ALPHA-2-ADRENERGIC AGONISTS - NEUROCHEMISTRY, EFFICACY, AND CLINICAL GUIDELINES FOR USE IN CHILDREN

The alpha(2) adrenergic agonists, clonidine and guanfacine. were first developed as antihypertensive agents. They are used in psychiatry to treat a variety of conditions, although they are not approved by the F ood and Drug Administration (FDA) for these indications and there are not yet clear guidelines for their usage. The data describing efficacy of the alpha(2) agonists in child and adolescent psychiatry is derive d principally from open studies, retrospective reviews, and case repor ts. There are several controlled studies, but most are plagued by smal l sample size. Consequently, some investigators have argued that clini cal efficacy and safety of the alpha(2) adrenergic agonists in psychia tric treatment of children has not been adequately established.(13) Ne vertheless, the use of these medications has increased dramatically in the past decade. Swanson and colleagues(66) estimated that approximat ely 89,000 prescriptions were written for clonidine alone in 1994 for the treatment of attention-deficit/hyperactivity disorder (ADHD), and another 61,000 prescriptions were written for the combination of methy lphenidate and clonidine. Another review indicates that over 100,000 c hildren in the United States are medicated with the combination of met hylphenidate and clonidine.(13) Psychoactive properties of the alpha(2 ) adrenergic agonists are related to their effects on noradrenergic (N A) neurotransmitter systems. Direct effects on NA systems also produce indirect effects on serotonergic (5-HT) and dopaminergic (DA) neurotr ansmission. Since the alpha(2) agonists can affect the principal monoa mine systems related to many psychiatric disorders, interest in the cl inical effects of these medications is not surprising. Initial use of the alpha(2) agonists for psychiatric indications can be traced as far back as the 1970s. Cohen and colleagues first noted beneficial effect s of clonidine in amelioration of ties,(16) and began to use it as an alternative to neuroleptic treatment in Tourette's disorder (TS). Bene fits were also observed in reducing motor activity and impulsive behav ior in ADHD, a disorder that frequently coexists in children with TS. One recent study(41) has indicated a possible role for clonidine in th e treatment of aggression. There have also been suggestions that cloni dine may have a role in treating several of the anxiety disorders, par ticularly those Linked to the occurrence of stress or traumatic events (i.e., post-traumatic stress disorder [PTSD]). in adult psychiatry, c lonidine has been used for an even wider array of disorders, including aggression, bipolar disorder, schizophrenia with active psychosis, pa nic disorder, withdrawal from benzodiazepines, social phobia, and PTSD . More recently, several studies(14. 34, 36) have demonstrated similar effects using guanfacine in the treatment of TS and ADHD, with the pr ospect of more sustained duration of action and fewer adverse effects. Despite the considerable promise of the alpha(2) agonists, many have remained skeptical. The high degree of polarization regarding these ag ents increased following the report of several sudden deaths of childr en who were medicated with clonidine and methylphenidate in combinatio n.(21, 56, 66) Although this medication combination has been reviewed by the FDA, and no causal Link between the medication and these catast rophic outcomes has been established, the controversy has sparked a re newed debate about the efficacy and safety of the alpha(2) agonists. A t the same time, recent interest at the national level in establishing a more extensive scientific data base to evaluate efficacy of treatme nts that are off-label yet frequently used, and drug company interests in obtaining FDA approval for new indications, suggests that larger a nd more systematic trials of alpha(2) agents are Likely to be undertak en in the near future. This article reviews the basic neurochemistry a nd neurophysiology of the alpha(2) agonists and examines the empiric s upport for their use in a variety of neuropsychiatric conditions in ch ildren and adolescents. The authors examine the safety of these medica tions and review the recent clonidine controversy in detail. Finally, the authors outline basic information for the clinician regarding ther apeutic management and adverse effects, and present case vignettes to illustrate how these medications can be safely and effectively used in clinical practice.