Clonazepam

Placebo-controlled studies

In a randomized, double-blind, placebo-controlled, three-arm study in 60 patients with panic disorder, paroxetine alone (40 mg/day) was compared with paroxetine co-administered with clonazepam (2 mg/day) followed either by a tapered benzodiazepine withdrawal phase or continuing combination treatment [ ]. The outcomes in the three groups were similar. Most of the patients had at least one adverse effect: 68% of patients given paroxetine alone, 85% in those given the two drugs, and 94% in those given the two drugs followed by withdrawal. The most common adverse effects of combined treatment were sedation, sexual dysfunction, and jitteriness; jitteriness and gastrointestinal symptoms were most common with monotherapy. Sedation and sleep disturbances were the most common adverse effects that made patients withdraw from the study.

Clonazepam is widely used for the treatment of sleep disturbances related to post-traumatic stress disorder, despite very limited published data supporting its use for this indication. In a randomized, single-blind, placebo-controlled, crossover trial of clonazepam 1 mg at bedtime for 1 week followed by 2 mg at bedtime for 1 week in six patients with combat-related post-traumatic stress disorder there were no statistically significant differences between clonazepam and placebo [ ]. Adverse effects of clonazepam were generally mild and essentially indiscernible from those attributed to placebo. Only one patient elected to continue taking clonazepam at the end of the trial. The small sample size was a significant limitation of the study.

Nervous system

In controlled trials with clonazepam, adverse events were recorded in 60–90% of cases and led to withdrawal rates as high as 36% [ ]. The most common effects were drowsiness, ataxia, and behavioral and personality changes. Other problems were hypersalivation, tolerance, and sometimes a paradoxical increase in seizure frequency.

Psychological, psychiatric

Behavioral adverse events associated with clonazepam include agitation, aggression, hyperactivity, irritability, property destruction, and temper tantrums. These adverse effects can be inadvertently confused with other behavioral or psychiatric conditions, especially if exacerbation of existing challenging behavior occurs.

• A 49-year-old man with severe mental retardation was given clonazepam 2 mg/day to treat aggression, self-injurious behavior, property destruction, and screaming, which got worse instead of better [ ]. When clonazepam was withdrawn, the behavior improved.

The addition of clonazepam to clomipramine has been reported to have caused acute mania [ ].

• A 48-year-old Japanese man with a history of bipolar affective disorder became depressed again. He was already taking lithium carbonate 800 mg/day and carbamazepine 800 mg/day. Clomipramine was added, and the dose was increased to 225 mg/day over 2 months and then maintained for 2 months. Because clomipramine had little effect, clonazepam 3 mg/day was added. On the first day after he took clonazepam, symptoms of hyperthymia, haughtiness, talkativeness, and flight of ideas suddenly appeared once more. Drug-induced delirium was excluded, because orientation was not disrupted and the symptoms did not fluctuate over time. Clomipramine and clonazepam were withdrawn. Because the symptoms were similar to the previous manic episode, the same prescription was reinstated, with the addition of sodium valproate 800 mg/day. After 3 months, he was discharged in remission and had no recurrence. He had not taken other benzodiazepines throughout the treatment.

This report suggests that clonazepam induced a switch to mania, possibly in combination with an effect of clomipramine.