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Regional Cerebral Metabolism and Treatment in Autism Spectrum Disorders

Regional Cerebral Metabolism and Treatment in Autism Spectrum Disorders

Autism and related spectrum disorders such as Asperger's syndrome and pervasive developmental disorder have been estimated to affect as many as 62.6 children per 10,000, with prevalence for autism affecting as many as 16.8 children per 10,000 and milder variants possibly affecting as many as 45 per 10,000 (Chakrabarti and Fombonne, 2001). Symptoms include deficits in social and communication abilities, as well as compulsive and repetitive behaviors such as stereotypic complex hand and body movements, rigidity, and narrow repetitive interests.

Currently, there are no pharmacological treatments approved by the U.S. Food and Drug Administration for autism. Although many pharmacological treatment studies have been published, most are inconclusive and suffer from methodological shortcomings in study design, including subject selection, outcome measures utilized and open-label design. The few controlled studies suggest efficacy rates of approximately 40% to 70% for the various pharmacological agents studied (Hollander et al., 1998; McDougle et al., 1996; Posey and McDougle, 2000). No one medication has yet emerged as a primary treatment, most likely due to the inherent heterogeneity in the neurobiology of these disorders. However, treatments for the core and associated symptom domains of the autism spectrum disorders show promise.

The most promising treatments include the use of atypical antipsychotics such as risperidone (Risperdal) for the treatment of disruptive behaviors (McCracken et al., 2002) and the selective serotonin reuptake inhibitors such as fluvoxamine (Luvox) and fluoxetine (Prozac) for the treatment of repetitive behaviors (Buchsbaum et al., 2001; Hollander et al., 1998; McDougle et al., 1996). Studies are attempting to determine the neurobiology of the symptom domains of autism spectrum disorders and predict treatment response to a variety of psychopharmacological agents.

One of the more thoroughly investigated aspects of the neurobiology of autism is the serotonin (5-HT) system. A significant amount of evidence supports altered serotonin function in autism (Buitelaar and Willemsen-Swinkels, 2000). Serotonin has been implicated in the regulation of many functions, such as learning, memory, sensory and motor processes, and, most important for treatment, repetitive behaviors that are relevant to autism (Ciaranello et al., 1982).

In a study of platelet 5-HT levels in a large sample of patients with autism, individuals with mental retardation or cognitive impairment, and healthy controls, hyperserotonemia was found to be unique to prepubertal children with autism (McBride et al., 1989). Genetic studies have also shown possible abnormalities in the serotonin system, although these have been inconclusive to date. One study suggested that the serotonin transporter polymorphism might affect the severity of autistic behavior (Tordjman et al., 2001).

Other neurobiological studies have also reported evidence of abnormalities in the serotonergic system in autistic disorders. Acute depletion of the 5-HT precursor tryptophan can exacerbate many behavioral symptoms of autistic disorder (McDougle et al., 1993), and people with autistic disorder appear to have decreased central 5-HT responsiveness, as shown by a blunted prolactin response to fenfluramine (Pondamin) (McBride et al., 1989). Neurobiological studies with the 5-HT1D agonist sumatriptan (Imitrex) have also demonstrated alterations in the sensitivity of this 5-HT subsystem that relate to the severity of repetitive behaviors in autism (Hollander et al., 2000).

Studies have also examined regional metabolic abnormalities of the serotonin system in individuals with autism spectrum disorders. A positron emission tomography (PET) study, using the radiolabeled serotonin precursor α-[11C]methyl-L-tryptophan, showed evidence of decreased serotonin synthesis in frontal and thalamic regions, with increased serotonin synthesis in contralateral cerebellar dentate regions (Chugani et al., 1997). Chugani et al. (1999) also found that children with autism had abnormal levels of serotonin synthesis.

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