What conditions is Klonopin most commonly prescribed for, and how does it work in the brain?
What are the potential long-term effects of taking Klonopin, and how can they be mitigated?
How does Klonopin compare to other benzodiazepines in terms of efficacy and side effects?
What precautions should be taken when discontinuing Klonopin to avoid withdrawal symptoms?
Can Klonopin be safely used alongside other medications, such as antidepressants or antipsychotics?
Objective: There is evidence supporting the efficacy and safety of Klonopin (clonazepam) in managing anxiety disorders in adults, but formal studies in children with similar conditions are lacking. Method: A double-blind pilot study was conducted with 15 children aged 7 to 13 years. Participants underwent a randomized, double-blind crossover trial consisting of 4 weeks of Klonopin (up to 2 mg/day) and 4 weeks of placebo. Results: Twelve children completed the study. All but one had a diagnosis of separation anxiety disorder, with most also presenting comorbid conditions. Nine children showed moderate to significant clinical improvement. However, statistical comparisons across various ratings failed to confirm a consistent benefit of Klonopin. Notable side effects such as drowsiness, irritability, and oppositional behavior occurred in 10 children during the Klonopin phase, compared to five in the placebo phase. Conclusions: Klonopin appeared clinically beneficial for some children, though statistical evidence was not confirmed in this small sample. Common side effects, possibly linked to rapid dose titration, included drowsiness and behavioral disinhibition. (Journal of the American Academy of Child and Adolescent Psychiatry, 1994, 33, 3:372-376). Key terms: Klonopin, childhood anxiety disorders, side effects.
There is extensive research from controlled studies confirming the effectiveness of benzodiazepines in treating anxiety disorders in adults. For example, the Cross-National Collaborative Panic Study (Ballenger et al., 1988) demonstrated that alprazolam (5 mg/day) was significantly more effective than a placebo in adults with panic disorder or agoraphobia. Similarly, controlled studies by Rickels et al. (1983), Pollack et al. (1986), and Tesar et al. (1987) showed comparable benefits for alprazolam (2-3 mg/day), diazepam (30-40 mg/day), and Klonopin (2-3 mg/day) in adults with various anxiety disorders.
However, the evidence for benzodiazepines in children and adolescents is sparse and mixed. Simeon and Ferguson (1987) and Simeon et al. (1992) conducted controlled studies involving small samples of children and adolescents with overanxious or avoidant disorders, finding minimal to no benefit with alprazolam (up to 3.5 mg/day) after 4 weeks. In contrast, Biederman (1987) reported positive outcomes in three children with anxiety disorders and panic-like symptoms treated with Klonopin (up to 3 mg/day), with minimal side effects. No studies to date have directly compared benzodiazepines with differing half-lives in children.
Klonopin Overview and Clinical StudyKlonopin (clonazepam) is a 7-nitrobenzodiazepine derivative with lipid solubility and a strong affinity for benzodiazepine receptors. It may enhance serotonin receptor activity and exhibits general distribution within the body. Klonopin exists in both protein-bound and free forms, diffusing passively between the plasma and brain without accumulating in brain tissues. In studies involving monkeys, Klonopin undergoes extensive biotransformation into nonactive amino derivatives and a small amount of active nitro derivatives. Its half-life ranges from 20 to 80 hours (though some studies suggest less than 40 hours), and the drug, along with its metabolites, is excreted primarily through urine and possibly other pathways (Dreifuss and Sato, 1982; Pippenger et al., 1978).
For over 20 years, Klonopin has been widely used in pediatric populations, particularly for seizure disorders, often in combination with other anticonvulsants like phenobarbital, at doses of up to 9 mg/day or 0.3 mg/kg per day (Aarli, 1973; Browne, 1976; Dummermuth and Kovacs, 1972; Tyrer, 1980; Vassella et al., 1973). Reported side effects are generally mild, transient, dose-dependent, and infrequent, particularly with doses below 3 mg/day. These include drowsiness, irritability, weight changes, and increased salivation. Dependence in children has not been reported.
Klonopin’s long-acting nature, favorable safety profile, once-daily dosing, and proven efficacy in adult anxiety disorders motivated a systematic trial to evaluate its use in children with anxiety disorders.
Study Design and RecruitmentThis trial involved medically healthy children aged 7 to 13 who met DSM-III-R criteria for an anxiety disorder (American Psychiatric Association, 1987) persisting for at least six months. Diagnoses were determined through clinical interviews by psychiatrists, supplemented by the Diagnostic Interview Schedule for Children (DISC 2.1, Shaffer et al., 1989). The study was conducted at a university-affiliated mental health clinic in Staten Island, New York City.
Participants were recruited through newspaper advertisements, professional referrals, and schools. Signed consent was obtained from parents and children aged 12 and older, while younger children provided verbal assent. Assessments included clinical interviews, the Parent Questionnaire (Gittelman, 1985b), Teacher Rating Scale (Gittelman, 1985a), Children's Manifest Anxiety Scale (Reynolds and Richmond, 1984), and the Child Global Assessment Scale (Shaffer et al., 1983).
Eligibility criteria excluded children on medication (except for minor medical issues), those with serious medical conditions, or mental retardation based on the Peabody Picture Vocabulary Test (Dunn and Dunn, 1981). Children with psychotic, obsessive-compulsive, or mood disorders were also excluded.
ProcedureParticipants were randomly assigned to a double-blind, placebo-controlled crossover trial, with Klonopin or placebo administered for four weeks each. Capsules were taken once daily, either before or just after breakfast. Dosing began at 0.25 mg and increased by 0.25 mg every three days up to 1 mg, and then by 0.25 mg every two days up to a maximum of 2 mg/day. After four days at the maximum dose, the medication was tapered to zero by the end of each phase. Adjustments were made for side effects or compliance issues.
This study aimed to investigate the safety and efficacy of Klonopin in children with anxiety disorders, building on its established use in adult populations and its safety record in pediatric seizure management.
AssessmentsChildren were evaluated weekly by a child psychiatrist who provided supportive therapy, monitored their clinical progress and medication adjustments, and systematically recorded side effects using the Side Effects Rating Scale. This scale measures severity on a scale from 1 to 3, where 1 indicates mild side effects with no interference in functioning, 2 indicates moderate effects with some interference, and 3 indicates severe effects with significant interference. Assessments were conducted at baseline, after 4 weeks, and after 8 weeks. These evaluations included the DISC 2.1 (parent and child versions), the Brief Psychiatric Rating Scale (BPRS; Overall and Pfefferbaum, 1982), and the Clinical Global Improvement Scale (CGI), which ranges from 1 to 8 (1 = completely well, 2 = much improved, 3 = improved, 4 = slightly improved, 5 = unchanged, 6 = slightly worse, 7 = worse, 8 = much worse).
Data AnalysisDifferences in treatment outcomes for continuous scale scores on the BPRS, the number of anxiety symptoms, and the CGI were analyzed using analysis of covariance, controlling for baseline values. Weekly averages of the Side Effects Rating Scale scores were compared across treatment phases using paired t-tests.
Results SubjectsOut of 89 referrals, 57 were excluded for not meeting the criteria for anxiety disorders. Other exclusions included 6 children with prominent attention deficit disorder (considered exclusionary if severe), 5 who refused treatment, 3 with subclinical dysfunction, 3 who responded well to psychotherapy before screening, and 3 with subclinical anxiety states. Ultimately, 15 children were enrolled in the study.
Diagnoses included separation anxiety disorder (14 cases), overanxious disorder (6 cases), avoidant disorder (2 cases), social phobia (5 cases), simple phobia (5 cases), oppositional disorder (3 cases), conduct disorder (1 case), and attention-deficit hyperactivity disorder (3 cases). All but one child had a diagnosis of separation anxiety disorder, and all but two had two or more co-occurring diagnoses. Four children had four diagnoses, including two who dropped out. The sample consisted of white children aged 7 to 13 (mean age = 9.8, SD = 2.1), with eight males and seven females.
Drug RegimenDuring phase I, eight children received Klonopin, while seven were given a placebo. Three boys dropped out during the active phase: two due to severe disinhibition marked by irritability, tantrums, aggression, and one instance of self-injury involving a rope. The third dropout was due to noncompliance.
Of the 12 children who completed the study, 3 showed no overall improvement in anxiety symptoms or functioning with Klonopin, 5 demonstrated moderate improvement, and 4 experienced marked improvement.