Classically, benzodiazepines have been used to treat anxiety disorders, and indeed, they have been remarkably effective in reducing the symptoms of generalized anxiety. In addition, selected benzodiazepines have been found to assist in the treatment of panic disorder with and without agoraphobia.1'1 Obsessive compulsive disorder (OCD) is classified as an anxiety disorder; however, the utility of benzodiazepines in this disorder has not been firmly established at this time.
DIAGNOSIS OF OCD
OCD is characterized by the presence of obsessions and/or compulsions. Obsessions are egodystonic thoughts or fears, often unusual or exaggerated in their character, which the individual generally attempts to ignore, with little success. Compulsions are ritualized or stereotyped behaviors that the individual carries out to alleviate a dreadful sense of discomfort. They are carried out either as a response to the obsessive fears or to relieve an overwhelming sense of incompletion or disarray. Obsessions and compulsions will interfere with the ability of afflicted individuals to carry out activities of daily living or to engage in their normal social relationships. These individuals are plagued by the uncertainty and urgency that rules their daily lives.
The proper diagnosis of OCD is particularly important in evaluating the usefulness of medications for treating this disorder. We have noted considerable confusion among practicing psychiatrists regarding the diagnosis of OCD, due in part to a definition that has changed over time, and in part to the nomenclature of the diagnostic manuals (DSM-IH5 and DSMIII-R6), which describe both Obsessive Compulsive Disorder and the Compulsive5 or Obsessive Compulsive Personality Disorder.6 It is important to note that while certain individuals with OCD may have obsessive compulsive personality traits, only 20% to 25% actually have compulsive personality disorder as defined by DSM-III criteria.7
It is beyond the scope of this review to detail the differential diagnosis of obsessions and compulsions; however, obsessions must be distinguished from phobias, ruminations, excessive worries, pathological romantic or sexual attractions, perseverative thinking, and other forms of intrusive or preoccupying thought processes. Likewise, the compulsions of OCD must be distinguished from meticulous or rigid behaviors occurring in the setting of obsessive compulsive personality traits. Similarly, driven or motivated behaviors (impulsive behaviors), which are carried out to gratify an urge or attraction, must be distinguished from the compulsions of OCD, which represent attempts to escape a dreadful or aversive internal experience.
TREATMENT OF OCD
Current treatment of OCD differs from the treatment of anxiety. The standard treatment for OCD involves the use of serotonin selective reuptake inhibitors - medications that block the neuronal uptake of serotonin to a far greater extent than they do other neurotransmitters. These medications include the antidepressant clomipramine, the best studied of the medications in OCD, as well as fluoxetine, fluvoxamine, sertraline, and paroxetine. The serotonergic reuptake inhibitors have consistently proved to be more effective than antidepressants, which affect noradrenergic uptake or monoamine oxidase.8
While the serotonergic reuptake inhibitors have been found effective in OCD, there has been remarkably little study of the efficacy of the benzodiazepines in this disorder. The findings from early studies of benzodiazepines in treating obsessional disorders are briefly reviewed below. However, caution must be used in interpreting the results of these studies because the diagnostic categories and criteria employed do not correspond consistently to those in use today.
The earliest reports of the use of benzodiazepines for "obsessional states" consisted of case reports describing the utility of high-dose chlordiazepoxide9,10 or diazepam.11 Early controlled trials reported the efficacy of diazepam,12 oxazepam,13 and lorazepam14 for obsessive symptoms.
Several studies, open-label, placebocontrolled, and benzodiazepine comparisons, were conducted with bromazepam, which is not currently available in the United States. Special attention was given to the efficacy of this medication in phobic and obsessive neuroses.1527 In an open-label study, Burrell et al26 reported marked or moderate improvement on bromazepam in 43 of 63 subjects (69%) with obsessive personality traits and 23 of 32 patients (72%) with compulsive rituals who had previously not responded to other unspecified pharmacologic trials.
In another open-label study, Okuma et al17 reported that 9 of 18 patients (50%) with obsessive compulsive neurosis achieved an "effective" or "markedly effective" response to bromazepam. Draper22 reported that four of six subjects with obsessional neurosis had a "distinct" response and one patient showed "some" improvement on bromazepam. In the same report, comparing chlordiazepoxide and bromazepam in four patients in a double-blind crossover design, subjects taking bromazepam were, on average, "a little better" while subjects taking chlordiazepoxide had no change in symptoms.
Cassano25 compared efficacy of bromazepam and diazepam in a randomized, double-blind study of 20 obsessives. There was significant dropout, and, while four of five subjects achieved marked or moderate improvement on bromazepam, seven of nine subjects improved on diazepam, including three who achieved "complete remission." Cassano concluded that there was no difference between the two medications in their efficacy in treating obsessional neurosis.
The only early study comparing the efficacy of a serotonergic reuptake inhibitor (clomipramine) with a benzodiazepine (diazepam) was reported by Waxman et al.28 Unfortunately, this double-blind study of phobic and obsessional illness reports only combined raw data on improvement for relief of anxiety, interference, and resistance, analyzed separately for different rituals and ruminations. The average frequency of improvement over these measures at six weeks in subjects with ruminations was 83% for clomipramine and 47% for diazepam, while the corresponding combined averaged improvement for rituals was 38% for clomipramine and 47% for diazepam.
Finally, Cassano et al29 compared the efficacy of clomipramine with and without the addition of diazepam in 54 patients with obsessive phobic neurosis. Both obsessive symptoms and rituals responded better to clomipramine alone than in combination with diazepam. In fact, while rituals responded to clomipramine as a monotherapy, there was no significant response to the combination of clomipramine and diazepam.
Unfortunately, most of the above studies are difficult to interpret or are severely flawed. The studies do not adhere to today's diagnostic criteria for OCD. Several of these studies have combined phobias, obsessive compulsive personality traits, and generalized anxiety under broad diagnostic categories such as "obsessionality," "obsessional nervous conditions," "anxiety neuroses," and "phobic obsessive psychoneuroses," without mentioning any criteria for these diagnoses. Case reports describe phenomena such as rumination, perseveration, romantic infatuation, meticulousness, and drug-seeking behavior that are now differentiated from the symptoms of OCD. In addition, several studies combined outcomes for phobic disorders and obsessive disorders, while others classified germ or dirt phobias as phobic rather than obsessive symptoms.
The second problem in evaluating these studies relates to assessment. Rating systems differ from study to study, so there is no mechanism to compare the various outcomes. Moreover, there is no way to assess the outcomes in these reports in relation to more current studies, especially given a changing definition of efficacy in treating OCD. At a time when there was no effective treatment for OCD, any decrease in the symptoms of anxiety associated with the disorder might have represented a significant clinical response. The availability of serotonergic reuptake inhibitors such as clomipramine, fluoxetine, and sertraline, which effectively treat core symptoms of the disorder, has led to more stringent standards for improvement. Medications that provide partial relief are no longer considered to be effective in this disorder. It is difficult to determine whether improvement seen in these early studies would be considered significant by today's standards.
MORE RECENT REPORTS
With current DSM-III-R criteria and standardized scales for measuring OCD symptoms,30,31 it has been possible to more effectively determine efficacy of benzodiazepines in the treatment of OCD. In addition, newer benzodiazepines are now available for testing.
Four case studies have described beneficial effects of alprazolam in open trials in seven patients.3235 Unfortunately, since no double-blind comparison trials have been reported, the utility of this medication in OCD remains to be assessed.
Another benzodiazepine, clonazepam, has attracted interest because of its unique serotonergic effects.'1640 Such effects have been noted in drugs effective in OCD and in affective disorders. In animal models, clonazepam will produce a serotonergic syndrome in animals, which can be blocked by serotonergic agents but not by benzodiazepine receptor antagonists.4043 In addition, clonazepam, but not diazepam, can be substituted for 5hydroxytryptophan, the serotonin precursor, in the treatment of certain human myoclonic conditions.36,44,45 Finally, recent endocrine studies in our lab have suggested that clonazepam will enhance serotonergic stimulation of prolactin release in OCD patients,46 in contrast to diazepam, which has been shown to decrease such stimulation.47
Clinically, there have been three case studies describing the use of clonazepam in OCD as a monotherapy,4850 two reports of its open-label use as an adjunctive agent with serotonergic reuptake inhibitors,51,52 and one controlled doubleblind report of its effectiveness in combination with these later medications.53 Recently, a multi-medication crossover double-blind study comparing the efficacy of clonazepam, clomipramine, and Clonidine to a control medication (diphenhydramine) has been reported.54 Because this is the only controlled study of a benzodiazepine in OCD using modern criteria and measurements, the results are summarized here.
Subjects in this study rotated through six-week intervals of each treatment. Maximum daily doses of 250 mg clomipramine, 10 mg clonazepam, and 1.0 mg Clonidine were used in a flexible dosing paradigm. In all, 20 trials of clonazepam and 25 trials of clomipramine were completed. There was no significant difference between clomipramine and clonazepam in the reduction of symptoms as measured by the Yale-Brown Obsessive Compulsive Scale (YBOCS) and by global clinician-rated improvement scores. Improvement on clonazepam was rapid with significant improvement occurring in the first two to three weeks of treatment. Improvement on this medication was not related to an effect on anxiety symptoms because there was no correlation between changes in anxiety and changes in OCD symptoms after six weeks of treatment with this medication.
An interesting finding of this study was the high degree of cross-response between clomipramine and clonazepam. Individuals who responded to one of these medications were inclined to respond to the other. Those who did not respond to one of these medications were less likely to respond to the other. However, 40% of those who failed on clomipramine did respond to clonazepam, averaging a 35% reduction in symptoms. This finding would suggest that clonazepam might be a useful alternative medication for individuals who fail a trial with a serotonergic reuptake inhibitor.
It should be recognized that the sixweek time frame of analysis in this study is considered short by todays standards. Improvement on serotonergic reuptake inhibitors can continue for up to 10 weeks or longer.05 While impiOvement on clonazepam has been reported to be maintained for periods of up to a year,49 it is notknown how the improvement over this time frame compares with that of the serotonergic reuptake inhibitors.
The results suggest that clonazepam may be a useful addition to the medications used in the treatment of OCD. In subjects who have failed the reuptake inhibitors, or who have responded but could not tolerate the side effects of these medications, clonazepam may well be a reasonable choice as a second monotherapy. In addition, clonazepam has been used effectively in patients with seizure disorders49 for whom these medications may be contraindicated. We have additionally used clonazepam in the initial weeks of treatment with clomipramine to hasten the relief of symptoms, and as an adjunctive medication to potentiate the benefits of this treatment.
When clonazepam is used as a monotherapy, treatment should begin at 0.5 mg to 1.0 mg per day, increasing as tolerated to achieve effect. Most subjects achieved a full response early in treatment; however, some continue to improve with doses up to 10 mg per day. The physician should be aware of the significant potential for unwanted side effects, particularly at the higher doses. These effects have been reviewed by Cohen and Rosenbaum52 and include ataxia, depression, and disinhibition. No subjects who displayed a significant augmentation of depressive symptoms showed improvement in their OCD symptoms. While one must heed these caveats, the promise remains for effective treatment of a significant subpopulation of OCD patients with clonazepam.
CURRENT STATUS OF BENZODIAZEPINES IN OCD
There is no evidence that traditional benzodiazepines such as diazepam or chlordiazepoxide have any utility in treating the core symptoms of this disorder. While certain novel benzodiazepines have been reported to be useful in isolated case studies, clonazepam is the only benzodiazepine that has been tested in modern double-blind comparison trials. The mechanism by which clonazepam exerts its antiobsessive effects is not clear, but may involve an enhancement of CNS serotonergic functioning. The serotonergic reuptake inhibitors remain as the initial treatment of choice for most cases of OCD; however, clonazepam may be a promising medication for treatment-refractory patients.
Tourettes syndrome (TS) is a psychomotor disorder characterized by vocal and multiple motor tics. This disorder may have significant obsessions and compulsions as an associated psychiatric problem.5659 The standard treatment for this disorder involves the use of highpotency neuroleptics such as haloperidol or pimozide; however, these medications may not be well tolerated because of their significant extrapyramidal effects, including possible risk of tardive dyskinesia.
The literature on treatment of TS with benzodiazepines is even more sparse than that for OCD. In general, benzodiazepines have been used to treat anxiety symptoms existing in this disorder, as opposed to the primary symptoms of vocal and motor tics. Except for scattered reports in the Russian literature of a benzodiazepine, phenazepam, and one report of alprazolam in a treatment-refractory patient,60 most of the literature on benzodiazepines in the treatment of tics has centered, again, on the use of clonazepam.
Gonce61 initially reported the use of clonazepam in treating seven TS patients. Of these, three were reported to have a positive response at doses of 4 mg to 6 mg of clonazepam used as a monotherapy, two were reported to have improvement with clonazepam in conjunction with haloperidol, and two did not respond to the medication. Kaim62 later reported one additional case and Voulters et al63 reported an open-label trial where clonazepam was effective in treating 17 of 25 subjects with either TS or chronic motor tics at doses averaging 3.5 mg per day. A total of seven subjects dropped out of this trial, including four subjects with a positive response.
Subsequently, several retrospective studies have been reported. Jankovic and Rohaidy64 found that 76% of subjects had an excellent or moderate response to clonazepam, although their clinical experience indicated that the more severe cases responded better to haloperidol, which was successful in 88% of subjects.
Trung et al65 reviewed treatment outcomes of 81 subjects with multifocal tics of which 48 met full criteria for Tourettes syndrome. Of these, 9 of 17 TS subjects (53%) showed marked or moderate improvement on clonazepam. In contrast, 13 of 21 TS patients (62%) showed similar improvement on haloperidol, while 4 of 11 showed improvement on Clonidine. Complete suppression of tics was seen in 8 of 21 cases (38%) treated with haloperidol, while clonazepam was associated with complete suppression in only 4 of 17 cases (24%). The mean dose in responders was 4.8 mg per day while the mean for nonresponders was 2.8 mg petday. The authors indicated that clonazepam appeared to be more effective in chronic motor tics than in the full TS.
The only single-blind comparison was conducted by Merikanga et al.66 In this crossover study, 12 subjects were treated with both haloperidol and clonazepam. Of these, six responded better to haloperidol, two showed a more significant response on clonazepam, while four responded equally to both medications. An additional eight, subjects in this study did not cross over. Of these, seven responded to clonazepam and one to haloperidol. Daily doses of clonazepam in this study ranged from 1 mg to 6 mg. This study reported the additional finding that subjects with high blood cell to plasma choline levels responded better to clonazepam than to haloperidol.
Other authors have reported their general clinical experience with benzodiazepines. Shapiro et al67 mentioned the use of clonazepam in subjects who had not responded to haloperidol or other neuroleptics. In this group he found clonazepam to be only marginally effective except in an occasional patient.
Singer et al68 suggest that benzodiazepines are most useful to achieve an antianxiety sedative, or hypnotic effect in TS. These authors describe the use of clonazepam as an adjunctive agent in five subjects; however, only one of these achieved any additional improvement in motor tics.
Comings60 describes the use of benzodiazepines in TS. indicating utility in the treatment of tics as well as panic and anxiety in TS. He suggests the use of clonazepam in cases of TS that have not responded to Clonidine or haloperidol. In addition, he mentions that a small number of subjects found unique relief from unspecified psychiatric symptoms when treated with diazepam.
Our own experience with clonazepam has been as an adjunct to neuroleptic treatment in doses of 1 mg to 4 mg per day to reduce both the intensity of tics and symptoms of anxiety. While we have not quantified our results, our impression is that this medication has been quite helpful for these purposes.
It is clear that more study is needed to determine the efficacy of benzodiazepines in OCD and TS. Double-blind studies comparing clonazepam to placebo are needed for both of these disorders. In addition, it is important to compare the efficacy of clonazepam in these disorders with doses of diazepam that are equipotent at central benzodiazepine sites, to determine whether the effects of clonazepam are related to general benzodiazepine effects or to unique properties associated with effects on the serotonergic system.
The specific utility of clonazepam in OCD for individuals who have failed trials of a serotonergic reuptake inhibitor should be investigated, since 40$ of such individuals responded to clonazepam treatment in our small trial. Finally, the long-term efficacy of clonazepam as a monotherapy needs to be studied in both OCD and TS. Until such studies are done, we cannot know whether benzodiazepines will have any lasting utility in the treatment of these disorders.
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