Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 15, Number 22, 2009

Contents

Perspectives in Psychopharmacological Neuroimaging
Executive Editor: Paolo Fusar-Poli


Editorial: Pp. 2533-2534


The Effects of Antipsychotics on the Brain: What have We Learnt from Structural Imaging of Schizophrenia? – A Systematic Review Pp. 2535-2549
R. Smieskova, P. Fusar-Poli, P. Allen, K. Bendfeldt, R.D. Stieglitz, J. Drewe, E.W. Radue, P.K. McGuire, A. Riecher-Rössler and S.J. Borgwardt
[Abstract] [Full Text Article]


Mechanisms Underlying Psychosis and Antipsychotic Treatment Response in Schizophrenia: Insights from PET and SPECT Imaging Pp. 2550-2559
O.D. Howes, A. Egerton, V. Allan, P. McGuire, P. Stokes and S. Kapur
[Abstract] [Purchase Article]


Functional Imaging as a Tool to Investigate the Relationship between Genetic Variation and Response to Treatment with Antipsychotics Pp. 2560-2572
A. Di Giorgio, F. Sambataro and A. Bertolino
[Abstract] [Purchase Article]


What do ERPs and ERFs Reveal About the Effect of Antipsychotic Treatment on Cognition in Schizophrenia?
Pp. 2573-2593
M. Korostenskaja and S. Kähkönen
[Abstract] [Purchase Article]


Imaging the Glutamate System in Humans: Relevance to Drug Discovery for Schizophrenia Pp. 2594-2602
J.M. Stone
[Abstract] [Purchase Article]


Imaging the Neural Effects of Cannabinoids: Current Status and Future Opportunities for Psychopharmacology Pp. 2603-2614
S. Bhattacharyya, J.A. Crippa, R. Martin-Santos, T. Winton-Brown and P. Fusar-Poli
[Abstract] [Purchase Article]


Connecting the Brain and New Drug Targets for Schizophrenia Pp. 2615-2631
H.C. Whalley, J.D. Steele, P. Mukherjee, L. Romaniuk, A.M. McIntosh, J. Hall and S.M. Lawrie
[Abstract] [Purchase Article]


Myelination in Bipolar Patients and the Effects of Mood Stabilizers on Brain Anatomy Pp. 2632-2636
P. Brambilla, M. Bellani, P.-H. Yeh and J.C. Soares
[Abstract] [Purchase Article]


Neuroimaging and Genetics of Antidepressant Response to Sleep Deprivation: Implications for Drug Development
Pp. 2637-2649
F. Benedetti and E. Smeraldi
[Abstract] [Purchase Article]




Abstracts


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Editorial: Perspectives in Psychopharmacological Neuroimaging

Over the past decade, psychiatry has grown in close contact with the advancements of clinical neurosciences. In particular, basic and clinical psychopharmacology has largely benefited from a large array of neuroimaging studies, which provided a direct way of investigating the pathophysiology of mental disorders in vivo.

The structural cerebral abnormalities of gray and white matter underlying the clinical features of schizophrenia and affective disorders, have been investigated respectively with Magnetic Resonance Imaging (MRI) and Diffusion Tensor Imaging (DTI). The function of neurotransmitters mostly implicated in major psychiatric illnesses, for example dopamine and glutamate, has been assessed by using molecular imaging techniques such as positron emission tomography (PET), single-photon emission tomography (SPET), and magnetic resonance spectroscopy (MRS). Regional brain activity associated with specific cognitive processes or symptoms underlying psychiatric disorders, has been studied by using functional magnetic resonance imaging methods (fMRI). Other advanced techniques have allowed researchers to investigate the connectivity patterns between different brain regions and integrate neuroimaging findings with electrophysiological measures. Overall, the potentials of neuroimaging methods in psychopharmacology are largely based on their promises to clarify the neurobiological substrates of psychiatric disorders and to assist clinicians in the diagnostic processes, as the core pathophysiological abnormalities that underlie these diseases have yet to be identified. This may, in turn, inform the discovery and the development of new medications for the treatment of psychiatric conditions.

The review articles included in this issue of Current Pharmacological Design feature leaders in the field related to psychopharmacological neuroimaging. Focus is given to psychosis and affective disorders (bipolar disorder and major depression). The encompassing aim of this issue is to provide the readers working in basic biomedical science and the clinicians a comprehensive understanding of different neuroimaging techniques and their psychopharmacological applications.

The first papers have focused on psychopharmacological investigations of the psychotic spectrum disorders. Smieskova et al. [1] have conducted a systematic review of cross-sectional and longitudinal MRI studies, addressing the effects of antipsychotic molecules on brain structure in schizophrenia. Howes et al. [2] have integrated the previous contribution by addressing the neurochemical mechanisms underlying psychosis (mainly associated with dopaminergic dysfunction) and have elucidated the neurobiological substrates of antipsychotic treatment in schizophrenia on the basis of PET and SPECT imaging evidence. Di Giorgio et al. [3] have reviewed the potentials of integrating fMRI techniques with genetic approaches in order to identify intermediate endophenotypes and improve the response to antipsychotic treatment. Korostenskaja et al. [4] have illustrated how electrophysiological techniques can complement imaging studies by addressing the effect of antipsychotic treatment on electrophysiological indexes of information processing in schizophrenia. However, the polyetiological origin of complex psychiatric diseases such as psychosis makes the notion untenable that they can be efficiently managed through drugs hitting a single target. Thus, the following papers have addressed the potentials of investigating with neuroimaging neurotransmitters other than dopamine. The recent accounts involving glutamate neurotransmission in schizophrenia and their relevance to drug discovery are addressed through a revision of MRS and SPECT studies by Stone [5], while the paper by Bhattacharyya et al. [6] is devoted to the neuroimaging studies of the endocannabinoid system in the light of the development of new treatments for schizophrenia.

The last three papers have extended the application of psychopharmacological neuroimaging to affective spectrum disorders. Whalley et al. [7] have considered the power of connectivity analyses of functional data as a tool for translational neuroscience and treatment, not only in schizophrenia but also in bipolar disorders. Brambilla et al. [8] have briefly overviewed abnormal white matter microstructure in bipolar disorders, as detected by diffusion imaging studies, addressing the effects of mood stabilizers on myelination processes. Finally, Benedetti et al. [9] have reviewed the brain changes associated with antidepressant response to sleep deprivation, providing a good model to identify new targets of treatment and study the pathophysiology of affective illness.

I would like to thank all the authors for their contributions which provided state-of-the-art reviews based on their imaging research and on their clinical experience in psychopharmacology. It is my hope that some of the imaging techniques presented in this issue will soon bring new drugs in clinical practice for the treatment of severe psychiatric conditions such as psychosis.

References

[1] Smieskova R, Fusar-Poli P, Allen P, Bendfeldt K, Stieglitz RD, Drewe J, Radue EW, McGuire PK, Riecher A, Borgwardt SJ. The Effects of Antipsychotics on the Brain: What have We Learnt from Structural Imaging of Schizophrenia? – A Systematic Review. Curr Pharm Des 15(22): 2535-2549.

[2] Howes OD, Egerton A, Allan V, McGuire P, Stokes P, Kapur S. Mechanisms Underlying Psychosis and Antipsychotic Treatment Response in Schizophrenia: Insights from PET and SPECT Imaging. Curr Pharm Des 15(22): 2550-2559.

[3] Di Giorgio A, Sambataro F, Bertolino A. Functional Imaging as a Tool to Investigate the Relationship between Genetic Variation and Response to Treatment with Antipsychotics. Curr Pharm Des 15(22): 2560-2572.

[4] Korostenskaja M, Kähkönen S. What do ERPs and ERFs Reveal About the Effect of Antipsychotic Treatment on Cognition in Schizophrenia? Curr Pharm Des 15(22): 2573-2593.

[5] Stone JM. Imaging the Glutamate System in Humans: Relevance to Drug Discovery for Schizophrenia. Curr Pharm Des 15(22): 2594-2602.

[6] Bhattacharyya S, Crippa JA, Martin-Santos R, Winton-Brown T, Fusar-Poli P. Imaging the Neural Effects of Cananbinoids: Current Status and Future Opportunities for Psychopharmacology. Curr Pharm Des 15(22): 2603-2614.

[7] Whalley HC, Steele JD, Mukherjee P, Romaniuk L, McIntosh AM, Hall J, Lawrie SM. Connecting the Brain and New Drug Targets for Schizophrenia. Curr Pharm Des 15(22): 2615-2631.

[8] Brambilla P, Bellani M, Yeh P-H, Soares J.C. Myelination in Bipolar Patients and the Effects of Mood Stabilizers on Brain Anatomy. Curr Pharm Des 15(22): 2632-2636.

[9] Benedetti F, Smeraldi E. Neuroimaging and Genetics of Antidepressant Response to Sleep Deprivation: Implications for Drug Development. Curr Pharm Des 15(22): 2637-2649.


Paolo Fusar-Poli
Department of Psychological Medicine
Neuroimaging Section
Institute of Psychiatry
King’s College London
UK


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The Effects of Antipsychotics on the Brain: What Have We Learnt from Structural Imaging of Schizophrenia? – A Systematic Review
R. Smieskova, P. Fusar-Poli, P. Allen, K. Bendfeldt, R.D. Stieglitz, J. Drewe, E.W. Radue, P.K. McGuire, A. Riecher-Rössler1 and S.J. Borgwardt

Despite a large number of neuroimaging studies in schizophrenia reporting subtle brain abnormalities, we do not know to what extent such abnormalities reflect the effects of antipsychotic treatment on brain structure. We therefore systematically reviewed cross-sectional and follow-up structural brain imaging studies of patients with schizophrenia treated with antipsychotics. 30 magnetic resonance imaging (MRI) studies were identified, 24 of them being longitudinal and six cross-sectional structural imaging studies. In patients with schizophrenia treated with antipsychotics, reduced gray matter volume was described, particularly in the frontal and temporal lobes. Structural neuroimaging studies indicate that treatment with typical as well as atypical antipsychotics may affect regional gray matter (GM) volume. In particular, typical antipsychotics led to increased gray matter volume of the basal ganglia, while atypical antipsychotics reversed this effect after switching. Atypical antipsychotics, however, seem to have no effect on basal ganglia structure.


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Mechanisms Underlying Psychosis and Antipsychotic Treatment Response in Schizophrenia: Insights from PET and SPECT Imaging
O.D. Howes, A. Egerton, V. Allan, P. McGuire, P. Stokes and S. Kapur

Molecular imaging studies have generated important in vivo insights into the etiology of schizophrenia and treatment response. This article first reviews the PET and SPECT evidence implicating dopaminergic dysfunction, especially presynaptic dysregulation, as a mechanism for psychosis. Second, it summarises the neurochemical imaging studies of antipsychotic action, focussing on D2/3 receptors. These studies show that all currently licensed antipsychotic drugs block striatal D2/3 receptors in vivo- a site downstream of the likely principal dopaminergic pathophysiology in schizophrenia- and that D2/3 occupancy above a threshold is required for antipsychotic treatment response. However, adverse events, such as extra-pyramidal side-effects or hyperprolactinemia, become much more likely at higher occupancy levels, which indicates there is an optimal ‘therapeutic window’ for D2/3 occupancy, and questions the use of high doses of antipsychotic treatment in clinical practice and trials. Adequate D2/3 blockade by antipsychotic drugs is necessary but not always sufficient for antipsychotic response. Molecular imaging studies of clozapine, the one antipsychotic licensed for treatment resistant schizophrenia, have provided insights into the mechanisms underlying its unique efficacy. To link this pharmacology to the phenomenology of the illness, we discuss the role of dopamine in motivational salience and show how i) psychosis could be viewed as a process of aberrant salience, and ii) antipsychotics might provide symptomatic relief by blocking this aberrant salience. Finally, we discuss the implications of these PET and SPECT findings for new avenues of drug development.


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Functional Imaging as a Tool to Investigate the Relationship between Genetic Variation and Response to Treatment with Antipsychotics
A. Di Giorgio, F. Sambataroand A. Bertolino

Recent evidence suggests that genetic variation is associated with individual variability in response to treatment with antipsychotics. Although numerous studies have been performed for identification of potential genetic variants affecting response to treatment, initial enthusiasm has been tempered by inconsistent results. Along with some specific methodological issues, another plausible explanation for such inconsistencies is lack of sensitivity of the phenotype (clinical measures) used to define response. In this paper, we review use of Imaging Genetics, a relatively new approach that combines genetic assessment with functional neuroimaging, to explore in vivo neurobiological effects of genetic variation. Moreover, we propose to use Imaging Genetics as a tool to evaluate and predict response to treatment with antipsychotics based on the individual genetic makeup.


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What do ERPs and ERFs Reveal About the Effect of Antipsychotic Treatment on Cognition in Schizophrenia?
M. Korostenskajaand S. Kähkönen

Cognitive dysfunction is considered to be a core feature in schizophrenia. It is believed that antipsychotic drugs, especially atypical ones, could improve cognitive functions in schizophrenia patients. Auditory event-related potentials (ERPs) such as mismatch negativity (MMN) and P300 response are potential candidates for objective investigation of pre-attentional and attention-dependent processing in schizophrenia patients, respectively. Both these responses were found to be altered in schizophrenia. Moreover, neurotransmitters play important role in generation of MMN and P300 components. Therefore, these ERPs are potential candidates for monitoring the cognitive changes caused by neurochemical modulation during antipsychotic treatment in schizophrenia patients. In addition, neurochemical ERP generation mechanisms discovered during drug-challenge studies in healthy subjects could explain these ERP findings in patients. To date, no effect of antipsychotic treatment on MMN was observed, whereas certain antipsychotics (e.g. clozapine) could modulate P300 response. At the same time, adjunctive glutamate-system affecting therapy seems to influence MMN response. The explanation of these phenomena could be a weak relationship between dopaminergic activities and MMN response and a strong connection between glutamate NMDA receptors and MMN generation. As to the P300 component, because of the multiple generators, it is more sensitive to the influences of different neurochemical activities. In the future, the combination of transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) with electroencephalography (EEG) will open new possibilities for understanding the drug-induced changes on the neural substrates of information processing in schizophrenia patients.


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Imaging the Glutamate System in Humans: Relevance to Drug Discovery for Schizophrenia
James M. Stone

There is growing evidence for the involvement of glutamatergic abnormalities in schizophrenia. Uncompetitive NMDA receptor (NMDAR) antagonists induce effects closely resembling both the positive and negative symptoms of schizophrenia; candidate risk genes for schizophrenia converge on the NMDAR expressing synapse; and a recent trial of a drug with direct action at metabotropic glutamate autoreceptors has demonstrated equivalent efficacy to olanzapine in patients with chronic schizophrenia. Imaging the glutamate system in humans in vivo poses a number of difficulties, and has progressed slowly in comparison to the relative ease of dopamine imaging. Indirect imaging of the glutamate system is possible using pharmacological challenges targeting the glutamate system combined with fMRI, PET or SPECT imaging. There are two methods of directly estimating glutamatergic neurotransmission in living patients using neuroimaging at present: [123I]CNS-1261 SPECT (measuring NMDAR binding), and proton magnetic resonance spectroscopy (MRS) of glutamate and glutamine. Both methods have yielded some intriguing insights into glutamatergic abnormalities and their relevance to psychotic symptoms. In this review, the glutamate hypothesis of schizophrenia, and its relationship to current findings in glutamate imaging in psychosis to this hypothesis will be discussed. The possibility of developing new drugs for schizophrenia in light of these findings will then be considered.


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Imaging the Neural Effects of Cannabinoids: Current Status and Future Opportunities for Psychopharmacology
S. Bhattacharyya, J.A. Crippa, R. Martin-Santos, T. Winton-Brown and P. Fusar-Poli

Although recreational and medicinal use of cannabis has been known for many centuries, it is only in recent decades that it has again attracted considerable systematic attention because of its adverse psychological and potential beneficial effects. This has also been prompted by better understanding of the molecular targets of cannabinoids in the living organism. While cannabis has attracted the attention of mental health professionals because of accumulating evidence linking regular frequent use of cannabis to psychotic disorders like schizophrenia, neuroscientists and pharmacologists have focused their attention on the potential beneficial effects of cannabinoids in neuropsychiatric diseases. However, evidence regarding the neurobiological basis of these adverse psychological or potential beneficial effects has been mainly derived from pre-clinical research. Developments in neuroimaging modalities now offer the unique opportunity to examine in vivo how the different cannabinoids may act on the human brain to mediate their effects. In this review, we focus on research investigating the effects of cannabinoids in the human brain using neuroimaging techniques and explore how this adds to the current understanding about the pathophysiological correlates of psychotic disorders and points towards newer therapeutic candidates for psychotic and anxiety disorders. Further, we also discuss how combining neuroimaging and pharmacological challenge with cannabinoids may open up newer avenues for target identification and validation in psychopharmacology.


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Connecting the Brain and New Drug Targets for Schizophrenia
H.C. Whalley, J.D. Steele, P. Mukherjee, L. Romaniuk, A.M. McIntosh, J. Hall and S.M. Lawrie

One thing we know for certain after decades of functional imaging in schizophrenia is that it is not a disorder that can simply be attributed to circumscribed lesions in the brain. It is, in other words, a disorder of the connectivity of the brain. In this overview, we will consider the power of connectivity analyses of functional MRI (and PET) data as tools for translational neuroscience. We describe the patterns of functional and effective disconnectivity seen in schizophrenia and particular psychotic symptoms, those that appear to be attributable to genetic and/or environmental risk factors for psychosis, the potential of these disconnectivities as trait and state biomarkers, and their sensitivity to drug effects. We conclude that substantial work needs to be done on standardising connectivity analyses across laboratories and that disconnectivity studies should be an integral part of drug discovery programmes.


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Myelination in Bipolar Patients and the Effects of Mood Stabilizers on Brain Anatomy
Paolo Brambilla, Marcella Bellani, Ping-Hong Yeh and Jair C. Soares

In this review, we debate the evidence for abnormal white matter microstructure and myelination in bipolar disorder, as mainly detected by diffusion tensor imaging (DTI) studies. The effects of mood stabilizers on white matter are discussed, based on available findings from human and animal studies. Last, perspectives in this field of research are also drawn.


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Neuroimaging and Genetics of Antidepressant Response to Sleep Deprivation: Implications for Drug Development
Francesco Benedetti and Enrico Smeraldi

Despite confirmed evidences about some neurochemical effects of antidepressant treatments, there is still a high level of uncertainty about which biological changes are needed to recover from a major depressive episode. Changes of monoaminergic neurotransmission are paralleled by profound changes in brain metabolism, neural responses to stimuli, sleep architecture, biological rhythms, and, at the intracellular level, neuronal signaling pathways regulating gene expression, neuroplasticity, and neurotrophic mechanisms.

Sleep deprivation targets the biological mechanisms which are responsible for the possibility, unique to mood disorders, of rapid switching between depression, euthymia, and mania. The rapidity of action of sleep deprivation enables the study of the correlates of antidepressant response at close time points, providing a good model to study the biological basis of the antidepressant response and of the patophysiology of affective illness.

Current knowledge suggests that multiple neurobiological effects of sleep deprivation are responsible for the clinical mood amelioration, suggesting a multi-target mechanism of action. An impressive group of brain imaging studies using different brain imaging techniques (positron emission tomography, single photon emission tomography, functional magnetic resonance imaging, proton spectroscopy, arterial spin labeling) showed that clinical response is associated with changes in the functioning of specific brain areas. The combination of these new methodological acquisitions with the classical neurobiological and pharmacogenetic perspective provides an evolving knowledge about brain changes associated with antidepressant response, and will then help to identify the real targets of antidepressant treatment.