AT001 Mechanism of Action

The effects of fluoxetine are presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine.

Antagonism of muscarinic, histaminergic, and α1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs.

The Serotonin Deficit in Autism

Serotonin (5 hydroxytryptamine [5-HT]) is a regulatory CNS neurotransmitter that also has physiologic functions in platelets and the gastrointestinal tract.  In the brain, serotonin-containing neurons have their cell bodies primarily in the midline of the brainstem with axonal projections that are widespread throughout the brain.  Serotonergic neurons play a key role in regulation of mood, sleep, sexual activity, motor activity, neuroendocrine function, and cognition.

It is suggested that the pathophysiological defect(s) in Autism may involve the serotonergic system, since there is substantial evidence implicating this system in Autism (Buchsbaum et al., 2001; Hollander et al., 1998; McDougle et al., 1996a).  For example, during normal childhood development, brain serotonin synthesis increases to a rate above adult levels, and this increase is absent in children with Autism (Chugani et al., 1999).  There is therefore a functional deficit in serotonin synthesis in the CNS in children with Autism.  Functional markers of alterations in serotonin function in Autism correlate with severity of symptoms, in adult patients (Novotny et al., 2000; Hollander et al., 2000).

Reducing CNS serotonin levels by means of a tryptophan depletion diet intervention worsens symptoms in patients with Autism (McDougle et al., 1996b). 

A large number of clinical investigations have explored the effects of drugs with serotonergic system effects.  Specifically, SSRIs have a mixed history in terms of clinically relevant effects in autism due to a variety of reasons including sample size, study design, and dose (Cook et al., 1992; Fatemi et al., 1998; Hollander et al., 2004; Kolevzon et al., 2006; Soorya et al., 2008).