Current Medicinal Chemistry (v.20, #3)

A Genetic Dissection of Antipsychotic Induced Movement Disorders by C. Crisafulli, A. Drago, A. Sidoti, A. Serretti (312-330).
Background. Antipsychotic medications (APM) are the first line pharmacological treatment for psychotic disorders and other behavioral disorders. Nevertheless, their use causes a number of side effects, including extrapyramidal symptoms (EPS). EPS decrease the efficacy of the antipsychotic treatments by causing poorer compliance to the treatment, stigma and a poorer quality of life for patients. Genetic studies hold the potential to unravel the molecular underpinnings of the EPS induced by APM but results are not conclusive and are far to be used in clinical practice despite decades of research. A more sophisticated selection of the list of genetic mutations explaining the genetic variance of EPS induced by APM could help in the definition of a personalized treatments for patients. Moreover, it would increase the quality of the current treatments with APM. Methods: We reviewed the literature searching for the genetic association studies focused on dystonia, parkinsonism, akathisia and tardive dyskinesia. Moreover, we reviewed the current biological knowledge of the APM induced side effects. Finally, we provide a reasoned list of candidate genes and their genetic variations, with the aim of identifying a list of candidates for APM induced EPS genetic investigations. Results: Variations located within PIK3CA (phosphoinositide-3- kinase, catalytic, alpha polypeptide), PLA2G4A (phospholipase A2, group IVA, cytosolic, calcium-dependent), PRKCA (protein kinase C, alpha), PRKACG (Phosphatidylinositol-4,5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma), ERK-1 (extracellular signalregulated kinase 1 (MAPK3)), ERK-2 (extracellular signal-regulated kinase 2 (MAPK1)), GNAS (guanine nucleotide binding protein (G protein), alpha stimulating activity polypeptide 1), PLCB1 (phospholipase C, beta 1 (phosphoinositide-specific)) and ITPR1 (inositol 1,4,5-triphosphate receptor type 1) were found to be relevant for APM induced EPS. Some of the genes are classical candidates for this kind of research, others were never investigated. For each of these genes we provide a list of variations that balances the limitations of multitesting with the advantages of the tagging approach. Conclusions: We undertook a review of the literature about the APM induced EPM to provide some rational genetic candidates to be tested in further genetic investigations.

Neurotransmitters, Psychotropic Drugs and Microglia: Clinical Implications for Psychiatry by T. A. Kato, Y. Yamauchi, H. Horikawa, A. Monji, Y. Mizoguchi, Y. Seki, K. Hayakawa, H. Utsumi, S. Kanba (331-344).
Psychiatric disorders have long and dominantly been regarded to be induced by disturbances of neuronal networks including synapses and neurotransmitters. Thus, the effects of psychotropic drugs such as antipsychotics and antidepressants have been understood to modulate synaptic regulation via receptors and transporters of neurotransmitters such as dopamine and serotonin. Recently, microglia, immunological/inflammatory cells in the brain, have been indicated to have positive links to psychiatric disorders. Positron emission tomography (PET) imaging and postmortem studies have revealed microglial activation in the brain of neuropsychiatric disorders such as schizophrenia, depression and autism. Animal models of neuropsychiatric disorders have revealed the underlying microglial pathologies. In addition, various psychotropic drugs have been suggested to have direct effects on microglia. Until now, the relationship between microglia, neurotransmitters and psychiatric disorders has not been well understood. Therefore, in this review, at first, we summarize recent findings of interaction between microglia and neurotransmitters such as dopamine, serotonin, norepinephrine, acetylcholine and glutamate. Next, we introduce up-to-date knowledge of the effects of psychotropic drugs such as antipsychotics, antidepressants and antiepileptics on microglial modulation. Finally, we propose the possibility that modulating microglia may be a key target in the treatment of various psychiatric disorders. Further investigations and clinical trials should be conducted to clarify this perspective, using animal in vivo studies and imaging studies with human subjects.

Brain-derived neurotropic factor (BDNF) is involved in the development of the brain, and likely influences the neuroplasticity in schizophrenia. BDNF is also believed to interact with other neurotransmitter systems implicated in schizophrenia, such as dopamine, glutamate, serotonin and GABA. Therefore, BDNF is a candidate gene for schizophrenia. In past decades, the blood (serum or plasma) BDNF protein levels and BDNF gene alleles and genotypes to the clinical features of schizophrenia, such as age of onset, clinical subtypes, symptom severity, and drug response, have been evaluated among different populations. However, the results are still inconsistent. Further, different drugs have been reported to have different effects on BDNF protein levels. A cross-sectional survey revealed that serum BDNF levels in chronic schizophrenic patients treated with clozapine exceeded those of patients treated with risperidone or with typical antipsychotics. In recent times, BDNF epigenetic studies have also been conducted in clinical studies of schizophrenia to address the question of why patients with the same gene genotype and alleles have different clinical presentations. In addition, the effects of different antipsychotic drugs on gene methylation and protein acetylation have also been reported. In conclusion, more data are needed regarding BDNF in the brain and in peripheral blood, including protein levels, single nucleotide polymorphisms, epigenetic regulation, and clinical data in order to understand the role of BDNF in schizophrenia.

Recent Developments in Neurochemical Imaging in Schizophrenia: An Update by Nora S. Vyas, Neva H. Patel, Peter Herscovitch, Basant K. Puri, Rupert Lanzenberger (351-356).
The advent of neurochemical brain imaging methods has provided an opportunity to study the neurochemistry of the human brain in normal and abnormal development. The aim of this article is to provide an update on recent major developments in neurochemical imaging in schizophrenia research. In this concise review, we discuss the major findings on three neurotransmitters, namely dopamine, serotonin and glutamate. The most promising radioligand for D2/D3 neuroreceptor imaging is the agonist [11C]PHNO, with higher in vivo affinity for D3 than D2 receptors, which can be used to measure amphetamine-induced release of dopamine, and therefore a potential model of dopaminergic alterations in schizophrenia. Recent development of selective radiotracers allow imaging of the serotonin transporter (SERT) using positron emission tomography (PET) with selective tracers such as [11C]DASB. Additionally, the glutamatergic hypothesis has evolved from theory to phase III clinical trials of newer agents with novel mechanisms. With the development of newer radioligands and the in vivo application of magnetic resonance spectroscopy (MRS) at relatively high magnetic field strengths, there is ample scope for further neuroimaging advances.

Disturbances of cognitive function are considered to largely affect the outcome in patients with schizophrenia. There is much attention to the role of psychotropic compounds acting on serotonin (5-HT) receptors in ameliorating cognitive deficits of the disease. Among the 5-HT receptor subtypes, the 5-HT1A receptor is attracting particular interests as a potential target for enhancing cognition, based on preclinical and clinical evidence. The neural network underlying the ability of 5-HT1A agonists to treat cognitive impairments of schizophrenia likely includes dopamine, glutamate, and gamma-aminobutyric acid neurons. Recent advances of electrophysiological measures, such as event-related potentials, have provided insights into facilitative effects on cognition of some atypical antipsychotic drugs or related compounds acting directly or indirectly on 5-HT1A receptors. These considerations are expected to promote the development of novel therapeutics for the betterment of functional outcome in people suffering from schizophrenia.

Antipsychotics, old and new varieties, are effective against positive symptoms such as hallucination and delusions, but are often of limited value in treating core features of schizophrenia particularly negative symptoms. Developments of new drugs based on current dogmas have produced similar drugs with no breakthroughs in effectiveness. New knowledge as to which mechanisms are responsible for symptom productions and treatment is needed. There is evidence that response may improve when antipsychotics are augmented with selective serotonin reuptake inhibitor (SSRI). This augmenting effect cannot be explained by summating pharmacological effects of the individual drugs. In a series of laboratory and clinical studies, we identified unique biochemical effects of the SSRI-Antipsychotic combination, different from each individual drug and suggested that some of these may mediate the clinical effect. In this paper, we review these studies and propose that modulation of the gamma-aminobutyric acid (GABA)-A receptor and its regulating system is the mechanism by which SSRI antipsychotic synergism exerts its clinical efficacy.

Serotonin Receptors of Type 6 (5-HT6): From Neuroscience to Clinical Pharmacology by Donatella Marazziti, Stefano Baroni, Franco Borsini, Michela Picchetti, Elena Vatteroni, Valentina Falaschi, Mario Catena-Dell'Osso (371-377).
The serotonin (5-HT) receptors of type 6 (5-HT6) are quite different from all other 5-HT receptors, as they include a short third cytoplasmatic loop and a long C-terminal tail, and one intron located in the middle of the third cytoplasmatic loop. A lot of controversies still exist regarding their binding affinity, effects of 5-HT6 ligands on brain catecholamines, behavioral syndromes regulated by them, and brain distribution. In spite of the lack of information on metabolic pattern of the various compounds, some of 5-HT6 receptor ligands entered the clinical development as potential anti-dementia, antipsychotic, antidepressant and anti-obese drugs. The present paper is a comprehensive review on the state of art of the 5-HT6 receptors, while highlighting the potential clinical applications of 5-HT6 receptor agonists/antagonists.

The need for innovation in research is leading to an increased use of imaging biomarkers, which have shown to reduce timings and increase productivity, thus saving costs. PET and SPECT neurotransmission imaging has shown usefulness in the discovery and development of drugs for the central nervous system, providing unique information on drug-target interactions in the living human brain. Among the different therapeutic areas, antipsychotic drugs pioneered the application of these technologies in early phases of development. PET and SPECT radioligands for the most commonly targeted neurotransmission systems in the development of these drugs, such as the dopaminergic and serotoninergic systems are available, thus fostering the inclusion of PET and SPECT studies in the antipsychotic drug development plans. Radioligands for other neurotransmission systems more recently implicated in the pathophysiology of schizophrenia, such as the glutamatergic system, are being currently investigated. This review focuses on neurotransmission PET and SPECT aiming to serve as guidance for procedure requirements and methodology choices to be applied in antipsychotic drug development, through specific examples. Cutting-edge study designs and quantification approaches will be reviewed. Finally, some clues to get the most out of the PET and SPECT studies in the development of antipsychotic drugs will be provided.

Tardive dyskinesia (TD) is a movement disorder characterized by abnormal involuntary facial movements induced by chronic therapy with classical antipsychotic medications. Currently, there is no satisfactory pharmacotherapy for TD, which represents a major limitation to therapy with classical antipsychotics. In order to develop or optimize therapies for TD, and to develop new APDs with lower indices of motor side effects, the pathology underlying TD must first be understood. The use of animal models has been used to further this objective. Here, we review different preparations that have been used to model TD and discuss the contribution of neuroimaging studies conducted in these models. Studies in animal models have lead to several hypotheses of TD pathology, although none has yet emerged as the ultimate underlying cause of this syndrome. We discuss alterations in functional indices, neuron and synapse morphology and changes in specific neurotransmitter systems that have been described in animal models of TD, and outline how these findings have contributed to our understanding of antipsychotic-induced dyskinesias. We conclude that several non-mutually exclusive theories of TD are supported by animal studies, including increases in oxidative stress leading to structural and functional changes in specific neurotransmitter systems. Elucidating the mechanisms underlying TD neuropathology partly through the use of animal models will lead to the development of APDs with superior side effect profiles or more effective therapies for TD.

Abnormal Striatal Dopamine Transmission in Schizophrenia by Jerome Brunelin, Shirley Fecteau, Marie-Francoise Suaud-Chagny (397-404).
Despite numerous revisions and reformulations, dopamine (DA) hypothesis of schizophrenia remains a pivotal neurochemical hypothesis of this illness. The aim of this review is to expose and discuss findings from positron emission tomography (PET) or singlephoton- emission computed tomography (SPECT) studies investigating DA function in the striatum of medicated, drug-naive or drug-free patients with schizophrenia and in individuals at risk compared with healthy volunteers. DA function was studied at several levels: i) at a presynaptic level where neuroimaging studies investigating DOPA uptake capacity clearly show an increase of DA synthesis in patients with schizophrenia; ii) at a synaptic level where neuroimaging studies investigating dopamine transporter availability (DAT) does not bring any evidence of dysfunction; iii) and finally, neuroimaging studies investigating DA receptor density show a mild increase of D2 receptor density in basic condition and, an hyperreactivity of DA system in dynamic condition. These results are discussed regarding laterality, sub-regions of striatum and implications for the at-risk population. Striatal DA abnormalities are now clearly demonstrated in patients with schizophrenia and at risk population and could constitute an endophenotype of schizophrenia. Subtle sub-clinical striatal DA abnormalities in at risk population could be a biomarker of transition from a vulnerability state to the expression of frank psychosis.

Transcranial magnetic stimulation (TMS) is a very popular tool used within neuroscience. This and other associated techniques allow the in vivo investigation of cortical excitability, cortical connectivity and cortical plasticity. Schizophrenia is a brain disorder and various theories other than the dopamine hypothesis have been developed to describe its underlying neurobiology. Supported by animal and post mortem studies, findings from TMS studies indicate that schizophrenia is a disease of reduced cortical inhibition and impaired intra- and intercortical connectivity. Further studies using repetitive TMS and other plasticity-inducing techniques have shown that cortical plasticity is altered in schizophrenia patients, supporting the recently discussed plasticity deficiency theory of schizophrenia. This review gives an introduction to the most frequently applied techniques, describes findings in schizophrenia patients and discusses these findings with regard to the neurotransmitters and associated receptors involved. In summary, there is emerging evidence of an important pathophysiological interplay between reduced inhibition, impaired connectivity and reduced plasticity in schizophrenia patients. Gammaaminobutyric- acid-receptors and glutamtergic N-Methyl-D-aspartic-acid-receptors are most likely to be involved in this complex interplay, which may reflect a disturbed signal-to-noise ratio in schizophrenia patients. This review will discuss this issue with regard to the available treatment options and will give implications for future research and therapeutic strategies regarding disinhibition and neuroplasticity in schizophrenia.

Proton Magnetic Resonance Spectroscopy Changes After Antipsychotic Treatment by Agata Szulc, Beata Galinska-Skok, Napoleon Waszkiewicz, Daniel Bibulowicz, Beata Konarzewska, Eugeniusz Tarasow (414-427).
Proton magnetic resonance spectroscopy (1H MRS) enables the observation of brain function in vivo. Several brain metabolites can be measured by the means of 1H MRS: N-acetylaspartate (NAA), choline containing compounds (Cho), myo-inositol (mI) and glutamate (Glu), glutamine (Gln) and GABA (together as Glx complex or separately). 1H MRS measures have been found to be abnormal in psychotic disorders such as schizophrenia. Here we specifically review the influence exerted by antipsychotic drugs on brain metabolism, as detected by1H MRS. We systematically reviewed the available literature and uncovered 27 studies, 16 before-after treatment and 11 cross-sectional. Most of them addressed the effects of antipsychotics in schizophrenia and mainly focusing on NAA alterations. Follow up studies indicated antipsychotic drugs may act by increasing NAA levels in selected brain areas (the frontal lobe and thalamus), especially during the short-time observation. This phenomenon seems to vanish after longer observation. Other studies indicated that glutamate measures are decreasing along with the duration of the disease, suggesting both a neurodegenerative process present in schizophrenic brain as well as an influence of antipsychotics. The above results were reviewed according to the most recent theories in the field accounting for the impact of antipsychotics 1HMRS measures.

The evidence that antipsychotics improve brain function and reduce symptoms in schizophrenia is unmistakable, but how antipsychotics change brain function is poorly understood, especially within neuronal systems. In this review, we investigated the hypothesized normalization of the functional magnetic resonance imaging (fMRI) blood oxygen level dependent signal in the context of antipsychotic treatment. First, we conducted a systematic PubMed search to identify eight fMRI investigations that met the following inclusion criteria: case-control, longitudinal design; pre- and post-treatment contrasts with a healthy comparison group; and antipsychotic-free or antipsychotic-naive patients with schizophrenia at the start of the investigation. We hypothesized that aberrant activation patterns or connectivity between patients with schizophrenia and healthy comparisons at the first imaging assessment would no longer be apparent or “normalize” at the second imaging assessment. The included studies differed by analysis method and fMRI task but demonstrated normalization of fMRI activation or connectivity during the treatment interval. Second, we reviewed putative mechanisms from animal studies that support normalization of the BOLD signal in schizophrenia. We provided several neuronal-based interpretations of these changes of the BOLD signal that may be attributable to long-term antipsychotic administration.

Volumetric Changes in the Basal Ganglia After Antipsychotic Monotherapy: A Systematic Review by B. H. Ebdrup, H. Norbak, S. Borgwardt, B. Glenthoj (438-447).
Introduction: Exposure to antipsychotic medication has been extensively associated with structural brain changes in the basal ganglia (BG). Traditionally antipsychotics have been divided into first and second generation antipsychotics (FGAs and SGAs) however, the validity of this classification has become increasingly controversial. To address if specific antipsychotics induce differential effects on BG volumes or whether volumetric effects are explained by FGA or SGA classification, we reviewed longitudinal structural magnetic resonance imaging (MRI) studies investigating effects of antipsychotic monotherapy. Material and Methods: We systematically searched PubMed for longitudinal MRI studies of patients with schizophrenia or non-affective psychosis who had undergone a period of antipsychotic monotherapy. We used specific, predefined search terms and extracted studies were hand searched for additional studies. Results: We identified 13 studies published in the period from 1996 to 2011. Overall six compounds (two classified as FGAs and four as SGAs) have been investigated: haloperidol, zuclophentixol, risperidone, olanzapine, clozapine, and quetiapine. The follow-up period ranged from 3-24 months. Unexpectedly, no studies found that specific FGAs induce significant BG volume increases. Conversely, both volumetric increases and decreases in the BG have been associated with SGA monotherapy. Discussion: Induction of striatal volume increases is not a specific feature of FGAs. Except for clozapine treatment in chronic patients, volume reductions are not restricted to specific SGAs. The current review adds brain structural support to the notion that antipsychotics should no longer be classified as either FGAs or SGAs. Future clinical MRI studies should strive to elucidate effects of specific antipsychotic drugs.

Functional Magnetic Resonance Imaging (FMRI) is a non-invasive technique for brain mapping and mostly performed using changes of the blood-oxygen-level-dependent (BOLD)–signal. It has been widely used to investigate patients with schizophrenia. Most of the studies examine patients treated with antipsychotic drugs, although little is known about the effects of these drugs on the BOLDsignal. Here we examined studies of patients with schizophrenia treated with different antipsychotics to address the question whether and to what extent antipsychotic drugs in themselves produce BOLD-signal changes. We performed a PubMed-search for the period from 1999 until January 2012 with the search items “schizophrenia” and “Magnetic Resonance Imaging” and “Antipsychotic Agents; or “Magnetic Resonance Imaging” and “Antipsychotic Agents”; or “schizophrenia” and “Antipsychotic Agents” and “FMRI”. We extracted articles that examined at least two patient groups with different treatments, or patients examined on different medications at different times and that provided information about drug effects. No common effect of antipsychotics on BOLD-signal was found. However, based on the results for different antipsychotics (haloperidol, olanzapine, quetiapine and risperidone) we found evidence that the affinity to the dopamine (DA) D2-receptor may influence BOLD-signal.

Meta-analyses are useful to summarize the exponential amount of inconsistent and conflicting neuroimaging data. However, they are usually separately conducted for each different neuroimaging modality, preventing the multimodal integration of different imaging findings in a given neuropsychiatric disorder. Here, we describe an innovative method to meta-analytically combine the results of different imaging modalities, such as structural and functional paradigms. The method accounts for the presence of noise in the estimation of the p-values, and can be easily applied to any meta-analytical software. We hope that with this advanced imaging tool, researchers will be able to provide more complete multimodal pictures of the brain regions affected in different neuropsychiatric disorders.

Do Subjects at Clinical High Risk for Psychosis Differ from those with a Genetic High Risk? - A Systematic Review of Structural and Functional Brain Abnormalities by R. Smieskova, J. Marmy, A. Schmidt, K. Bendfeldt, A. Riecher-Rossler, M. Walter, U. E. Lang, S. Borgwardt (467-481).
Introduction: Pre-psychotic and early psychotic characteristics are investigated in the high-risk (HR) populations for psychosis. There are two different approaches based either on hereditary factors (genetic high risk, G-HR) or on the clinically manifested symptoms (clinical high risk, C-HR). Common features are an increased risk for development of psychosis and similar cognitive as well as structural and functional brain abnormalities. Methods: We reviewed the existing literature on longitudinal structural, and on functional imaging studies, which included G-HR and/or C-HR individuals for psychosis, healthy controls (HC) and/or first episode of psychosis (FEP) or schizophrenia patients (SCZ). Results: With respect to structural brain abnormalities, vulnerability to psychosis was associated with deficits in frontal, temporal, and cingulate regions in HR, with additional insular and caudate deficits in C-HR population. Furthermore, C-HR had progressive prefrontal deficits related to the transition to psychosis. With respect to functional brain abnormalities, vulnerability to psychosis was associated with prefrontal, cingulate and middle temporal abnormalities in HR, with additional parietal, superior temporal, and insular abnormalities in C-HR population. Transition-to-psychosis related differences emphasized prefrontal, hippocampal and striatal components, more often detectable in C-HR population. Multimodal studies directly associated psychotic symptoms displayed in altered prefrontal and hippocampal activations with striatal dopamine and thalamic glutamate functions. Conclusion: There is an evidence for similar structural and functional brain abnormalities within the whole HR population, with more pronounced deficits in the C-HR population. The most consistent evidence for abnormality in the prefrontal cortex reported in structural, functional and multimodal studies of HR population may underlie the complexity of higher cognitive functions that are impaired during HR mental state for psychosis.