Improving cognition in schizophrenia with antipsychotics that elicit neurogenesis through 5-HT_1A receptor activation

Highlights

• Cognition and neurogenesis are impaired in schizophrenia.

• Pattern separation is a cognitive process that depends on new born neurons.

• The postsynaptic 5-HT1A agonist F15599 improves pattern separation.

• 5-HT1A agonists increase neurogenesis.

• These agonists may improve cognition in schizophrenia by increasing neurogenesis.

Abstract

Atypical antipsychotics fail to substantially improve cognitive impairment associated with schizophrenia (CIAS) and one strategy to improve it is to stimulate adult neurogenesis in hippocampus, because this structure is part of an altered circuitry that underlies aspects of CIAS. Deficits in hippocampal adult neurogenesis may disrupt cognitive processes that are dependent on newborn neurons, such as pattern separation (the formation of distinct representations of similar inputs). Mechanisms by which hippocampal adult neurogenesis can be increased are therefore of therapeutic interest and a promising molecular target is the activation of serotonin 5-HT_1A receptors because agonists at this site increase adult neuronal proliferation in the dentate gyrus. We hypothesize that use of antipsychotics possessing 5-HT_1A receptor agonist properties may protect against or attenuate CIAS by a dual mechanism: a favorable influence on adult neurogenesis that develops upon sustained drug treatment, and an increase in dopamine levels in the prefrontal cortex that starts upon acute treatment. This hypothesis is consistent with the beneficial properties of 5-HT_1A activation reported from pilot clinical studies using 5-HT_1A agonists as adjunct to antipsychotic treatments. Recent antipsychotics, including clozapine and aripiprazole, exhibit different levels of 5-HT_1A receptor partial agonism and may, therefore, differentially elicit hippocampal adult neurogenesis and increases in prefrontal cortex dopamine. We suggest that comparative studies should elucidate correlations between effects of antipsychotics on adult neurogenesis and prefrontal cortex dopamine with effects on performance in translational cognitive tasks known to involve new born neurons, such as tasks involving pattern separation, and working memory tasks sensitive to prefrontal cortex dopamine levels.

Introduction

Schizophrenia and psychotic disorders constitute a serious mental health problem and a substantial burden on health care (Rossler, Salize, van Os, & Riecher-Rossler, 2005). Although a variety of pharmacological mechanisms have been proposed to underlie antipsychotic efficacy, dopamine D₂ receptor antagonism remains the cornerstone of the activity of current antipsychotic drugs. Indeed, the fundamental concept underlying antipsychotic activity is the dopamine hypothesis (Carlsson, 1988) characterized by subcortical hyper-dopaminergia with prefrontal hypo-dopaminergia (Davis, Kahn, Ko, & Davidson, 1991). Thus, the “first generation” antipsychotic, haloperidol, controls positive symptoms of schizophrenia by opposing the excessive stimulation of D₂ receptors resulting from hyperactivity of mesolimbic dopaminergic projections. However, it fails to alleviate the hypoactivity of mesocortical dopaminergic neurons (i.e., “hypofrontality”), thought to underlie negative symptoms such as social withdrawal and flattened affect, and cognitive deficits including working memory impairment and loss of cognitive flexibility (Meltzer & Sumiyoshi, 2008). Further, selective dopamine D₂ receptor antagonists also block nigrostriatal dopaminergic activity, leading to extrapyramidal symptoms, and pituitary D₂ receptors that control prolactin release, leading to hyperprolactinemia (Goff & Shader, 2003). To overcome these limitations, a variety of “atypical” or “second generation” antipsychotics have been developed that act at other receptors as well as antagonizing D₂ receptors. The “gold standard” among these antipsychotics is clozapine, which is considered to possess superior therapeutic efficacy whilst inducing negligible extrapyramidal symptoms. The molecular targets of clozapine’s activity have been extensively investigated, with a particular focus on blockade of serotonin 5-HT_2A receptors and of dopamine D₃ and D₄ receptors, among others. Whilst selective ligands at these receptors have not shown antipsychotic activity in clinical trials, combinations of these pharmacological activities diminish extrapyramidal symptoms liability and improve negative and cognitive symptoms. Indeed 5-HT_2A receptor antagonism favors cortical dopaminergic neurotransmission when associated with D₂ receptor antagonism. Increasing cortical dopamine release is expected to alleviate hypofrontality in schizophrenic patients (Ichikawa and Meltzer, 1999, Lahti et al., 2004) and a variety of “atypical” antipsychotics that combine 5-HT_2A receptor antagonism with D₂ receptor antagonism have therefore been developed (e.g., risperidone, olanzapine and ziprasidone) (Richtand et al., 2008). Nevertheless, the ability of these drugs to control negative symptoms and cognitive deficits remains, at best, limited and serious problems of metabolic dysfunction are elicited by olanzapine and clozapine, likely via antagonism of histamine H₁ and 5-HT_2C receptors. Further, antagonism of muscarinic M₁ receptors can impair cognitive function.

Taken together, these considerations indicate that, notwithstanding the progress made in the discovery and development of second generation antipsychotics, these have only shown modest advances, compared with first generation antipsychotics (Kane & Correll, 2010). This is perhaps not surprising, as drug discovery efforts typically aim for incremental progress; often selecting existing treatments as a starting point and trying to improve side effect profile. Such a strategy may, however, not take into account potentially game-changing new insights into the pathogenesis of schizophrenia based on genetics, molecular biology, and imaging studies. Recently, a version of the dopamine hypothesis that incorporates these novel insights has been formulated (Howes & Kapur, 2009) and may assist in the development of novel drug discovery strategies.