Current Pharmaceutical Design - Volume 15, Issue 22, 2009

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.