Antipsychotic drug actions on gene modulation and signaling mechanisms

Abstract

Schizophrenia is a debilitating chronic mental disorder characterized by significant lifetime risk and high social costs. Although its etiology remains unknown, many of its symptoms may be mitigated by treatment with antipsychotic drugs (APDs). These compounds, generally classified as first- or second-generation antipsychotics, have complex receptor profiles that may account for short-term clinical response and normalization of acute manifestation of the disease. However, APDs have additional therapeutic properties that may not be directly related to receptor mechanisms, but rather involve neuroadaptive changes in selected brain regions. Indeed the neurodevelopmental origin of schizophrenia suggests that the disease is characterized by neuroanatomical and pathophysiological impairments that, at molecular level, may reflect compromised neuroplasticity; the process by which the brain adapts to changes in a specific environment. Accordingly, it is possible that the long-term clinical efficacy of APDs might result from their ability in modulating systems crucially involved in neuroplasticity and cellular resilience. We have reviewed and discussed the results of several studies investigating the post-receptor mechanisms in the action of APDs. We specifically focused on intracellular signaling cascades (PKA, DARPP-32, MAPK, Akt/GSK-3, β arrestin-2), neurotrophic factors and the glutamatergic system as important mediators for antipsychotic drug induced-neuroplasticity. Altogether, these data highlight the possibility that post-receptor mechanisms will eventually be promising targets for the development of novel drugs that, through their impact on neuroplasticity, may contribute to the improved treatment of patients diagnosed with schizophrenia.

Introduction

Antipsychotic drugs (APDs) are the first pharmacotherapeutic line for the treatment of schizophrenia. They are also widely used for the treatment of bipolar disorder and other idiopathic psychotic disorders. These drugs are important for treatment as well as prevention of relapse, suggesting that they may not only interfere with mechanisms that are responsible for the acute manifestation of the disease, but that they also normalize brain functions, through complex mechanisms that will eventually lead to patient stabilization.

APDs are generally divided into two groups: first generation APDs (FGAs, also known as conventional or typical) and second generation APDs (SGAs, also known as non conventional or atypical). SGAs include aripiprazole, clozapine, olanzapine, quetiapine, risperidone, paliperidone, ziprasidone and more recently iloperidone. We will use the distinction between FGAs and SGAs rather than the concept of atypical antipsychotic, which has been recently re-considered (Grunder et al., 2009). While FGAs and SGAs appear to be equally effective for the treatment of positive symptoms, which are primarily produced by an excessive tone of the mesolimbic dopaminergic system, they are different with respect to the occurrence of neurological side effects. Moreover SGAs seem to be more effective on negative symptoms and cognitive deterioration, although this notion has been recently challenged (Keefe et al., 2007).

Neurotransmitter receptors are the primary molecular targets of APDs and their interaction is thought to be important for the ‘normalization’ of neurotransmitter imbalances that are associated with specific symptoms and acute manifestation of schizophrenia (and bipolar disorder). However, although a potential relationship between pharmacodynamic and therapeutic properties of APDs can be established, the picture is complicated by the observation that most drugs show very complex receptor profiles. It is feasible to hypothesize that the functional outcome of these complex mechanisms is not the pure ‘algebraic’ summation of single mechanisms, but is rather the consequence of their down-stream interactions with second messengers, signaling proteins and transcriptional molecules.

Accordingly, we will review data demonstrating the impact of different APDs on post-receptor mechanisms, which might contribute to specific aspects of their therapeutic activity. The relevance of this approach is twofold. First of all, it may allow a more precise characterization of available drugs in order to establish differences not only between FGAs and SGAs, but also within the group of SGAs. Second, it offers the opportunity to identify potential novel targets for antipsychotic activity that will eventually lead to the development of novel drugs with more defined actions on different symptoms of schizophrenia.