Posted by sdb on June 10, 2006, at 16:32:27
In reply to Klonopin Mechanisms?, posted by blueberry on June 9, 2006, at 15:53:08
thats an summary, update of some previous studies on clonazepam in psychiatry.
How clonazepam works needs more research and meta-analysis. Look to the referrals, <name> et al.
Do not believe all things what is written in studies it depends on many variables and e.g. not by all means on the impact factor of a journal.sdb
© 2006 Lippincott Williams & Wilkins, Inc. Volume 21(3), May 2006, pp 131-142
Clonazepam in the treatment of psychiatric disorders: an update
[REVIEW]Nardi, Antonio E.a; Perna, Giampaolob
aInstitute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
bAnxiety Disorders Clinical and Research Unit, Vita-Salute University, Istituto Scientifico Ospedale San Raffaele, Milan, Italy
Correspondence and requests for reprints to Professor Antonio Egidio Nardi, Institute of Psychiatry, Federal University of Rio de Janeiro, R. Visconde de Piraja, 407/702 Rio de Janeiro, RJ 22410-003, Brazil
Tel: +55 21 25216147; fax: +55 21 25236839;
e-mail: antonionardi@terra.com.br
Received 22 February 2005 Accepted 18 November 2005
Outline* Abstract
* Introduction
o Efficacy in anxiety disorders
+ Panic disorder
+ Pivotal studies with clonazepam in panic disorder
+ Other clonazepam studies in panic disorder
+ Long-term therapy
+ Clonazepam cotherapy
+ Quality of life
+ CO2-induced panic attacks
+ Panic disorder subtypes
+ Social phobia
+ Meta-analysis/reviews
+ Cotherapy
+ Long-term therapy
+ Comparison versus cognitive behavioural group therapy
+ Blood-injury phobia
+ Other anxiety disorders
+ Obsessive–compulsive disorder
+ Post-traumatic stress disorder
+ Childhood anxiety
+ Hallucinogen persisting perception disorder
o Efficacy in other psychiatric disorders
+ Acute mania
+ Cotherapy
+ Augmentation therapy in depression
+ Long-term therapy
o Plasma concentration, dose and response
o Safety
+ Tolerability
+ Discontinuation and withdrawal symptoms
+ Discontinuation with cotherapy
* Conclusions
* Acknowledgements
* ReferencesGraphics
* Table 1
Abstract^
An updated overview over the past decade is provided with respect to the use of clonazepam in a variety of psychiatric disorders. The efficacy of clonazepam monotherapy for the short-term treatment of panic disorder (PD) was fully established in two large pivotal multicentre studies in the late 1990s in a total of >800 patients. Other studies support a role for clonazepam, in association with selective serotonin reuptake inhibitors (SSRIs), to accelerate treatment response in PD. Although some longitudinal data suggest an ability to maintain improvement without tolerance for up to 3 years, long-term controlled studies of clonazepam in PD are lacking. Studies have shown that clonazepam can also block CO2-induced panic and improve certain aspects of quality of life in PD. Clonazepam has shown some efficacy in social phobia; however, because this evidence is based on few studies, further studies are warranted before definitive conclusions can be drawn. Finally, evidence for the use of clonazepam in acute mania and as augmentation therapy with SSRIs to accelerate response in depression is examined. The long half-life and higher potency of clonazepam may allow easier discontinuation with fewer withdrawal symptoms compared to other benzodiazepines and studies using a slow clonazepam taper appear promising.
Introduction^
Clonazepam, a benzodiazepine with anticonvulsant and anxiolytic properties, is increasingly used in various psychiatric disorders. In addition to activation of the benzodiazepine-GABA receptor complex, unlike many other benzodiazepines, clonazepam appears to have serotonergic effects, which may contribute to its psychotropic and antimyoclonic effects (Moroz, 2004).
Clonazepam is a high-potency benzodiazepine with greater receptor affinity than, for example, alprazolam; it is approximately twice as potent as alprazolam on a mg per mg basis (Bennett et al., 1998) and may potentially achieve a therapeutic effect at lower doses. Clonazepam also has a long elimination half-life (typically 30–40 h), high bioavailability and a rapid onset of action: maximum plasma concentrations occur 1–4 h after oral administration and responses can be seen as quickly as 1–2 h post-dose. The long half-life and higher potency of clonazepam may allow easier tapering of dosage and potentially fewer withdrawal symptoms compared to other benzodiazepines when tapered (Bennett et al., 1998).
Here, an updated overview over the past decade is provided with respect to the use of clonazepam in a variety of psychiatric disorders. A search of MEDLINE was conducted for the period 1 January 1994 to 1 April 2004 using the search term clonazepam (in humans) alone and in combination with the following terms: panic disorder, social phobia, anxiety, obsessive–compulsive disorder (OCD), post-traumatic stress disorder, depression or mania. From these searches, the authors identified English language papers of studies or reviews (excluding case reports) of clonazepam use in psychiatric disorders that were considered suitable for inclusion in the review. The review was augmented with relevant non-English language papers with English abstracts and additional key review papers in the indications in the above list where these were considered by the authors to be relevant, and also one recent clinical paper on long-term clonazepam use (Nardi et al., 2005). Although not part of the original scope of this review, we also performed a MEDLINE search using the terms clonazepam and simple phobia or clonazepam and blood injury phobia to identify any publications on the use of clonazepam in these disorders. A summary of the clinical studies of clonazepam included in the review is presented in Table 1.
Table 1 Clinical studies of clonazepam in psychiatric disorders 1994–2004 (excluding meta-analyses/reviews)aCBGT, Cognitive behavioural group therapy; CGI, clinical global impression; CO, crossover; DB, double-blind; HAM-A, Hamilton Anxiety Scale; HAM-D, Hamilton Depression Rating Scale; HPPD, hallucinogen persisting perception disorder; max, maximum; min, minimum; NA, not available; PC, placebo-controlled; PG, parallel group; OCD, obsessive–compulsive disorder; PD, panic disorder; PTSD, post-traumatic stress disorder; QOL, quality of life; R, randomized; SF-36, Medical Outcomes Study 36-Item Short Form Health Survey; SP, social phobia; SSRI, selective serotonin reuptake inhibitor; UC, uncontrolled.aA recent study by Nardi et al. (2005) has also been included.
Efficacy in anxiety disorders^
Panic disorder^Benzodiazepines are one of several drug classes [selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monamine oxidase inhibitors (MAOIs)] with approximately comparable efficacy in panic disorder (PD). American Psychiatric Association (APA) guidelines recommend that treatment choice should be based on individualized assessment (APA, 1998). Non-benzodiazepine antipanic medication and cognitive behavioural therapy (CBT) often take weeks before beneficial effects are realized, and some patients express an urgent need for a diminution of both high levels of anticipatory anxiety and severity of panic attacks. Consequently, benzodiazepines may be preferentially used when very rapid control of symptoms is critical (APA, 1998). Interestingly, despite guideline recommendations supporting the use of SSRIs, in a study over the last decade, benzodiazepines were the most commonly used medication for PD (Bruce et al., 2003). Moreover, the clinical course of SSRI users was found to be no more favourable than that of benzodiazepine users; patients whose PD remitted were no more likely to be receiving SSRIs or benzodiazepines before remission (Bruce et al., 2003).
Pivotal studies with clonazepam in panic disorder^The efficacy of clonazepam in PD was first noted in the 1980s and early 1990s. However, the efficacy of clonazepam was fully established in two large pivotal multicentre studies in the late 1990s in a total of >800 patients (Rosenbaum et al., 1997; Moroz and Rosenbaum, 1999). These were a 6-week dose-optimization study (clonazepam 0.5–4 mg/day titrated over 3 weeks and then maintained at the optimal dose for 3 weeks) (Moroz and Rosenbaum, 1999) and a 9-week dose–response study (clonazepam dose escalated over 3 weeks to 0.5–4 mg/day followed by a 6-week fixed-dose phase) (Rosenbaum et al., 1997); both studies utilized a 7-week discontinuance phase. In the dose-optimization trial (mean optimized dose 2.3 mg/day), clonazepam was clinically and statistically superior to placebo in change in number of panic attacks, Clinical Global Impression (CGI) Severity of illness and Change scores, Patient's Global Impression of Change scores, duration of anticipatory anxiety and amount of fear and avoidance associated with phobic symptoms (Moroz and Rosenbaum, 1999). At the therapeutic endpoint, the proportion of patients panic-free was 61.9% with clonazepam versus 36.8% with placebo (P<0.001); reduction in anxiety [according to Hamilton Anxiety Rating Scale (HAM-A)] was also significantly greater with clonazepam (P<0.001). In the dose–response study, 9 weeks of clonazepam at 1 mg/day (minimum effective dose) achieved panic-free rates of 73% versus 55% with placebo (P<0.05). The 1 mg dose showed the most consistent significant differences from placebo in panic attack frequency, phobic fear and avoidance, and CGI scores for severity of illness and change from baseline, and intensity of anticipatory anxiety. Together, these trials suggested an optimal clonazepam dose for most PD patients of 1–2 mg/day.
Other clonazepam studies in panic disorder^The efficacy of clonazepam in PD has been further confirmed in the last decade in two small, short-term (<=6 weeks) placebo-controlled studies in 32 and 24 patients, respectively, using both flexible (Beauclair et al., 1994) and fixed-dose (Valenca et al., 2000) regimens. In the fixed-dose trial, clonazepam 2 mg/day achieved panic-free status in 61.5% of patients versus 11% on placebo (P=0.031). In the flexible-dose study (mean clonazepam dose 2.2 mg/day at week 4), the response (>=50% reduction from baseline in CGI-severity of PD score) rate was 85% with clonazepam versus 6% with placebo (P<0.001) at week 4. The most common adverse event in these studies was somnolence/drowsiness. Finally, a recent review considered that the results from both open and controlled clinical trials, and trials of CO2-induced panic attacks, established the inclusion of clonazepam in the group of drugs with proven efficacy in PD (Nardi, 2001).
Long-term therapy^PD is a chronic condition often requiring ongoing treatment in clinical practice. Indeed, many patients, although improved, remain partially symptomatic and relapse rates with treatment discontinuation remain relatively high (Worthington et al., 1998). Few studies have examined the long-term use of clonazepam in PD. A naturalistic PD outpatient study examined the use of clonazepam in patients with a primary diagnosis of PD with (78%) or without (22%) agoraphobia. Comorbid disorders included social phobia (30%), simple phobia (32%), generalized anxiety disorder (25%), major depression (11%) and OCD (5%). Fifty-seven patients were receiving clonazepam alone, 36 were receiving clonazepam plus ‘other medications’ and another 111 patients were receiving other treatment (unspecified), which did not include clonazepam. In patients receiving clonazepam+‘other medications’, the medications included: TCAs in 50% of patients; SSRIs in 22%; another benzodiazepine in 36%; MAOIs in 3%; TCA+SSRI in 3%. Remission rates were 51.5% for clonazepam alone, 63.6% for clonazepam plus ‘other medications’ and 67.5% for those receiving no clonazepam at the 2-year follow-up. There was no significant difference between clonazepam doses at baseline or 2-year follow-up (1.39 mg and 1.59 mg/day, respectively, for clonazepam alone and 2.00 mg and 1.99 mg/day, respectively, for clonazepam+other medications) in the two groups receiving clonazepam (Worthington et al., 1998). Remission rates tended to improve over time and were similar for patients receiving clonazepam versus those receiving no clonazepam (other medications only). This maintenance of improvement without the need for dose escalation suggests that therapeutic tolerance to clonazepam did not develop. In a recent trial, Nardi et al. (2005) described the therapeutic response of respiratory PD patient subtypes versus non-respiratory subtypes openly treated with clonazepam for a 3-year period. In the first 8 weeks of treatment (acute phase), the respiratory subtype group had a significantly faster response on all major scales. During the follow-up (week 12 to week 156), there was no difference in the scores, and the reduction in panic attacks from baseline to end-point did not differ significantly between the two groups. In the clonazepam 3-year follow-up, the respiratory subtype had a faster response at 8 weeks and an equivalent response in the follow-up period. Clonazepam had a sustained drug effect during the whole treatment period.
A critical issue for the maintenance of longer-term benefit after discontinuation may be symptom severity before discontinuation rather than duration of treatment, with optimal outcome relying on achieving remission before treatment withdrawal/taper (Doyle and Pollack, 2004). A study of patients in remission after 6 months of imipramine therapy found no difference in relapse rates after discontinuation in patients treated for 6 months compared to those treated for 12–30 months (Mavissakalian and Pereal, 2002).
Clonazepam cotherapy^Despite their usefulness in PD, SSRIs/serotonin-noradrenaline reuptake inhibitors (SNRIs) are associated with a delay of several weeks in onset of therapeutic effect and have the potential to exacerbate anxiety and panic early in the treatment course. Therefore, a relatively common practice is to combine SSRIs/SNRIs with benzodiazepines to provide more rapid, and potentially additive, clinical efficacy. Two placebo-controlled trials have examined early coadministration of clonazepam and SSRIs in PD. Goddard et al. (2001) combined clonazepam (1.5 mg/day) or placebo with sertraline (target dose 100 mg/day) in 50 patients with moderate to severe PD for 4 weeks, followed by a 3-week clonazepam taper. Response rates after weeks 1 and 3 were significantly (P<=0.05) higher with clonazepam/SSRI versus placebo/SSRI (41% versus 4% and 63% versus 32%, respectively). In a second 12-week study in 60 PD patients (Pollack et al., 2003), clonazepam plus paroxetine was compared with placebo/paroxetine [clonazepam was given for 5 weeks (mean dose titrated to 1.6 mg/day by week 5) and then either discontinued (3-week taper) or continued; paroxetine was titrated to 40 mg/day by week 4]. The clonazepam/paroxetine groups displayed an earlier onset of response with significant advantage in the PD Severity Scale from weeks 1–5 versus placebo/paroxetine (P<0.05); there appeared to be no additional benefit in maintaining benzodiazepine after week 5. Together, these studies suggest that early coadministration of clonazepam/SSRI therapy (followed by benzodiazepine taper after a few weeks) may provide early improvement and be a clinically useful strategy to achieve rapid stabilization of PD patients.
Quality of life^PD is associated with a seriously degraded quality of life (QOL) and impaired work-related productivity. In a trial in 144 patients, a 6-week regimen of clonazepam (titrated to 4 mg/day by week 3; dose then maintained for 3 weeks) significantly (P<0.05) improved mental health-related QOL and work productivity compared to placebo (treatment was followed by a <=6-week tapered withdrawal) (Jacobs et al., 1997). Indeed, the improvement in work productivity with clonazepam compared to placebo was equivalent to 6 h of full productivity per week. These authors considered it reasonable to attribute the greater mental health-related improvement with clonazepam to its greater amelioration of PD symptoms.
CO2-induced panic attacks^CO2 increases anxiety and induces panic attacks in PD patients (Valenca et al., 2002a). Moreover, CO2-induced panic appears to be a valid analogue of spontaneous panic attacks (Nardi et al., 1999). A true antipanic agent should therefore block CO2-induced panic as well as spontaneous attacks (Rosenbaum, 2004). Several studies have examined the efficacy of clonazepam in CO2-induced attacks. In a pilot study in six PD patients, CO2-induced attacks were attenuated after approximately 10 days treatment with clonazepam 2 mg/day (Nardi et al., 1999). In an open trial, 12 of 14 PD patients (86%) who had had a panic attack after CO2 challenge-test at baseline did not have a panic attack after the CO2 challenge-test after 6 weeks of clonazepam 2 mg/day (Valenca et al., 2002a). In a trial in 22 PD patients, a CO2 challenge-test induced a panic attack (mild) in only 18% of patients after single-dose clonazepam 2 mg compared to 82% of placebo recipients (moderate-severe attack) (Nardi et al., 2000). These findings were confirmed in a double-blind study of 34 PD patients, where the panicogenic effect of CO2 was significantly attenuated after acute dosing with clonazepam and also after 2 and 6 weeks of treatment (2 mg/day) compared to placebo (Valenca et al., 2002b). A possible mechanism for clonazepam may involve reducing the activity of brainstem centres that receive input from the central nucleus of the amygdala and which control autonomic response during exposure to CO2 (Valenca et al., 2002b; Gorman et al., 2000).
Panic disorder subtypes^PD is common in patients with recurrent chest pain but normal coronary arteries. In a 6-week study in 27 such patients with PD, the proportion of responders (HAM-A total score <=50% of baseline score) at week 4 was significantly higher in the clonazepam (1–4 mg/day) group (58% versus 14% on placebo, P=0.038) (Wulsin et al., 1999). However, evidence of clonazepam efficacy was otherwise not consistent and further studies are needed in this population.
PD subtypes have been described (e.g. respiratory and non-respiratory) and studies have tried to associate different subtypes with different responses to treatments (Briggs et al., 1993). Clonazepam 2 mg/day for 6 weeks was significantly superior to placebo in panic attack remission and reduction in anxiety in a study of 34 PD patients; clonazepam was equally effective in respiratory and non-respiratory subtypes (Valenca et al., 2003).
Social phobia^Clonazepam has also shown evidence of efficacy in social phobia (social anxiety disorder). The largest study was a 75-patient, double-blind study reported in the early 1990s showing that clonazepam (up to 3 mg/day) for up to 10 weeks achieved a response in 78% of patients versus 20% with placebo (Davidson et al., 1993). In a 2-year retrospective follow-up study, 56 of these patients were evaluated using telephone interview and self-report questionnaires (Sutherland et al., 1996). The results suggest that short-term treatment with an effective therapy such as clonazepam in social phobia may be associated with longer-term benefits because, at follow-up, the group as a whole showed maintenance of the gains made in initial treatment. Indeed, clonazepam-treated patients showed significantly lower symptom scores than placebo on a number of rating scales; perhaps the beneficial effects of clonazepam therapy provided the impetus for these patients to seek further treatment, which afforded longer-term benefits. The 78% response rate with clonazepam contrasts with reported rates as low as 38% with alprazolam (Gelernter et al., 1991).
In a more recent open, uncontrolled study of 40 social phobia patients, clonazepam was highly efficacious; after 16 weeks of treatment with clonazepam (mean 4.8 mg/day), the majority of cases (86.8%) showed a very robust degree of improvement in a combination of the three main outcome measures compared to baseline (Versiani et al., 1997).
Meta-analysis/reviews^In a recent meta-analysis of pharmacotherapy for social anxiety disorder (Blanco et al., 2003), although only the above 75-patient, double-blind study was included for clonazepam (Davidson et al., 1993), this had the largest Liebowitz Social Anxiety Scale (LSAS) effect size of all medications. However, the authors considered that further trials were needed to confirm the extent of efficacy of clonazepam before claims of superior efficacy can be established (Blanco et al., 2003). Nevertheless, these authors noted that, although not statistically significant, the effect size estimate for SSRIs was substantially smaller than for clonazepam. This strengthens the case for clonazepam as a promising alternative in the pharmacotherapy of social phobia. In a review of 19 placebo-controlled trials, which considered two controlled trials with clonazepam and bromazepam, these benzodiazepines were positioned together with SSRIs relative to efficacy (Versiani, 2000); however, despite such similarities in efficacy, the clinician has to be aware of the adverse effects associated with each of these drug classes. Finally, in a comprehensive review of social anxiety disorder, examination of pharmacological therapies found that benzodiazepine, monoamine oxidase inhibitor and SSRI treatments yielded the highest effect sizes (Hidalgo et al., 2001).
Cotherapy^Although SSRIs are the most studied drugs for social phobia (Davidson et al., 1993; Van Ameringen et al., 2003), benzodiazepines may benefit patients refractory to other treatments or as augmenting agents. Only 20–30% of patients experience significant remission and so adjunctive medications may be particularly useful in improving outcome (Seedat and Stein, 2004). Coadministration of clonazepam with an SSRI has only recently been investigated in social phobia. However, in contrast to PD, cotherapy comprising clonazepam (1–2 mg/day) with paroxetine (20–40 mg/day) for 10 weeks (followed by a 2-week taper and 8-week SSRI open-label therapy) did not achieve more rapid resolution of social phobia symptoms (Seedat and Stein, 2004). Nevertheless, at 10 weeks, a trend in favour of the clonazepam augmentation group was noted (79% response rate versus only 43% with paroxetine/placebo, P<0.06). Failure to achieve statistical significance may be a consequence of the small population (28 patients) and relatively low clonazepam dose. Indeed, the group effect size (based on LSAS) was 1.7 for clonazepam/paroxetine at week 10 and 1.9 at week 20 (versus 1.0 and 1.2, respectively, for paroxetine/placebo), suggesting that efficacy gains persisted after clonazepam withdrawal. The relatively high non-response and non-remission rates in this disorder warrant further investigation of such combination strategies in larger populations.
Long-term therapy^In the first controlled investigation of long-term benzodiazepine treatment and discontinuation in social phobia, patients responding well to 6 months of open-label clonazepam (doses titrated up to 1–2.5 mg/day) were randomized to treatment continuation for 5 months (at the same dose) or slow-taper discontinuation (Connor et al., 1998). Relapse rates were markedly lower with continuation of clonazepam (0% versus 21% for discontinuation) and the results were significant on Kaplan–Meier survival analysis (P<0.05) with a shorter time to relapse in the discontinuation group. Clinical efficacy scales at endpoint also favoured the continuation group. This preliminary evidence suggested that continuation therapy with clonazepam for social phobia is well tolerated and effective.
Comparison versus cognitive behavioural group therapy^In a meta-analysis, CBT and pharmacotherapy were shown to have approximately equal efficacy in social phobia (Gould et al., 1997). Indeed, the effect size for clonazepam was similar to the overall effect size for CBT. In a recent 12-week study, the efficacy of clonazepam (titrated to maximum of 4 mg/day) was compared with cognitive behavioural group therapy (CBGT) in 45 social phobia patients (Otto et al., 2000). Overall, there were few differences in efficacy between the two treatments. Patients were considered equally likely to respond to clonazepam or CBGT during the acute treatment phase. Nevertheless, at week 12, there was a significantly better outcome with clonazepam in several patient-rated measures including the Fear of Negative Evaluation Scale, the Rathus Assertiveness Schedule and the Social Interaction Anxiety Scale.
Blood-injury phobia^In one study into social phobia, clonazepam was shown to be significantly more effective than placebo in reducing the blood-injury phobia subscale of the Marks Fear Questionnaire after 10 weeks (Davidson et al., 1994). The authors suggested that clonazepam may deserve further investigation in the treatment of blood-injury phobia.
Other anxiety disorders^
Obsessive–compulsive disorder^Guidelines indicate that SSRIs are the most effective medications for OCD (Expert Consensus Panel, 1997). However, there is often a therapeutic lag before achieving full response. In addition, most responders report only a partial reduction in symptoms and not all patients may tolerate the potential side-effects of SSRIs (Hollander et al., 2003). In an earlier randomized, multiple crossover study, clonazepam was shown to be effective in reducing OCD symptoms compared to control medication (diphenhydramine) (Hewlett et al., 1992). However, recent data, from a 10-week placebo-controlled trial in 27 patients suggest that clonazepam (intent-to-treat mean maximum dose 3.2 mg/day) is not effective as monotherapy in OCD, with response rates to clonazepam no different to those with placebo (Hollander et al., 2003). A similar lack of efficacy was found with alprazolam in an open study in 14 OCD patients (Stein et al., 1992). Moreover, in a recent study comparing the combination of sertraline plus clonazepam versus sertraline plus placebo, there was no significant difference in effect on OCD symptoms between groups (Crockett et al., 2004). However, clonazepam augmentation therapy has been reported to improve anxiety symptoms in OCD (Pigott et al., 1992) and it is possible that such augmentation may benefit OCD patient subgroups with comorbid panic or social phobia.
Post-traumatic stress disorder^There are few data on benzodiazepine use in post-traumatic stress disorder (PTSD) and it was recently suggested that benzodiazepines should be used with caution in this condition (Davidson, 2004). Experience with clonazepam is very limited. One earlier report in five patients with multiple personality disorder and PTSD showed positive results with long-term clonazepam (1–5 mg/day) therapy (Loewenstein et al., 1988; Sutherland and Davidson, 1994). However, in a more recent study in 13 trauma survivors, early administration of clonazepam (n=10; mean dose 2.7 mg/day) or alprazolam (n=3; mean 2.5 mg/day), continued for 1–6 months, although reducing physiological expression of arousal, failed to show a beneficial effect on the course of PTSD (Gelpin et al., 1996).
Childhood anxiety^There is little published literature on the efficacy of benzodiazepines in child/adolescent anxiety. A small, placebo-controlled, crossover study was conducted in 12 children aged 7–13 years with anxiety disorders (11 with separation anxiety disorder) using clonazepam up to 2 mg/day for 4 weeks (Graae et al., 1994). Although nine children had moderate or marked clinical improvement in response to clonazepam, this trend for clinical benefit over placebo was not confirmed statistically. Nevertheless, these authors believed that there was sufficient evidence to warrant a larger study of benzodiazepine efficacy in childhood anxiety.
Hallucinogen persisting perception disorder^Benzodiazepines are one of the recommended treatments for hallucinogen persisting perception disorder (HPPD) and a tendency for prescribing low-potency agents has been noted (Lerner et al., 2003). However, in a recent preliminary trial in 16 patients with LSD-induced HPPD with anxiety features, clonazepam 2 mg/day for 2 months was associated with a significant improvement (e.g. significant relief of visual disturbances and accompanying anxiety features), which was sustained during a 6-month follow-up period (Lerner et al., 2003). These authors thus suggest that high-potency long-acting benzodiazepines such as clonazepam may be preferable to low-potency short-acting agents in the management of HPPD.
Efficacy in other psychiatric disorders^
Acute mania^APA guidelines for acute manic or mixed episodes suggest that the sedative effects of benzodiazepines may make them effective treatment adjuncts while awaiting the effects of a primary antimanic agent to become evident or in severely ill or agitated patients (APA, 2002a). Of five randomized controlled studies of clonazepam identified in acute mania (Curtin and Schulz, 2004), only one, a 4-week comparative study versus lithium, was conducted within the last decade (Clark et al., 1997). Because these trials were conducted in small (<=40) patient populations, a Bayesian hierarchical meta-analysis with three models was used to compare the efficacy of clonazepam and lorazepam in acute mania versus placebo, lithium, haloperidol or each other (Curtin and Schulz, 2004). In all three models, clonazepam reduced psychopathology scores statistically significantly, with a standardized response magnitude of around 1.2. By contrast, lorazepam yielded a non-significant standardized response of around 0.8 in these models. These results suggest a trend towards a higher efficacy of clonazepam versus lorazepam and suggest that clonazepam is efficient in reducing symptoms of acute mania even when used as monotherapy.
Finally, in an uncontrolled trial in 11 newly admitted patients with an affective/schizoaffective disorder, clonazepam (mean daily dose 5.3 mg on day 14) administered for 14 days was associated with a significant reduction in manic symptoms and 67% of patients completing the trial were markedly improved (Bottai et al., 1995). Clonazepam in combination with lithium and carbamazepine or valproate has been proposed as a third-choice therapy in rapid cycling, a clinical subtype of manic-depressive illness (Yamada, 1999).
Cotherapy^APA guidelines recommend combination therapy for patients inadequately controlled within 10–14 days of optimized-dose first-line treatment (APA, 2002b). The combination of clonazepam (given twice daily at a fixed dose of 1 mg in the morning and 2 mg in the evening; up to 2 mg/day additional per need medication in week 1 only) with the antipsychotic zuclopenthixol (20 mg/day) has been compared with clonazepam plus lithium (dose adjusted to achieve serum levels of 0.9–1.0 mEq/l) for the treatment of manic episodes in 28 hospitalized patients (Gouliaev et al., 1996). After 4 weeks of treatment, neither regimen was superior, with approximately two-thirds of patients fully or partially improved in both treatment groups and with no significant difference in treatment acceptability or tolerance.
Augmentation therapy in depression^Antidepressants such as SSRIs typically involve a 2–4-week delay in full efficacy onset, and benzodiazepines have been used as augmentation therapy to reduce the anxiety and insomnia components of the illness and the stimulating side-effects of SSRIs. In an 8-week, double-blind study in 80 patients with major depression, a clonazepam (titrated to maximum of 1 mg/day until day 10, dose then maintained until tapered withdrawal from day 21–33)/fluoxetine (20–40 mg/day) combination was superior to fluoxetine monotherapy (i.e. plus placebo) in relieving symptoms of moderate to marked depression, especially during the first 3 weeks (i.e. accelerated response) (Smith et al., 1998). In 10 days, clonazepam/fluoxetine achieved the same improvement in the Hamilton Depression Rating Scale (HAM-D) that fluoxetine alone reached by day 56. Further analysis showed that clonazepam cotherapy decreased anxiety and sleep disturbance as symptoms and partially suppressed them as SSRI adverse effects; it also modestly reduced core symptoms of low mood and loss of interest (Londborg et al., 2000). This was consistent with the concept of benzodiazepines such as clonazepam having a direct or synergistic antidepressant effect. To examine the potential long-term benefits of cotherapy, 50 outpatients with moderate-marked depression received 18 weeks of clonazepam/fluoxetine (clonazepam up to 1 mg/day for 2 weeks, steady dosing continued to week 12, then a 3-week taper, then no clonazepam for 3 weeks) or fluoxetine (20–40 mg/day)/placebo (Smith et al., 2002). Cotherapy was superior to fluoxetine monotherapy only at day 7 (HAM-D and CGI-Improvement); the only significant benefit of extending treatment was a more rapid response to increased fluoxetine dose (at 6 weeks).
A recent small (n=38), 4-week open study, examined whether the response to clonazepam (3 mg/day) augmentation therapy differed in unipolar versus bipolar depression (Morishita and Aoki, 2002). After 4 weeks of clonazepam supplementation of antidepressant therapy, 84% of patients with unipolar depression had improved compared to only 10.5% of those with bipolar depression (P<0.05). However, further controlled trials using stricter patient classification are needed before conclusions can be drawn. In a study of 69 patients with prolonged depression undergoing augmentation therapy, clonazepam 3 mg/day was more effective (80% improvement) than 1.5 mg/day (29% improvement) (Morishita and Aoki, 1999). Finally, average clonazepam doses of 2.4–6.54 mg/day for 3–4 weeks achieved complete remission in 60% of 55 patients with depressive disorder (Svestka et al., 1995).
Long-term therapy^The long half-life of clonazepam may facilitate efficacy in maintenance therapy of affective disorder. In a retrospective chart review of 34 patients who received clonazepam (mean 2 mg/day as monotherapy or adjunctive therapy in lithium non-responders) for a mean of 1.5 years, those with unipolar depression had significantly fewer depressive episodes, whereas those with bipolar disorder did not benefit (Winkler et al., 2003). Thus, clonazepam may be effective as a long-term treatment option in major depressive disorder. However, such preliminary findings require confirmation in prospective randomized controlled trials.
Plasma concentration, dose and response^In PD patients, clonazepam plasma concentrations correlated significantly with therapeutic improvement by the global assessment of illness (with similar trends for decreases in attack intensity and frequency), and also with dosage (in agreement with Labbate et al., 1994), indicating good compliance (Beauclair et al., 1994). Correlations of plasma clonazepam levels with dose were also noted in acute mania patients (therapeutic range: 6.5–83.9 µg/l) (Bottai et al., 1995).
Safety^
Tolerability^Somnolence is the most frequent adverse event associated with clonazepam therapy in clinical studies (Beauclair et al., 1994; Rosenbaum et al., 1997; Moroz and Rosenbaum, 1999; Valenca et al., 2000). From pooled data for the two large US multicentre PD trials, the other most common events with clonazepam included depression, abnormal coordination and ataxia [Klonopin® (clonazepam) product information, 2001]; in the dose–response study, somnolence and ataxia were clearly dose-related. In these two trials, depression was a patient complaint/adverse event and not a formal clinically established diagnosis; moreover, a larger decline in HAM-D scores in the clonazepam group suggested that clonazepam-treated patients were not experiencing a worsening or emergence of clinical depression. Clonazepam has not been commonly associated with sexual dysfunction; however, in a retrospective study of the records of male veterans with PTSD who had received clonazepam (mean maximum dose 3.4 mg/day) for a mean of 6.5 months, sexual dysfunction was reported in 43% of patients who had received clonazepam at some point during their treatment (Fossey and Hamner, 1995); however, these patients had a significantly higher mean highest dose and a longer duration of treatment compared to those with no mention of sexual dysfunction. In an earlier study in social phobia, the incidence of clonazepam-related sexual dysfunction was much lower (15%) (Davidson et al., 1991).
The safety and efficacy of clonazepam in patients <18 years with PD has not been established; however, clonazepam is approved for use in children with epilepsy. There is no clinical trial experience with clonazepam in PD patients >=65 years and it is recommended that, in general, elderly patients should be started on low doses and observed closely [Klonopin® (clonazepam) product information, 2001]. However, the tolerability of clonazepam has been assessed in a series of demented and non-demented geropsychiatric patients receiving clonazepam (mean dose of 1.2 mg for a minimum of 2 weeks) for acute mania, breakthrough anxiety or agitation resistant to other treatments (Calkin et al., 1997). These patients showed improvement in functional ability with no increases in reported side-effects. Thus, clonazepam did not cause a worsening of symptoms and shows promise as a benzodiazepine with good tolerability in the elderly.
SSRI/benzodiazepine coadministration may result in a pharmacokinetic interaction (e.g. fluvoxamine with alprazolam in vitro and fluoxetine with alprazolam) (Greenblatt et al., 1992; Von Moltke et al., 1995). However, 10 days of sertraline (100 mg/day) coadministration did not alter the pharmacokinetics or pharmacodynamics of clonazepam (1 mg/day) in healthy volunteers (Bonate et al., 2000).
Discontinuation and withdrawal symptoms^A major risk of benzodiazepine therapy is the abuse potential associated with long-term use. Most concerns about benzodiazepine withdrawal and dependence are based on studies in PD and generalized anxiety disorder, both of which may be associated with enhanced sensitivity to somatic stress. Patients with PD are very sensitive to bodily sensations, making treatment discontinuation difficult (Rosenbaum, 2004). Problems of benzodiazepine withdrawal and dependence may be, in part, diagnosis-specific or partially determined by the particular benzodiazepine used and the rate of withdrawal (Connor et al., 1998). For example, in one study, rapid discontinuation (<=4 weeks) of alprazolam was associated with rebound panic in 27% of patients and withdrawal symptoms in 35% during taper (Pecknold et al., 1988). The short half-life of alprazolam increases the likelihood of inter-dose recurrence of symptoms (Bennett et al., 1998). In another study in PD patients, a 4-week taper resulted in a withdrawal syndrome in almost all alprazolam-treated patients and one-third were unable to discontinue their medication regimen successfully (Rickels et al., 1993).
Although withdrawal symptoms can occur with abrupt discontinuation, the longer half-life of clonazepam (allowing administration twice daily, as opposed to four times daily for alprazolam) minimizes the risk of inter-dose rebound anxiety. The longer half-life and higher potency of clonazepam may allow easier tapering/withdrawal; this could result in fewer symptoms of withdrawal than other benzodiazepines when tapered (Bennett et al., 1998), although the rate of withdrawal remains a factor (Connor et al., 1998).
In the two large US multicentre trials in PD, overall the 7-week discontinuation periods were associated with good tolerability and a very modest clinical deterioration without evidence of a significant rebound phenomenon [Klonopin® (clonazepam) product information, 2001]. In a long-term study in social phobia (Connor et al., 1998), using a slow taper (0.25 mg every 2 weeks for up to 18 weeks) after 6 months of treatment, the overall degree of benzodiazepine withdrawal was mild, with no significant difference in withdrawal symptoms between patients discontinued and those continuing clonazepam therapy. However, a rapid 3-week taper after 1 year of treatment appeared to be associated with more evident withdrawal symptoms. Further well-controlled long-term studies are needed to fully determine the risks of withdrawal symptoms associated with clonazepam in psychiatric disorders.
Discontinuation with cotherapy^In the 18-week study of clonazepam/fluoxetine cotherapy for patients with depression, clonazepam discontinuation after 3 months using a 3-week taper was not associated with regression in efficacy, discomfort or significant increases in adverse events (Smith et al., 2002). Similarly, uneventful discontinuation of clonazepam was observed using 3-week tapers after 4 or 5 weeks of cotherapy with sertraline (Goddard et al., 2001) or paroxetine (Pollack et al., 2003) for PD.
Conclusions^Benzodiazepines, such as clonazepam, are one of the most broadly effective pharmacotherapies for a variety of anxiety and other psychiatric disorders. Clonazepam has well-established efficacy and safety for the short-term treatment of PD as monotherapy and some studies support a role, in association with serotonin reuptake inhibitors, to accelerate treatment response. Encouraging longitudinal data suggest an ability to maintain improvement without tolerance for up to 2 years (Worthington et al., 1998) or 3 years (Nardi et al., 2005), respectively; however, because PD is a chronic condition and thus long-term treatment is often needed, a definitive statement on the usefulness of clonazepam in PD relies on the results of long-term controlled studies, which are currently lacking. The validity of clonazepam in the treatment of PD is also supported by evidence of its ability to block CO2-induced panic and to improve certain aspects of QOL in PD. Clonazepam has also shown strong efficacy in social phobia; however, because this evidence is based on few studies, further studies are warranted before definitive conclusions can be drawn. Finally, some evidence suggests that treatment with clonazepam might be useful in acute mania and that augmentation therapy with SSRIs might be helpful to accelerate response in depression.
Long-half life and higher potency are the two main characteristics that give clonazepam a specific and potentially unique value among benzodiazepines because they might allow easier discontinuation with fewer withdrawal symptoms than other benzodiazepines; studies using a slow clonazepam taper appear promising, with generally few reports of major problems in terms of withdrawal symptoms or rebound phenomena.
Acknowledgements^This study was supported by an unrestricted educational grant from F. Hoffmann-La Roche Ltd, Basel, Switzerland. Professor A.E. Nardi has received grants as a speaker from F. Hoffmann-La Roche Brazil, Pfizer, GlaxoSmithKline and Solvay Pharmaceuticals.
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Keywords: acute mania; anxiety disorder; clonazepam; panic disorder; social phobia
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