Improvement in Anxiety (HAM-A, CGI-S, PGE),

PAR = CLO > P

Agoraphobia (MSPS),Functional Disability (SDS). Dropouts

PAR = CLO = P

Side Effects

CLO > PAR ii

High End-Stage (HES) responders (after [7])

i

PAR = CLO > P

Note: PAR=Paroxetine, CLO=Clomipramine, P=Placebo, CNS=Central Nervous System, GIT=Gastrointestinal, HAM-A=Hamilton Anxiety rating, CGI-S= Clinical Global Impression Severity subscale, PGE=Patient’s Global Evaluation, MSPS=Modified Sad Person’s Score, SDS=Sheehan Disability Scale Despite a substantial placebo response (31.6% having none and 60% having at least a 50% reduction in panic attacks by week 12), both Paroxetine and Clomipramine were significantly more effective than placebo (see Table 2). Paroxetine had a faster onset than Clomipramine and was better tolerated. This study offers powerful evidence that Paroxetine is at least as effective as Clomipramine in the acute treatment of PD.

Paroxetine vs Benzodiazepines Until relatively recently, benzodiazepines were considered ineffective in the treatment of PD apart from a circumscribed role in alleviating accompanying anticipatory anxiety. The anti-panic effects of the

i

Trend: CLO (15%) > PAR (7%) Lydiard [7] has defined “High End-Stage” (HES) responders as those patients (LOCF, ITT) reporting zero panic attacks and who were rated as having a CGI rating of 1 (very much improved) or 2 (much improved). ii

benzodiazepine Alprazolam has now been shown to be superior to placebo and at least as effective as agents such as Imipramine [8]. There are no ideal studies comparing Paroxetine and benzodiazepines although one deserves mention:

PAR 223 [See 7] was a randomised, double-blind, placebo-controlled, flexible-dose study of 226 patients comparing placebo, Alprazolam (1-6 mg), and Paroxetine (10-60mg) over a 10 week period. This was a “failed” trial in that the response rates to both Paroxetine (58.8%) and Alprazolam (62.0%) were similar to that of placebo (62.7% with zero panic attacks). The average doses of active drug were modest – 26.3 mg /day of Paroxetine and 2.8 mg / day of Alprazolam - which may have contributed to the inability to show a difference.

Paroxetine Dose A definitive dose finding study was conducted by Ballenger et al. [9] in a randomised, 10-week, placebocontrolled design. Of 425 patients screened, 278 completed 2 weeks of single-blind placebo washout and then were assigned to placebo or fixed dose 10, 20 or 40 mg /day Paroxetine. Primary outcome measures were frequency of panic attacks (using Panic Inventory) and Clinical Global Improvement (CGI, a clinician based rating). Patients were seen weekly for 4 weeks then every 2 weeks for the remainder of the study. Analysis was conducted on ITT samples, 68% completed the 10-week trial.

Table 3. Outcomes in Ballenger et al. 1998 Outcome

Result 40mg

20mg

10mg

Percentage free of full panic attacks.

PAR > P

-

-

Reduction in number of full panic attacks

PAR > P

-

-

Improvement in CGI-S

PAR > P

-

-

> 50% reduction in full panic attacks

-

-

-

High End-Stage (HES) responders (after [7])

PAR > P

-

-

Agoraphobic Fear (MSPS-F)

PAR < P at

PAR < P at

-

week 4, 10

week 10

Agoraphobic Avoidance (MSPS-A)

-

-

-

Anxiety Rating (HAM-A)

PAR < P

-

-

Depression Rating (MADRS)

PAR < P

-

-

Total Dropouts

-

-

-

ii

Note: Results where PAR (Paroxetine) was not significantly different to P (Placebo) are shown as “-“. Doses are of Paroxetine. CGI-S = Severity subscale of Clinical Global Impression scale. MSPS-F = Marks-Sheehan Phobia Scale-Fear subscale. MSPS-A = Marks-Sheehan Phobia Scale-Avoidance subscale. MADRS= Montgomery-Åsberg Depression Rating Scale. HAM-A = Hamilton Anxiety Rating Scale total score.

The 40 mg / day Paroxetine group had significantly greater improvement on 3 out of 4 primary outcome measures and was superior to placebo on the majority of other measures. Side-effects were relatively few, and there was no increase in drop-outs in the first two weeks due to increased anxiety or “jitteriness”. A target dose of 40 mg was established as being effective and well tolerated.

Long-Term Efficacy As Panic disorder often runs a chronic course it is important to assess the long-term efficacy and tolerability of treatments.

Participants who completed the comparative study of Paroxetine, Clomipramine and placebo ([6], above) were invited to continue their double-blind treatment for a further 36 weeks [10]. Of 176 patients participating in this phase of the trial, 60 (34%) withdrew. Paroxetine withdrawal rates due to adverse effects did not differ from placebo and withdrawal rates were highest for Clomipramine. Paroxetine (but not Clomipramine) was significantly more effective than placebo throughout the study with respect to reduction from baseline of full panic attacks, and at the end of treatment with respect to the proportion of patients who eventually experienced no panic attacks.

Burnham et al [11] have examined relapse rates in 105 patients who responded to a 10-week double-blind Paroxetine or Placebo trial by re-randomisation for a further 12 weeks. Paroxetine treated patients who were then randomised to Placebo relapsed significantly more often (30%) than those who continued with Paroxetine (5%). Side effects were similar to that seen in the first 10 weeks.

These studies confirm that Paroxetine continues to protect against relapse and is well tolerated in PD for up to a year.

Time to Response The time to response to SSRIs in PD is often longer than that typically seen in the treatment of depressive conditions. Paroxetine provides significant improvement in PD over the first 4 [9] to 12 weeks of treatment [6]. Further improvement is sometimes seen with even longer treatment [10].

Comparative Efficacy There are no comparative studies between individual SSRIs in PD. The database for Paroxetine in PD is the most extensive of the SSRIs although there is also good evidence of the efficacy of other SSRIs such as

Fluvoxamine and Citalopram. Choice of SSRI should also be guided by availability, clinician familiarity, and broader considerations such as comorbidities and previous treatment history.

Comparison with TCAs and benzodiazepines has been made above. The quality of evidence for anticonvulsants is limited. It is notable that β-blockers are ineffective treatments in panic disorder, despite their frequent prescription for this condition by GP’s.

Side Effects and Discontinuation The side effect profile for Paroxetine in PD does not appear to differ markedly from that seen when it is used to treat depression [3] and its tolerability in PD has been discussed above. The most common adverse effects are nausea, headache, somnolence, dry mouth, insomnia, asthenia, sweating, and abnormal ejaculation [12]. Sexual side effects are dose related, and 21% of males with PD reporting abnormal ejaculation and 5% impotence [12]. The clinical practise of starting at 10 mg / day and gradually increasing the dose, together with gradually reducing the dose over a few weeks is very effective at reducing side effects and avoiding withdrawal reactions respectively. Fluvoxamine appears to be less likely than other SSRI’s to cause ejaculatory retardation [13, 14] and thus is a useful alternative.

Discontinuation reactions may be more common with Paroxetine than other SSRI’s [15], especially when ceasing abruptly from high doses. This is typically mild and begins 2 – 7 days after stopping treatment. Typically gastrointestinal effects such as nausea, vomiting, and cramps are noted; vertigo, malaise, muscular cramps and pseudo-influenza are also described [12, 16].

Comorbid Conditions Comorbidity is usual in panic disorder, with major depressive episode, social anxiety disorder, other anxiety disorders and alcohol dependence commonly seen. Paroxetine has proven efficacy in treating comorbid depressive symptomatology [6, 9, 10, 17], social anxiety disorder [12, 18] and Obsessive Compulsive Disorder (OCD) [12, 19] which can minimise polyprescribing.

Conclusions Paroxetine has proven efficacy and tolerability in the treatment of Panic Disorder. It is at least as effective as conventional treatments such as CBT, TCADs and benzodiazepines in short-term trials. A daily dose of 40 mg has been shown to be the most efficacious, however a graded titration to this dose will help to minimise side effects. A clinical response is usually seen within 4 to 12 weeks, it continues to protect against relapse for up to 12 months, and is an effective treatment of frequently co-morbid psychiatric conditions. It is therefore a treatment of first choice in Panic Disorder.

Declaration of Interest One of the authors (SDH) is the recipient of a grant from SKB.

Bibliography 1.

Ballenger, J.C., et al., Consensus statement on panic disorder from the International Consensus Group on Depression and Anxiety. J Clin Psychiatry, 1998. 59 Suppl 8: p. 47-54.

2.

Shiloh, R., D. Nutt, and A. Weizman, Atlas of Psychiatric Pharmacotherapy. 1999, London: Martin Dunitz.

3.

Oehrberg, S., et al., Paroxetine in the treatment of panic disorder. A randomised, double-blind, placebo-controlled study. British Journal of Psychiatry, 1995. 167(3): p. 374-9.

4.

Cassano, G.B., et al., Clomipramine for panic disorder: I. The first 10 weeks of a long-term comparison with imipramine. J Affect Disord, 1988. 14(2): p. 123-7.

5.

Modigh, K., P. Westberg, and E. Eriksson, Superiority of clomipramine over imipramine in the treatment of panic disorder: a placebo-controlled trial. J Clin Psychopharmacol, 1992. 12(4): p. 251-61.

6.

Lecrubier, Y., et al., A comparison of paroxetine, clomipramine and placebo in the treatment of panic disorder. Collaborative Paroxetine Panic Study Investigators. Acta Psychiatrica Scandinavica, 1997. 95(2): p. 145-52.

7.

Lydiard, R.B., et al., Efficacy studies of paroxetine in panic disorder. Psychopharmacology Bulletin, 1998. 34(2): p. 175-82.

8.

Anonymous, Drug treatment of panic disorder. Comparative efficacy of alprazolam, imipramine, and placebo. Cross-National Collaborative Panic Study, Second Phase Investigators [published erratum appears in Br J Psychiatry 1992 Nov;161:724] [see comments]. Br J Psychiatry, 1992. 160: p. 191-202; discussion 202-5.

9.

Ballenger, J.C., et al., Double-blind, fixed-dose, placebo-controlled study of paroxetine in the treatment of panic disorder. American Journal of Psychiatry, 1998. 155(1): p. 36-42.

10.

Lecrubier, Y. and R. Judge, Long-term evaluation of paroxetine, clomipramine and placebo in panic disorder. Collaborative Paroxetine Panic Study Investigators. Acta Psychiatrica Scandinavica, 1997. 95(2): p. 153-60.

11.

Burnham, J.C., M. Steiner, and I.P. Gergel. Paroxetine long-term safety and efficacy in Panic disorder and prevention of relapse: a double-blind study. in American College of Neuropsychopharmacology. 1995. San Juan, Puerto Rico.

12.

Gunasekara, N.S., S. Noble, and P. Benfield, Paroxetine. An update of its pharmacology and therapeutic use in depression and a review of its use in other disorders. Drugs, 1998. 55(1): p. 85120.

13.

Waldinger, M.D., et al., Effect of SSRI antidepressants on ejaculation: A double-blind, randomized, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine, and sertraline. JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY, 1998. 18(4)): p. 274-281.

14.

Waldinger, M.D. and B. Olivier, Selective serotonin reuptake inhibitor-induced sexual dysfunction: clinical and research considerations. INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY, 1998. 13 Suppl. 6: p. S27-S33.

15.

Stahl, M.M., et al., Withdrawal reactions with selective serotonin re-uptake inhibitors as reported to the WHO system. Eur J Clin Pharmacol, 1997. 53(3-4): p. 163-9.

16.

Haddad, P., The SSRI discontinuation syndrome. JOURNAL OF PSYCHOPHARMACOLOGY, 1998. 12(3)): p. 305-313.

17.

Ballenger, J.C., Comorbidity of panic and depression: implications for clinical management. International Clinical Psychopharmacology, 1998. 13(Suppl 4): p. S13-7.

18.

Stein, M.B., Medication treatments for panic disorder and social phobia. Depression & Anxiety, 1998. 7(3): p. 134-8.

19.

Mancini, C. and M.V. Ameringen, Paroxetine in social phobia. J Clin Psychiatry, 1996. 57(11): p. 519-22.