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-HT_1D 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.

A magnetic resonance spectroscopic (MRS) study in the rat hyperserotonemic model of autism indicated that a reduction in N-acetylaspartate, a marker of neuronal integrity, might reflect delayed or arrested cortical maturation due to loss of serotonin during development (Kahne et al., 2002). This finding is consistent with similar findings from MRS studies of children with autism (Otsuka et al., 1999) and with findings of increased 5-HT_1D inhibitory autoreceptor sensitivity in adult patients with autism (Hollander et al., 2000; Novotny et al., 2000).

Currently, the Seaver Autism Research Center, in conjunction with Columbia University, is conducting a study exploring the distribution of the 5-HT_2A receptor in people with autistic spectrum disorders using the radio-labeled serotonin receptor ligand [11C]MDL 100907. Preliminary findings suggest an increase in 5-HT_2A receptor availability, particularly in the dorsolateral and medial prefrontal cortices, in patients with autism spectrum disorders compared to controls. Further investigation is needed to substantiate these early findings and to elucidate the role of this receptor in autism.

Studies by our group (Buchsbaum et al., 2001; Haznedar et al., 2000, 1997) have demonstrated abnormalities in the anterior cingulate gyrus (ACG) of individuals with autism spectrum disorders. The ACG is an area with an abundance of serotonergic innervation, and abnormal metabolism in this area has been implicated in many psychiatric disorders, including obsessive-compulsive disorder and depression.

In our study (Buchsbaum et al., 2001), individuals with autism underwent PET scans to assess the metabolic activity of both the ACG and other cortical areas, including the prefrontal cortex, prior to participating in a placebo-controlled, double-blind, crossover study with fluoxetine. The PET scans were repeated at the end of the drug phase, with mock PET scans done after the placebo phase for each individual. Fifty percent of the individuals were assessed as responders to fluoxetine treatment. Response was defined as a decrease in repetitive behaviors as shown on the Yale-Brown Obsessive Compulsive Scale (YBOCS) (mean baseline=21, mean endpoint=9.6) and improvement on the Clinical Global Improvement (CGI) scale modified for autism (mean baseline=4.00, mean endpoint=2.00). Increased right ACG metabolic activity, as well as increased metabolic activity in the left and right medial frontal cortices, was correlated with treatment response to fluoxetine. Although all the individuals had low-to-normal metabolic activity in the ACG, those individuals with relatively increased activity in the ACG and the medial frontal areas were more likely to respond to treatment with fluoxetine than were those with lower levels of activity. Additionally, the metabolic activity in these areas increased overall after treatment with fluoxetine, although the sample was too small to determine if the responders had a greater increase than did the nonresponders. This study is the first of its kind to be published in this population, and it will need to be extended to a larger sample of patients to further assess the validity of the findings. Using fluorine magnetic spectroscopy, Strauss et al. (2002) looked at the distribution of fluoxetine in the brains of children with autism. They found that, overall, the distribution of fluoxetine and other SSRIs correlated with dosage and was similar to that found in the brains of adults on these medications in other studies. Friedman et al. (2003) are examining regional differences in metabolism using a similar technique in 3-year-old to 4-year-old children with autism, but this has not yet been coupled with treatment studies.

Other studies are looking at regional differences in other neurotransmitters in the brains of individuals with autism and have used pathological specimens to examine regional differences. Recently, a postmortem study found abnormalities in cholinergic activity, particularly reduced nicotinic receptors, in the cerebellar cortex in the brains of individuals with autism but not in the brains of normal controls (Lee et al., 2002). The results of this study suggest that treatment with nicotinic receptor agonists might be useful in improving mental function in individuals with autism. However, studies examining the improvement in nicotinic receptors after treatment with these agonists have not yet been done. Preliminary open-label studies with donezepil (Aricept), an acetylcholinesterase inhibitor, have also shown some promise (Hardan and Handen, 2002).

Abnormalities have also been found in the γ-aminobutyric acid (GABA) neurotransmitter system in individuals with autism (Buxbaum et al., 2002). The Seaver Autism Research Center is investigating the use of divalproex sodium (Depakote), a GABAergic agent, for the treatment of autism spectrum disorders (Hollander et al., 2001). It is hypothesized that this medication will improve symptoms of autistic disorders, including affective instability and impulsive aggression. Individuals with abnormalities on electroencephalograms and with seizures disorders are particularly expected to benefit.

Other neurotransmitter systems, including the glutamate system and the norepinephrine system, have been found to be abnormal in individuals with autism (Purcell et al., 2001; Robinson et al., 2001). The dopamine system may also have abnormalities, although nothing specific regarding its regional metabolism in autism has yet been reported in the literature. There are a number of medications (e.g., the atypical antipsychotic medications and the stimulant medications, both of which have shown efficacy in treatment trials in autism) that target these neurotransmitters and have shown efficacy in treatment trials in autism (Handen et al., 2000; McCracken et al., 2002). However, these abnormalities have not yet been linked with treatment response or specific regional metabolic abnormalities in autism spectrum disorders.

Studies looking at changes in regional metabolism after treatment and baseline predictors of treatment response are particularly important in helping to understand the neurobiology of the autism spectrum disorders, as well as the changes that occur after treatment with different medications. Future treatments in autism are likely to be influenced by these techniques.

Acknowledgement

The work discussed in this paper is supported in part by grants from the Seaver Foundation, Orphan Products Division of the U.S. Food and Drug Administration grants #FD-R-001520-03 and #FD-R-002026, National Institute of Neurological and Developmental Disorders grant #1 R21 NS43979-01, and National Alliance for Research in Schizophrenia and Depression.

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