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Multiple Doses of Paroxetine Safe and Well Tolerated in Children and Adolescents with Major Depressive Disorder and Obsessive-Compulsive Disorder: Presented at AACAP

By Paula Moyer

TORONTO, CANADA -- November 14, 2005 -- Children and adolescents appear to tolerate paroxetine (Paxil) well, whether they have major depressive disorder (MDD) or obsessive-compulsive disorder (OCD), according to research presented here at the joint annual meeting of the American and Canadian Academies of Child and Adolescent Psychiatry (AACAP/CACAP).

The new research was presented on October 20^th by Robert L. Findling, MD, Professor of Psychiatry and Pediatrics, Case Western Reserve University, and Director of Child & Adolescent Psychiatry, University Hospitals of Cleveland, Cleveland, Ohio, United States.

Paroxetine, a selective serotonin reuptake inhibitor (SSRI), is not approved for use in children and adolescents, Dr. Findling stressed, and noted that patients should be monitored at the start of treatment for clinical signs of worsening, suicidality, or unusual changes in behavior.

Although no such events occurred in their study, Dr. Findling and colleagues referenced earlier studies that had linked SSRIs to increased suicidal ideation and behavior in children and adolescents with major depressive disorder and other psychiatric diagnoses.

"The pharmacokinetic parameters … in all important respects, mirrored those previously reported in adults," Dr. Findling said.

Dr. Findling and his team conducted their study to address the paucity of data regarding multiple doses of paroxetine in children and concerns about the safety and tolerability of repeat doses in this population.

They recruited 52 children with MDD and 10 with OCD. The children were an average of 12 years old; 40 were boys and 22 were girls.

Treatment consisted of 10 mg of paroxetine daily for 2 weeks, 20 mg daily for the next 2 weeks, and 30 mg daily for the final 2 weeks.

Patients were assessed over a 24-hours period at baseline and on the final day of each dosing phase. The treatment period for the highest dose was followed by a 2-week dose tapering period and a 2-week follow-up period.

Among the 62 subjects, 41 completed the study. There was considerable inter-patient pharmacokinetic variability, Dr. Findling said.

The investigators divided the subjects into two age groups, those eight to 11 years old and those 12 and older, in order to see if younger children and adolescents responded differently. In both age groups, the plasma concentrations increased in a larger-than-proportionate manner with the dosage increase.

The average steady-state peak plasma concentration (Cmax) and area-under-the-curve over a 24-hour period was higher in children than in adolescents, primarily because of their lesser body weight rather than their age, Dr. Findling said. However, weight-normalized clearance at each dose level was relatively constant across the entire age range.

The clearance from plasma (CL/F) and volume of distribution at a steady state (Vdss/F) were slower with higher paroxetine doses, although those rates rose in children with higher weights. No association was found between the paroxetine dose and age or gender.

"The broad between-subject variability and the absence of a clear relationship between exposure and effectiveness in adult patients treated with paroxetine argue against a weight-based dosing recommendation in the pediatric population," Dr. Findling said.

"There was no apparent relationship between paroxetine plasma levels and the occurrence of adverse events leading to withdrawal from the study," he noted.

Although all subjects had some adverse effects, these were primarily mild, consisting of headache, abdominal pain, and somnolence. However, there were two serious adverse events, including one manic episode involving suicidal ideation in one child and one adolescent having an overdose that involved taking 50 mg in 1 day to try to compensate for missed doses.

The study was funded by GlaxoSmithKline, which manufactures Paxil.


[Presentation title: Multiple Dose Pharmacokinetics of Paroxetine in Children and Adolescents. Abstract C-4]

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