Current Pharmaceutical Biotechnology - Volume 13, Issue 8, 2012

The concept that the efficacy of all antipsychotic drugs (APDs) can be explained by their action on dopamine (DA) D2 receptors is most challenged by drugs such as clozapine which target serotonin (5-HT)2A receptors as an essential component of their efficacy and tolerability. The 5-HT2A receptor, along with 5-HT1A, 5-HT 2C, 5-HT 6 or 5-HT 7 receptors, all of which are components of the mechanism of action of clozapine, represent important targets for treating multiple aspects of schizophrenia, especially psychosis and cognitive impairment. The class of atypical antipsychotic drugs (APDs), of which clozapine is the prototype, share in common more effective 5-HT 2A receptor inverse agonism and weaker interference with D2 receptor stimulation, either through D2 receptor blockade or partial D2 receptor agonism. This has led to development of a selective 5-HT2A antagonist, ACP-103 (pimavanserin), which has been found to be effective as monotherapy in L-DOPA psychosis and has promise as an add-on agent for sub-effective doses of atypical APDs. We review here the extensive preclinical evidence to support the importance of 5-HT2A receptor inverse agonism to the action of clozapine and related atypical APDs, and evidence supporting the potential of selective 5-HT2A, 5-HT 6 , and 5-HT 7, antagonists, 5-HT1A partial agonists and 5-HT2C agonists for development of drugs which ameliorate psychosis or cognitive impairment.

Cognitive impairment is a core feature of schizophrenia that substantially accounts for poor functional outcomes associated with this disease in areas such as work, independent living and social relationships. Until recently, drug development in schizophrenia has focused on developing compounds that mainly target the positive psychotic symptoms of the illness. Although current antipsychotic drugs treat psychosis in schizophrenia rather well, their impact on cognitive dysfunction is minimal. In recent years there has been growing interest in developing novel treatments for cognitive deficits in schizophrenia. In this review we discuss pharmacologic strategies considered most likely to improve cognition. These putative molecular targets include receptors for acetylcholine, dopamine, glutamate, g-aminobutyric acid (GABA), serotonin and histamine. In addition, we propose that not only pharmacological, but also psychological treatments should be considered to enhance cognition in schizophrenia.

Schizophrenia is a brain disorder associated with subtle, but replicable cerebral volume loss mostly prevalent in frontal and temporal brain regions. Post-mortem studies of the hippocampus point to a reduction of the neuropil constituting mainly of synapses associated with changes of molecules mediating plastic responses of neurons during development and learning. Derived from animal studies interventions to enhance neuroplasticity by inducing adult neurogenesis, synaptogenesis, angiogenesis and long-term potentiation (LTP) were developed and the results translated into clinical studies in schizophrenia. Out of these interventions aerobic exercise has been shown to increase hippocampal volume, elevate N-acetyl-aspartate in the hippocampus as neuronal marker, and improve short-term memory in schizophrenia. The hematopoietic growth factor erythropoetin (EPO) is involved in brain development and associated with the production and differentiation of neuronal precursor cells. A first study demonstrated a positive effect of EPO application on cognition in schizophrenia patients. In randomised controlled studies with small sample size, the efficacy of repetitive transcranial magnetic stimulation (rTMS), a biological intervention focussing on the enhancement of LTP, has been shown for the improvement of positive and negative symptoms in schizophrenia,. The putative underlying neurobiological mechanisms of these interventions including the role of neurotrophic factors are outlined and implications for future research regarding neuroprotection strategies to improve schizophrenia are discussed.

The exact pathophysiological mechanism leading to dopaminergic dysfunction in schizophrenia is still unclear, but inflammation is postulated to be a key player: a dysfunction in the activation of the type 1 immune response seems to be associated with decreased activity of the key enzyme in tryptophan/kynurenine metabolism, indoleamine 2,3- dioxygenase (IDO), resulting in increased production of kynurenic acid - a N-methyl-D-aspartate (NMDA) antagonist in the central nervous system (CNS) - and reduced glutamatergic neurotransmission. The differential activation of microglia cells and astrocytes as functional carriers in the immune system in the CNS may also contribute to this imbalance. Existing antipsychotics, which predominantly act as dopamine D2 receptor antagonists, have several shortcomings. The immunological effects of many existing antipsychotics, however, rebalance in part the immune imbalance and the overproduction of kynurenic acid. The immunological imbalance results in an inflammatory state with increased prostaglandin E2 (PGE2) production and increased cyclo-oxygenase-2 (COX-2) expression. Growing evidence from clinical studies with COX-2 inhibitors points to favourable effects of anti-inflammatory therapy in schizophrenia, in particular in an early stage of the disorder. Further options for immunomodulating therapies in schizophrenia will be discussed.

Schizophrenia is a devastating brain disease. The mode of inheritance is complex and non-Mendelian with a high heritability of ca. 65-80%. Given this complexity, until most recently it was notoriously difficult to identify disease genes. Due to new technologies the last few years have brought an explosion of interest in human genetics of complex diseases. The knowledge resulting from the availability of the complete sequence of the human genome, the systematic identification of single nucleotide polymorphisms (SNPs) throughout the genome, and the development of parallel genotyping technology (microarrays) established the conditions that brought about the current revolution in our ability to probe the genome for identifying disease genes. All these studies have opened a window into the biology of common complex diseases and have provided proof of principle and yielded a multitude of genes showing strong association with complex diseases. New findings in schizophrenia will be summarized in this review and discussed in the light of a possible translation into the development of better treatment.

Neurobiological correlates of various treatment approaches (e.g. psychopharmacology, cognitive behavioural therapy) have become an important issue in recent neuroimaging studies. In schizophrenia, dysfunctions especially in frontal and parietal brain regions as well as the ventral striatum have been demonstrated in numerous studies. The review includes functional MRI studies about neurobiological correlates of treatment effects in schizophrenic patients. Treatmentassociated changes in brain activity were shown especially in the anterior cingulate cortex, the dorsolateral prefrontal cortex, the ventral striatum and the amygdala. In addition, the differential effects of various treatment approaches including different neuroleptics (atypical neuroleptics, typical neuroleptics) as well as cognitive behavioural therapy will be considered in this review. The influence of functional differences on the differential effect of typical and atypical antipsychotics on cognitive functions will be discussed.