Monoamine-Based Treatments in Schizophrenia: Time to Change the Paradigm?

Functional deficit in the prefrontal cortex (PFC), also known as hypofrontality, is one of the major manifestations in schizophrenia. This is characterized by a failure of the PFC to support behavior. Although the neuronal mechanisms underlying hyporontality are still under debate, most of the neuroimaging findings have been consistent with a hypofunctional PFC state in response to working memory tasks. These cognitive impairments are typically evidenced by lack of PFC activation (for review see Manoach, 2003). However, there are also studies showing either no changes or increased activation of the dorsolateral PFC (Manoach et al., 1999, 2000; Callicott et al., 2000, 2003a, b; Honey et al., 2002). Perhaps these apparently contradictory findings could simply reflect the different strategy used to examine PFC activation and the nonlinear relationship between PFC activation and task demand (Braver et al., 1997; Goldberg et al., 1998; Callicott et al., 1999; Manoach, 2003). PFC response increases parametrically with working memory load until the demand exceeds the functional capacity, during which activation decrease. Despite the fact that patients suffering schizophrenia usually exhibit a relative lower task performance than controls, a similar nonlinear relationship between PFC activation and task demand may also exist in schizophrenia, but shifted toward the left of the curve. A relative decrease or increase of PFC activation could be obtained in schizophrenia subjects depending on the loads required to perform the task and the actual cortical functional level.

Since the early 1950s to our days, pharmacologically oriented treatments in schizophrenia have been monopolized by monoamine modulating drugs. Beginning with the first generation of relatively pure dopamine (DA) antagonists followed by a second generation of antipsychotic drugs with dual DA and serotonin (5HT) antagonist effects, and more recently by partial DA agonists and acetylcholine (Ach) receptor modulating drugs, modern pharmacological interventions in schizophrenia have been fueled with the idea of changing the curse of this devastating disorder by modifying brain monoamine function. However, despite the effectiveness of treating psychotic symptoms, these monoamine-based drugs have very limited effect in restoring the cognitive and emotional disabilities associated to schizophrenia.

In this chapter we will discuss and provide insights on how and why drugs that target the central monoamine system are not necessary effective to prevent cognitive and emotional impairments in schizophrenia. We will summarize evidence indicating that this failure in treating cognitive deficits could be caused by at least two factors. First, most of the cognitive and emotional deteriorations in schizophrenia appear during early adolescence, years before the emergence of psychosis. Secondly, DA antagonists may interfere with several neuronal signaling pathways critically involved in maintaining normal cognitive functions. We hypothesize that a new generation of glutamate modulating drugs could be used to prevent cognitive deteriorations related to schizophrenia in high risk adolescents.