Associate editor: F TaraziAntipsychotic drug actions on gene modulation and signaling mechanisms
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.
Section snippets
Schizophrenia: from neurotransmitter imbalance to molecular and structural alterations
Schizophrenia is a complex disease with a heterogeneous origin. As many psychiatric conditions, it is thought that schizophrenia originates from the interaction and concurrence of genetic, environmental and etiological factors. Many vulnerability genes have been identified and linked to the neuropathology of schizophrenia (Harrison & Weinberger, 2005). With regard to environmental factors, there is a general agreement that adversities that occur during early brain development can play a key
Antipsychotic drugs: receptor mechanisms
Neurotransmitter receptors are the direct synaptic target of APDs, which initiate a series of events that leads to intracellular changes as described in details in this review. When examining receptor mechanisms, a primary distinction should be made between FGAs and SGAs, although it has become apparent that SGAs are quite heterogeneous with regard to their pharmacodynamic properties. These receptor profiles can contribute to the beneficial therapeutic effects of APDs, but may also lead to
Modulation of signaling mechanisms by antipsychotic drugs
The description of post-receptor mechanisms starts from the analysis of the modulation of signaling mechanisms, taking into account that these systems represent a point of convergence for signaling initiated at different receptors that may be present on a specific neuronal cell. These mechanisms are reviewed not only after acute treatment, which provides information on the integration of multiple and diverse synaptic mechanisms, but also after long-term drug administration in order to identify
Modulation of neurotrophic factors by antipsychotic drugs
Neurotrophic factors (NTF) represent a heterogeneous class of polypeptides displaying a wide array of activities on different cellular phenotypes. Reduced expression of NTF may cause abnormalities during neurodevelopment or, otherwise, may represent the consequence of altered neurodevelopment. Based on the close connection between schizophrenia and neurodevelopment, it is expected that the expression of NTF may be altered in schizophrenia. Indeed, the expression of Brain-Derived Neurotrophic
Modulation of the glutamatergic system by antipsychotic drugs
Although dopamine plays a central role in the disease (Duncan et al., 1999), the contribution of other neurotransmitter systems is also relevant. A glutamatergic hypothesis of schizophrenia has been put forward, suggesting that a hypofunction of glutamatergic neurotransmission might underlie specific aspects of this neuropsychiatric disorder (Carlsson and Carlsson, 1990, Jentsch and Roth, 1999).
Glutamate, the major excitatory neurotransmitter in the mammalian central nervous system, exerts its
Concluding remarks
Schizophrenia is a complex disorder characterized by psychosis and a progressive clinical deterioration. Treatment with APDs can improve the condition of affected people. However, whereas it appears that APDs have a similar and consistent impact on psychosis, they are much less effective on functional deterioration, which is primarily linked to negative symptoms and cognitive impairment. Moreover, a variety of side effects can hinder the patient’s recovery and represent a major cause for
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These authors have equally contributed to this manuscript.