Perspectives of Neuroscience in Psychiatry

 

 Buy Article Permissions and Reprints

The last decade saw a rapid increase in the knowledge on the neurobiological foundations of psychiatric disorders. We are just beginning to understand the complex interaction between environmental and genetic factors on neuronal organization and neuroadaptivity. Neuroimaging has started to identify interactions between the genetic constitution and availability of neuroreceptors and transporters and functional brain activation elicited by emotionally and motivationally salient stimuli. The emerging field of emotional neuroscience will help to increase our understanding of psychiatric disorders and improve treatment possibilities. Furthermore, neuroscience data should help to reduce the stigma of psychiatric disease, for example, when they demonstrate that drug addiction and relapse are not a moral fault of the individual but rather associated with identifiable neuroadaptive changes that interfere with cortical and, hence, conscious control of behavior.

In 1865, Wilhelm Griesinger (1817 - 1868) chaired the Department of Psychiatry and Neurology at the Charité Hospital in Berlin, Germany, after he had successfully demanded that the two medical disciplines are integrated under his directorship. This suggestion was based on his belief that mental disorders are brain diseases, a view that was not meant to support reductionist views in psychiatry but to relieve psychiatric patients from the prejudice that their disorders were based on moral sins rather than organic diseases. Notwithstanding this focus on central correlates of psychiatric disorders, Griesinger’s understanding of mental disorders was based on the concept of alienation, a term that was able to integrate both social and neurobiological factors in the development and maintenance of psychiatric diseases [2]. It is only in the last years that neurobiological findings shed more light on the question how social exclusion or isolation stress can promote mental disorders [5] [6]. It was found that the genetic constitution, e. g., of the promotor for the serotonin transporter can modulate the effect of external stress factors [1], and genotype effects may more readily detected if neurobiological correlates such as stimulus-associated brain activation are assessed rather than general behavioral correlates that are influenced by a multitude of neuronal networks [3] [4]. Increasing knowledge of the neurobiological foundations of mental disorders will not only help to improve pharmacotherapy. It can also help to show that psychiatric disorders are diseases with an organic correlate and that psychiatric patients have the right to be treated and respected like all other patients suffering from organic diseases.

The Charité Department of Psychiatry has a distinguished history of more than 200 years of psychiatric research and clinical practice. In recognition of this tradition, the 1^st international ”Charité Conference on Psychiatric Research - Challenges and Goals” was held in October 2002 in Berlin and aimed at elucidating the historic dimensions and evolving perspectives of modern psychiatric research. The conference was meant to promote a lively discussion on psychosocial and biological factors that affect brain function and mental health and to bridge the gap between psychosocial and neuroscientific research in the main fields of psychiatric disorders: schizophrenia, unipolar and bipolar affective disorders and drug and alcohol dependence. This supplement highlights presentations from the conference that focused on the genetic and neurobiological basis as well as on treatment perspectives of these disorders.

Andreas Heinz, Daniel Weinberger and associates review the literature on functional brain imaging in schizophrenia and discuss genotype effects on core psychotic symptoms. They argue that the identification of genetic and environmental factors that contribute to intermediate phenotypes, such as working memory deficits, is a promising research strategy, and that molecular brain imaging may help to unravel the complex interactions between genes and environment and its association with neuronal network dysfunction in schizophrenia. Peter Falkai and coworkers discuss migrational disturbances in the entorhinal cortex in schizophrenia. As a follow-up to their earlier studies, authors present new evidence from post-mortem studies supporting the hypothesis that schizophrenia is a developmental disorder. Stephan Ruhrmann, Joachim Klosterkötter and colleagues who are among the pre-eminent pioneers in this field in Germany, illustrate the importance of early detection and intervention during the initial prodromal phase of schizophrenia. Authors emphasize that early intervention aims to improve prodromal symptoms, avoid functional deterioration and suppress or delay transition to psychosis. Results from pilot studies targeting an earlier or later prodromal phase are promising, however, the authors suggest that studies with longer follow-up periods and larger samples are clearly needed. Wolfgang Gaebel and associates present contemporary treatment principles for schizophrenia leading to phase- or stage-oriented, multidimensional treatment approaches on the basis of available practice guidelines for schizophrenia. Furthermore, based on current research programs, future treatment developments in schizophrenia are presented.

The article by Georg Juckel and coauthors emphasizes that anhedonia is not only a symptom of depression and drug and alcohol dependence but also of schizophrenia. Studies in humans and non-human animal models indicate that dysfunction of central dopaminergic neurotransmission interferes with the process of motivation rather than with the ability to experience pleasure. There is evidence that the latter may be mediated to a greater extent by opioidergic and serotonergic neurotransmission. Authors conclude that the understanding of the neurobiological correlates of motivation and pleasure may provide new options for the treatment of anhedonia in patients with schizophrenic disorders. A case in point is the paper by Martin Lambert, Dieter Naber and colleagues who argue that patient’s subjective experiences with antipsychotic drug treatment has been a neglected research area in the past. Subjective well-being with treatment appears to be strongly related to the readiness of patients to take their medication. Evidence suggests that atypical antipsychotics induce less negative subjective effects than conventional neuroleptics, and that various new-generation antipsychotics may be evaluated differently by patients.

Functional brain imaging techniques have offered promising novel insights into the neurocircuits associated with the processing of affective stimuli. Sabine Klein and associates demonstrate that gender differences in the response to emotional paradigms may be identified in healthy subjects using functional magnetic resonance imaging (fMRI) studies. Another example on how functional brain imaging techniques have provided a new understanding of the relationship between psychiatric disorders and mood modulation is presented in the paper by Michael Bauer, Edythe London, Peter C. Whybrow and colleagues. Recent studies using positron emission tomography (PET) with [¹⁸F]-fluorodeoxyglucose demonstrate that treatment with levothyroxine alters regional brain metabolism in patients with bipolar depression and also in patients with hypothyroidism. These studies have confirmed that thyroid hormones are active in modulating metabolic function in the mature adult brain, and provide some intriguing neuroanatomical clues as to the locus of that action.

How progress in molecular research has strongly improved our understanding of complex mental disorders becomes evident in the papers by Drs. Maier, Ströhle, Holsboer, Schäfer and colleagues. Wolfgang Maier and associates conclude from their review that the molecular-genetic basis of non-mendelian, genetically influenced disorders is beginning to be uncovered. They report on recent major progress in localization and detection of disposition genes of schizophrenia and bipolar disorder, and provide a comprehensive overview of recent results of linkage and association studies in these disorders. Authors also discuss the limitations of current research strategies in the search of disposition genes of complex disorders and suggest alternatives that may overcome these limitations. Andreas Ströhle and Florian Holsboer review the evidence pertaining to the stress response alterations that play a major role in the development of major depression, panic disorder and posttraumatic stress disorder. Particularly, they review the role of one of the major neuroendocrine systems, the HPA system, in these disorders and outline some of the potential future treatment options, e. g., CRH-R1 or glucocorticoid receptor antagonists and ANP receptor agonists. The link between cytokines, a large group of peptides with immunmodulatory effects, and neurotransmitter systems is discussed in the contribution of Martin Schäfer and colleagues. Treatment of chronic viral infections and malignant disorders with the cytokine interferon-alpha (IFN-α) leads to severe neuropsychiatric disorders such as major depression and paranoid states in a substantial number of patients. It is hypothesized that these IFN-α effects on behaviour might be modulated through the opioid, serotonin, dopamine and glutamate system.

The implementation of novel treatment strategies is a critical procedure in clinical research. Treatment algorithms and pharmacogenomic approaches to individualize drug treatment are among those in the treatment of affective disorders. Mazda Adli, A. John Rush and their coauthors present an overview of the major German and US-based projects of algorithm research in the field of antidepressant therapy: the Berlin Algorithm Project, the German Research Network on Depression funded by the German Ministry for Education and Research, the Texas Medication Algorithm Project (TMAP) and the Sequenced Treatment Alternatives to Relieve Depression Project (STAR*D), a large, NIMH-funded multicenter project in the US. Despite being one of the oldest medications in psychiatry, lithium has not fallen out of fashion. Tom Bschor and associates argue that lithium augmentation - the addition of lithium to an ongoing antidepressant - is an important strategy in a systematic treatment algorithm of unipolar major depressive episodes. They show evidence that this method is the scientifically best documented treatment strategy for refractory major depression, and that lithium has also a major impact on the serotonergic system as well as on the HPA system. Julia Kirchheiner and a group of international investigators emphasize the increasing evidence that genetic factors are contributing to the inter-individual variability in antidepressant drug response. Subsequently, the authors present a pharmacogenomic approach to individualize antidepressant drug treatment based on identifying and validating the candidate genes involved in drug-response, and developing a pharmacogenetic test-system for future bedside-genotyping (”lab-on-a-chip”). How new technologies will help to uncover the mysteries of chronic, recurrent mood disorders is demonstrated in the paper by Peter C. Whybrow et al. who present a novel, computer-based approach to improve the evaluation of the highly variable course of bipolar disorder in longitudinal studies.

There is growing evidence that severe mood disorders are associated with impairments in signaling pathways that regulate neuroplasticity and cell survival. Therefore, drug treatments with possible neuroprotective effects are becoming increasingly a focus of research. Recent attention has been directed at the potential therapeutic beneficial effects of lithium on neuroprotection [7]. Michael Bauer and colleagues from the International Group for the Study of Lithium Treated Patients (IGSLI) review the most recent literature on this topic and propose implications of the neuroprotective effects of lithium for the treatment of bipolar and neurodegenerative disorders.

Finally, Andreas Heinz and collaborators from the US National Institute on Alcohol Abuse and Alcoholism (NIAAA) review the neurobiological foundations of alcoholism and outline novel treatment options that include pharmacological as well as psychoeducational and behavioral approaches.

References

• 1 Caspi A, Sugden K, Moffitt T E, Taylor A, Craig I W, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene.  Science. 2003;  301 386-389
  CrossrefPubMedGoogle Scholar
• 2 Griesinger W. Die Pathologie und Therapie der psychischen Krankheiten. Krabbe Stuttgart; 1845
  Google Scholar
• 3 Egan M F, Goldberg T E, Kolachana B S, Callicott J H, Mazzanti C M, Straub R E, Goldman D, Weinberger D R. Effect of COMT Val 108/158 Met genotype on frontal lobe function and risk for schizophrenia.  Proc Natl Acad Sci USA. 2001;  98 6917-6922
  Google Scholar
• 4 Hariri A R, Mattay V S, Tessitore A, Kolachana B, Fera F, Goldman D, Egan M F, Weinberger D R. Serotonin transporter genetic variation and the response of the human amygdala.  Science.. 2002;  297 400-403
  CrossrefPubMedGoogle Scholar
• 5 Heinz A, Jones D W, Gorey J, Bennet A, Suomi S J, Linnoila M, Weinberger D R, Higley D. Serotonin transporter availability correlates with alcohol intake in non-human primates.  Mol Psychiatry. 2003;  8 231-234
  Google Scholar
• 6 Higley J D, Suomi S S, Linnoila M. A non-human primate model of type II excessive alcohol consumption. Part 1 & 2.  Alc Clin Exp Res. 1996;  20 629-651
  PubMedGoogle Scholar
• 7 Pilcher H R. Drug research: the ups and downs of lithium.  Nature. 2003;  425 118-120
  CrossrefPubMedGoogle Scholar

Prof. Dr. Andreas Heinz, Priv.-Doz. Dr. Dr. Michael Bauer

Department of Psychiatry and Psychotherapy

Charité - University Medicine Berlin

Campus Charité-Mitte (CCM)

Schumannstr. 20/21

10117 Berlin

Germany

Phone: *49-30-450517001

Fax: *49-30-450517910

Email: andreas.heinz@charite.de, michael.bauer@charite.de

URL: http://www.charite.de/psychiatrie