Double-blind clonazepam vs placebo in panic disorder treatment

Estudo duplo-cego com clonazepam e placebo no tratamento do transtorno do pânico

DOUBLE-BLIND CLONAZEPAM VS PLACEBO IN PANIC DISORDER TREATMENT

ALEXANDRE MARTINS VALENÇA^*, ANTONIO EGIDIO NARDI^*, ISABELLA NASCIMENTO^*, MARCO A. MEZZASALMA^*, FABIANA L. LOPES^*, WALTER ZIN^**

ABSTRACT - OBJECTIVE: To assess the effectiveness of clonazepam, in a fixed dose (2 mg/day), compared with placebo in the treatment of panic disorder patients. METHOD: 24 panic disorder patients with agoraphobia were randomly selected. The diagnosis was obtained using the structured clinical interview for DSM-IV . All twenty-four subjects were randomly assigned to either treatment with clonazepam (2 mg/day) or placebo, during 6 weeks. Efficacy assessments included: change from baseline in the number of panic attacks; CGI scores for panic disorder; Hamilton rating scale for anxiety; and panic associated symptoms scale. RESULTS: At the therapeutic endpoint, only one of 9 placebo patients (11.1%) were free of panic attacks, compared with 8 of 13 (61.5%) clonazepam patients (Fisher exact test; p=0,031). CONCLUSION: the results provide evidence for the efficacy of clonazepam in panic disorder patients.

KEY WORDS: panic disorder, panic attack, clonazepam, treatment.

Estudo duplo-cego com clonazepam e placebo no tratamento do transtorno do pânico

RESUMO - OBJETIVO: Avaliar a eficácia do clonazepam, em uma dose fixa (2 mg/dia), comparado ao placebo, no tratamento de pacientes com transtorno do pânico. MÉTODO: Foram selecionados randomicamente 24 pacientes com transtorno do pânico com agorafobia. O diagnóstico foi obtido através da entrevista clínica estruturada do DSM-IV. Todos os 24 pacientes foram randomicamente designados para tratamento com clonazepam (2 mg/dia) ou placebo, durante 6 semanas. Para avaliação da eficácia foram utilizadas: mudança do número de ataques de pânico em relação ao período anterior ao tratamento; escala de Hamilton de ansiedade; escala de sintomas associados ao transtorno do pânico. RESULTADOS: No final da sexta semana, apenas um de 9 dos pacientes que receberam placebo(11,1%) ficaram livres de ataques de pânico, comparados a 8 de 13 (61,5%) pacientes que receberam clonazepam (prova exata de Fisher; p=0,031). CONCLUSÃO: Os resultados evidenciam a eficácia do clonazepam no tratamento de pacientes com transtorno do pânico.

PALAVRAS-CHAVE: transtorno do pânico, ataque de pânico, clonazepam, tratamento.

Panic disorder is a common psychiatric illness that can have a chronic course¹. The symptoms include recurrent panic attacks and persistent concern about having another attack or worry about the implications and consequences of the attack¹. Epidemiologic data have documented a lifetime prevalence of 1.6% - 2.2%, age at first onset in the age of 20s and higher risk in females (about twofold)². Prompt recognition and treatment of panic attacks is important because quality of life is typically poor, chronic illness can develop and sufferers are at particular risk of developing other psychiatric conditions, such as agoraphobia, anxiety and depression³. Medications from several classes have been shown to be effective in panic disorder treatment: selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants and high-potency benzodiazepines and MAO-I. Benzodiazepines have been extensively studied and used in the treatment of panic disorder over the last 10 years. Many studies have reported the efficacy of alprazolam⁴, and there is evidence for the efficacy of others benzodiazepines, particularly clonazepam⁵ .

Beaudry et al.⁶ registered the first report of the efficacy of clonazepam for panic disorder patients.They reported the effectiveness of clonazepam (1-2 mg/day) in the treatment of 7 patients with agoraphobia with panic attacks and one patient with panic disorder. Subsequent work^7-9 continued to underscore the drug's ability to control panic attacks and anticipatory anxiety.Tesar et al.⁷ studied 44 randomized subjects who took alprazolam (n=14), conazepam (n=15) and placebo (n=15) for 6 weeks. The average dose of each active agent was 5.2 mg/day for alprazolam and 2.4 mg/day for clonazepam.There were no statiscally significant differences between the clonazepam and alprazolam groups on any of the outcome measures: CGI (clinical global impression) , PGI (patient global impression), Hamilton scale for anxiety. Both were superior over placebo. Svebak et al.⁸ studied 12 panic disorder patients who were randomly assigned to imipramine (n=6) and clonazepam (n=6) for 6 months. It was found that both drugs were efficacious in eliminating panic attacks.

Clonazepam has some atypical features in comparison with other benzodiazepines, including the demonstration of elevated serotonin levels in the brain suggesting that this drug may also act by increasing the concentration of the neurotransmitter at synaptic receptor sites¹⁰. The pharmacodynamic and pharmacokinetic characteristics of clonazepam¹¹ may be advantageous in the treatment of panic disorder, like the emergence of interdose rebound anxiety, which is observed at times with the shorter-acting antipanic benzodiazepines, alprazolam and lorazepam. The half-life of clonazepam is longer (20 to 80 hours), allowing once or twice-a-day dosing. In addiction, the long half-life of clonazepam may reduce the severity of the withdrawal syndrome during discontinuance compared with that associated with alprazolam.Clonazepam was also found to be useful in patients treated with alprazolam by reducing the interdose rebound anxiety¹², possibly because its longer elimination half-life.

A trial¹³ suggested that clonazepam may be a safe and effective alternative for patients who are treatment resistant, for those intolerant of antidepressant adverse effects (phenelzine, imipramine, desipramine, trazodone and amytriptyline), and for those having breakthrough panic ("interdose rebound") on alprazolam treatment. In this open trial, after clonazepam treatment(1.5-8 mg/day, average duration of 8 to 68 weeks) 7 of 10 patients who had been resistant to standard pharmacological treatments of panic attacks and agoraphobia achieved cessation of their attacks while 3 had mild to moderate sympton persistence.

The objective of this study was to assess the effectiveness of clonazepam, a fixed dose (2 mg/day) for 6 weeks , compared with placebo in the treatment of panic disorder patients.

METHOD

We randomly selected twenty-four panic disorder subjects with agoraphobia at the Laboratory of Panic & Respiration in the Federal University of Rio de Janeiro, who agreed to participate in this protocol. The diagnosis was obtained using the structured clinical interview (SCI)¹⁴ for DSM-IV¹. The study design of the investigation were explained to the patients and a they signed a voluntary written inform consent for their participation in this study. The protocol complying with the principles laid down in the Declaration of Helsinki was approved by our local Ethical Commitee.

To participate the subjects were required to be between the ages of 18 and 55, report at least three panic attacks in the last two consecutive weeks before the first challenge test day. They should be free of psychotropic drugs for at least one week and test negative for benzodiazepines and other medications. All patients underwent a physical examination and laboratory tests to ensure they were healthy enough to participate in the study. Exclusion criteria were the existence of any current mental disorder (other than panic disorder), history of psychosis or bipolar disorder, epilepsy, pregnancy, substance abuse within the prior 6 months and major medical disorders (uncontrolled thyroid, renal, hepatic, cadiac, pulmonary, or endocrinological diseases as determined by the physical examination, vital signs, or laboratory evaluations).

At each visit, weakly, patients were given a diary to record any panic attacks between visits. Efficacy assessments included: 1) change from baseline in the number of panic attacks; 2) CGI (clinical global impression) scores for panic disorder (change from baseline with respect to panic disorder, phobic avoidance, and anticipatory anxiety); 3) Hamilton rating scale for anxiety (HAM-A) and panic associated symptoms scale (PASS)¹⁵ .The PASS measures the severity of the core symptoms of panic disorder: panic attacks(situational, spontaneous and limited symptom); antecipatory anxiety (average percentage of waking hours and intensity on a 0-10 scale ); and phobias(on a 0-10 scale that is a global score of how distressing or restricting phobias have been).

Data Analysis - A two-way ANOVA was used to evaluate the differences among measurements. When pairwise multiple comparisons were required, Tukey test was applied. Fisher exact test and t test were also used. The significant level was set at 5%.

RESULTS

The patients were 14 women and 10 men with a mean age (±SD) of 37 (±6,9) years. In the clonazepam group were 9 women and 5 men (mean age±SD = 37,5±6,6 years) and in the placebo group were 5 women and 5 men (mean age±SD = 36,8±7,2 years).The difference of age between the two groups was not statiscally different (t test, p=0,780). One women of the clonazepam group was excluded because she had a major depression episode. Other woman of the placebo group was dropped out in the 2^nd week because she was worse.

At the endpoint, only one of 9 placebo patients (11,1%) were free of panic attacks, compared with 8 of 13 (61,5%) clonazepam patients(Fisher exact test , p=0,031) (Table 1).

In the placebo and clonazepam groups the CGI in first day ("baseline") were 4,7±0,8 and 4,4±0,7, respectively. After 6 weeks of treatment with placebo and clonazepam, this scores were 3,5±1,2 and 1,5±0,8 (two-way ANOVA with Tukey test, F=13,885, df=1, p<0,05). At the end of 6 weeks PGI (patient global impression) in the clonazepam group were 2±0,87. In the placebo group this score were 3,1±1,66 (t test, p= 0,108). It was also found an important reduction in anticipatory anxiety and phobias in the clonazepam group, when compared to placebo group. The percentage of waking hours in the clonazepam group at baseline and at endpoint were 55±32,9 x 14,7±7,6. In the placebo group these scores were 51±27,6 x 40,5±25,5 (t test, p=0,037, statiscally significant). In the placebo group 3 of 9 (33.3%) patients had reduction of 50% or more in the scores of Hamilton scale. In the clonazepam group 10 of 13(76,9%) patients had reduction of 50% or more in this score (Fisher exact test, p= 0,079) showing an important reduction of anxiety in clonazepam group compared to placebo, although not statiscally significant.

The most common adverse effects associated with the use of clonazepam were neuropsychiatric events: somnolence, reported by 7 (53,8%) and ataxia, reported by 4 (30,76%) patients. Other side effects that occurred with patients of the clonazepam group were memory problems (n=2, 15,38%), dizziness (n=3, 23%), irritability (n=1), depression (n=1) and libido decrease (n=1). Six (66,6%) of the placebo group and 2 (15,38%) of the clonazepam group reported no adverse events during the 6 weeks of the study (Table 2).

DISCUSSSION

The results of the current study suggest that the administration of clonazepam reduces panic attacks and anxiety in panic disorder patients. Clonazepam was superior over placebo in the study's efficacy outcomes (panic attacks, anticipatory anxiety and phobias). Although in a small sample the results of clonazepam reducing anxiety and panic attacks are striking and statiscally significant, when compared over placebo.

Our results are consistent with some studies reported previously. Tesar et al¹⁶, in their 6 week-study with administered clonazepam up to a mean maximum dosage of 2.5 mg/day, compared with 5.3 mg/day of alprazolam and placebo.Good clinical efficacy was seen on observed ratings of global severity of illness, phobic distress and on patient-rated global improvement, on clonazepam and alprazolam groups. Fifty percent of patients in the clonazepam group, 46% of those in the alprazolam group and only 14% of those in the placebo group were panic free at the end of the study.

Beauclair et al¹⁷ in their 4 week study with 29 panic disorder patients compared the efficacy of a mean daily dose of clonazepam 2.3 mg over placebo, double-blindly. It was found that clonazepam was superior (with statistical significance) in reducing the number of panic attack and Hamilton scores. The treatments were also compared with respect to the frequency of responders at endpoint as defined by 50% or greater reduction from baseline in CGI Severity of Panic Disorder score. There were 11(84.6%) of 13 responders in the clonazepam-treated group compared with 1 (6.5%) of 16 in the placebo-treated group (statiscally significant).

Rosenbaum et al¹⁸, in a multicenter trial of clonazepam versus placebo, with a sample of 413 panic disorder patients found out that clonazepam was superior to placebo in changing the number of panic attacks from baseline, as well as changes in the mean duration of anticipatory anxiety, frequency of avoidance behaviour and phobic fear.

Moroz and Rosenbaum¹⁹ also in a multicenter trial with 455 panic disorder patients, who were randomly assigned to treatment with clonazepam (n=230) or placebo (n=225), found that the number of patients who were free of panic attacks was greater in the clonazepam group (62%) than in the placebo group(p<0,001). Also, the percent of subjects achieving a 50 percent reduction in panic attacks was greater in the clonazepam group (79%) than in the placebo group (57%) (p<0,001).

In our study clonazepam in a fixed dose of 2 mg/day was safe and well tolerated. The main adverse events reported by patients were neuropsychiatric events, specially somnolence and ataxia. In this respect, our results are similar to that of Rosenbaum et al¹⁸ and Moroz and Rosenbaum¹⁹.

The analysis of the data presented supports our major study hypotheses that clonazepam is superior to placebo in the treatment of panic disorder, having a marked therapeutic effect in these patients with panic attacks. The frequency of panic attacks, phobic avoidance, anticipatory anxiety, and free floating anxiety often seen in panic disorder patients all showed significant improvement.

CONCLUSION

This trial provide evidence for the efficacy of clonazepam in panic disorder. Our results are supported by the evidence in the literature of the therapeutic effects of clonazepam in patients with panic disorder.Despite the controversies associated with dependence and adverse events²⁰ clonazepam is an useful treatment option for panic disorder.

Dr. Alexandre Martins Valença - Rua da Cascata 13/501 - 20530-080 Rio de Janeiro RJ - Brasil. E-mail: [e-mail]

• 1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4Ed (DSM-IV). Washington, DC: APA, 1994.
• 2. Weissman MM, Bland RC, Canino GJ, Faravelli C, Greenwald S, Hwu HG, Joyce PR, Karam EG, Lee CK, Lellouch J, Lepine JP, Newman SC, Oakley-Browne MA, Rubio-Stipec M, Wells JE, Wickramaratne PJ, Wittchen HA, Yeh EK. The cross-national epidemiology of panic disorder. Arch Gen Psychiatry 1997;54:305-309.
• 3. Ballenger JC. Comorbidity of panic and depression: implications for clinical management. Int Clin Psychopharmacol 1998;13(Suppl 4):13-17.
• 4. Ballenger JC, Burrows GD, DuPont RL , Lesser IM, Noyes R , Pecknold JC, Rifkin A, Swinson RP. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial, I: efficacy in short-term treatment. Arch Gen Psychiatry 1988;45:413-422.
• 5. Tesar GE. High-potency benzodiazepines for short-term manangement of panic disorder: The U.S. experience. J Clin Psychiatry 1990;51(Suppl 5):4-10.
• 6. Beaudry P, Fontaine R, Chouinard G, Annable L. Clonazepam in the treatment of patients with recurrent panic attacks. J Clin Psychiatry 1986;47:83-85.
• 7. Tesar GE, Rosenbaum JF, Pollack MH, Herman JB, Sachs GS, Mahoney EM, Cohen LS, McNamara M, Goldstein S. Clonazepam versus alprazolam in the treatment of panic disorder: interim analysis of data from a prospective, double žblind , placebo-controlled trial. J Clin Psychiatry 1987;48(Suppl 10):16-21.
• 8. Svebak S, Cameron A, Levander S. Clonazepam and imipramine in the treatment of panic attacks: a double-blind comparison of efficacy and side effects.J Clin Psychiatry 1990;51(Suppl5):14-17.
• 9. Pols H, Zandbergen J, Lousberg H, Loof C, Griez E. Low doses of clonazepam in the treatment of panic disorder. Can J Psychiatry 1991;36:302-303.
• 10. Davidson JR, Moroz G. Pivotal studies of clonazepam in panic disorder. Psychopharm Bull 1998;34:169-174.
• 11. Greenblatt DJ, Miller LG, Shader RI. Clonazepam pharmacokinetics, brain uptake, and receptor interactions. J Clin Psychiatry 1987;48(Suppl 10):4-9.
• 12. Herman JB, Rosenbaum JF, Brotman WA. The alprazolam to clonazepam switch for the treatment of panic disorder. J Clin Psychopharmacol 1987;7:175-178.
• 13. Tesar GE, Rosenbaum JF. Successful use of clonazepam in patients with treatment-resistant panic disorder. J Nerv Ment Dis 1986;174:477-482.
• 14. First MB, Spitzer RL, Gibbon M, Williams JBM. Structured clinical interview diagnostic (SCID) for DSM-IV axis I Disorders ž Clinician Version (SCID-CV). Washington American Psychiatric Press 1997.
• 15. Argyle N, Deltito J, Allerup P, Maier W, Albus M, Nutzinger D, Rasmussen S, Ayuso JL, Bech P. The panic-associated symptom scale: measuring the severity of panic disorder.Acta Psychiatr Scand 1991;83:20-26.
• 16. Tesar GE, Rosenbaum JF, Pollack MH, Otto MW, Sachs GS, Herman JB, Cohen LS, Spier SA. Double-blind, placebo-controlled comparison of clonazepam and alprazolam for panic disorder. J Clin Psychiatry 1991;54:69-76.
• 17. Beauclair L, Fontaine R, Annable L, Holobow N, Chouinard G. Clonazepam in the treatment of panic disorder: a double-blind, placebo-controlled trial investigating the correlation between clonazepam concentrations in plasma and clinical response. J Clin Psychopharmacol 1994;14:111-118.
• 18. Rosenbaum JF, Moroz G, Bowden CL. Clonazepam in the treatment of panic disorder with or without agoraphobia: a dose-response study of efficacy, safety, and discontinuance. J Clin Psychopharmacol 1997;17:390-400.
• 19. Moroz G, Rosenbaum JF. Efficacy, safety, and gradual discontinuation of clonazepam in panic disorder: a placebo-controlled, multicenter study using optimized dosages. J Clin Psychiatry 1999;60:604-612.
• 20. Davidson JR.Use of benzodiazepines in panic disorder. J Clin Psychiatry 1997;58(Suppl 2):26-28.

*

Laboratory of Panic & Respiration, Institute of Psychiatry, Federal University of Rio de Janeiro, Brazil:

**

Laboratory of Respiration Physiology, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Brazil. Supported by the Brazilian Council for Scientific and Technological Development (CNPq). Aceite: 3-agosto-2000.

Publication Dates

• Publication in this collection
  01 Dec 2000
• Date of issue
  Dec 2000

History

• Accepted
  03 Aug 2000