Recent advances in psychoneuroimmunology relevant to schizophrenia therapeutics.

PURPOSE OF REVIEW: Immunological understanding of neurological and cognitive alterations of schizophrenia has made a significant breakthrough in unfolding the pathophysiological mechanisms of schizophrenia, at least in a group of patients. Such psychoneuroimmunological aberrations essentially argue for an alternative treatment approach based on immunomodulation in schizophrenia. RECENT FINDINGS: Recent findings in schizophrenia have shown exaggerated immuno-inflammatory responses due to persistent systemic inflammation and neuroinflammation involving microglia activation. The existing antipsychotic drugs have shown substantial benefits in the control of positive symptoms, but they have not demonstrated adequate immuno-dampening effects specifically and effectively. However, a group of emerging nonsteroidal as well as other anti-inflammatory drugs currently being used as an adjunct therapy seem to exhibit increased target specificity and effectiveness in reducing symptom severity to some extent. SUMMARY: The anti-inflammatory drugs that have been shown to reduce the levels of pro-inflammatory mediators and inhibit microglia activation have paved the way for better outcomes of schizophrenia treatment. However, many of the currently tested anti-inflammatory drugs often lack methodological robustness. The identification of novel target(s) that will integrate the processes evoked by various risk determinants into a common signalling pathway is urgently required, and this may take immunomodulation into a new therapeutic domain in schizophrenia.

Psychoneuroimmunology - psyche and autoimmunity.

Psychoneuroimmunology is a relatively young field of research that investigates interactions between central nervous and immune system. The brain modulates the immune system by the endocrine and autonomic nervous system. Vice versa, the immune system modulates brain activity including sleep and body temperature. Based on a close functional and anatomical link, the immune and nervous systems act in a highly reciprocal manner. From fever to stress, the influence of one system on the other has evolved in an intricate manner to help sense danger and to mount an appropriate adaptive response. Over recent decades, reasonable evidence has emerged that these brain-to-immune interactions are highly modulated by psychological factors which influence immunity and autoimmune disease. For several diseases, the relevance of psychoneuroimmunological findings has already been demonstrated.

[Schizophrenic disorders. The development of immunological concepts and therapy in psychiatry]. / Schizophrene Störungen. Die Entwicklung immunologischer Krankheits- und Therapiekonzepte.

Immunological changes reported in patients with schizophrenia may play an aetiological role in these disorders. Further, immunomodulatory medications can influence the symptoms of psychiatric disorders. Antipsychotic agents such as clozapine may act therapeutically through the modulation of the immune system and also lead to side effects in that domain.Both the understanding and factual foundations of immunological concepts and immunological therapies of schizophrenic disorders have changed throughout the history of medicine. These are important considerations in psychiatry where diagnostic, nosological and therapeutic complexity is the norm. The article exemplarily presents publications of the psychiatrists such as Julius Wagner von Jauregg, Lewis Campbell Bruce and Friedrich Ostmann as well as neuropathologist Hermann Lehmann-Facius and haematologist William Dameshek.

Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior.

The potential contribution of chronic inflammation to the development of neuropsychiatric disorders such as major depression has received increasing attention. Elevated biomarkers of inflammation, including inflammatory cytokines and acute-phase proteins, have been found in depressed patients, and administration of inflammatory stimuli has been associated with the development of depressive symptoms. Data also have demonstrated that inflammatory cytokines can interact with multiple pathways known to be involved in the development of depression, including monoamine metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits relevant to mood regulation. Further understanding of mechanisms by which cytokines alter behavior have revealed a host of pharmacologic targets that may be unique to the impact of inflammation on behavior and may be especially relevant to the treatment and prevention of depression in patients with evidence of increased inflammation. Such targets include the inflammatory signaling pathways cyclooxygenase, p38 mitogen-activated protein kinase, and nuclear factor-κB, as well as the metabolic enzyme, indoleamine-2,3-dioxygenase, which breaks down tryptophan into kynurenine. Other targets include the cytokines themselves in addition to chemokines, which attract inflammatory cells from the periphery to the brain. Psychosocial stress, diet, obesity, a leaky gut, and an imbalance between regulatory and pro-inflammatory T cells also contribute to inflammation and may serve as a focus for preventative strategies relevant to both the development of depression and its recurrence. Taken together, identification of mechanisms by which cytokines influence behavior may reveal a panoply of personalized treatment options that target the unique contributions of the immune system to depression.

A psychoneuroimmunological review on cytokines involved in antidepressant treatment response.

OBJECTIVES: The literature exploring the role that cytokine functioning plays in the pathogenesis and treatment of depressive illness is reviewed. The review focuses on the influence of antidepressants on cytokines, and on how treatment response might be affected by genetic variants of cytokines. METHOD: The authors systematically reviewed the scientific literature on the subject over the last 20 years, searching PubMed, PsychInfo, and Cochrane databases. RESULTS: Antidepressants modulate cytokine functioning, and these mechanisms appear to directly influence treatment outcome in depression. Antidepressants appear to normalize serum levels of major inflammatory cytokines, including interleukin (IL)-1beta, IL-6, tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma). Antidepressants are postulated to modulate cytokine functioning through their effects on intracellular cyclic adenosyl monophosphate (cAMP), serotonin metabolism, the hypothalamo-pituitary-adrenocortical (HPA) axis or through a direct action on neurogenesis. Preliminary research shows that cytokine genotypes and functioning may be able to help predict antidepressant treatment response. CONCLUSIONS: Current literature demonstrates an association between antidepressant action and cytokine functioning in major depression. Improved understanding of the specific pharmacologic and pharmacogenetic mechanisms is needed. Such knowledge may serve to enhance our understanding of depression, leading to promising new directions in the pathology, nosology, and treatment of depression.

Sex and gender in psychoneuroimmunology research: past, present and future.

To date, research suggests that sex and gender impact pathways central to the foci of psychoneuroimmunology (PNI). This review provides a historical perspective on the evolution of sex and gender in psychoneuroimmunology research. Gender and sexually dimorphic pathways may have synergistic effects on health differences in men and women. We provide an overview of the literature of sex and gender differences in brain structure and function, sex steroids, gender role identification, hypothalamic-pituitary-adrenal axis function, genetics, immunology and cytokine response. Specific examples shed light on the importance of attending to sex and gender methodology in PNI research and recommendations are provided.

From psychosomatic to psychological medicine: what's the future?

PURPOSE OF REVIEW: Recent research findings into putative psychobiological mechanisms of emotional disorders as the future development of psychosomatic medicine are discussed. RECENT FINDINGS: Recent studies reinforce the communication between the immune and central nervous systems and identify the large set of peptide and nonpeptide neurotransmitters and ligands they share. Cytokines are seen as humoral mediators that may explain the interaction between endocrine and immune systems. The hypothalamic-pituitary axis has been investigated as part of the regulatory circuits that interact with autonomic regulation to expose immunologic processes related to stress or depression, and also to several diseases. Immune dysregulation and psychological distress have been linked to each other in disease, chronic stress, bereavement and other major life events. Research findings in depressive disorders and cancer may generate new theoretical paradigms in psychosomatic medicine. SUMMARY: The clinical understanding and management of distress or emotional disorders associated with physical illness may change in future because of the results of interdisciplinary research, where environmental factors will be integrated with psychological and biological systems, mainly of endocrine or neuroimmunological nature. The ultimate goal of psychosomatic medicine may be the integration of different levels of individual functioning on a systemic basis.

Human psychoneuroimmunology: 20 years of discovery.

An important component of psychoneuroimmunology research is to reveal the myriad ways that behaviors and health are inter-related, with a focus on the immunological mechanisms that underlie these interactions. Research in human psychoneuroimmunology has shown that immunoregulatory processes are an integral part of a complex network of adaptive responses. As such, this review provides a perspective from our laboratory over the last 20 years to define the inter-relationships between behavior and immunity; to identify the hypothalamic pituitary adrenal (HPA) and autonomic mechanisms that link the central nervous system and immune responses; to examine the clinical implications of immune alterations during depression or life stress on inflammatory and infectious disease risk; and to explore the reciprocal role of immune mediators on behavior in humans.

Stress, NK cells, and cancer: Still a promissory note.

Although the last decades have provided ample evidence for deleterious effects of stress on immunity and on cancer development and suggested mediating mechanisms, no psychoneuroimmunology (PNI)-related intervention has become a standard of care in conventional cancer treatment. We believe the reasons for this include the unique nature of cancer evolvement and interactions with the immune system, and the many conceptual and technical obstacles to studying stress effects on immune activity and their implications for human resistance to malignancy. However, the numerous and diverse interactions between malignant tissue and immunocytes are now better understood, and suggestions can be made with respect to certain critical periods to be investigated in cancer-PNI research. Animal models of cancer progression are instrumental in suggesting neuroendocrine and immunological mediators of stress effects on specific aspects of cancer progression, especially with respect to the role of NK cell activity. The ultimate clinical relevance, however, must be tested in cancer patients. Recent animal studies suggest a role for the sympathetic nervous system in mediating biologically relevant stress effects on immunity and on tumor progression. Related interventions can now be tested in patients to support or refute the promise of such studies.

Psychoneuroimmunology--cross-talk between the immune and nervous systems.

Psychoneuroimmunology is a relatively new field of study that investigates interactions between behaviour and the immune system, mediated by the endocrine and nervous systems. The immune and central nervous system (CNS) maintain extensive communication. On the one hand, the brain modulates the immune system by hardwiring sympathetic and parasympathetic nerves (autonomic nervous system) to lymphoid organs. On the other hand, neuroendocrine hormones such as corticotrophin-releasing hormone or substance P regulate cytokine balance. Vice versa, the immune system modulates brain activity including sleep and body temperature. Based on a close functional and anatomical link, the immune and nervous systems act in a highly reciprocal manner. From fever to stress, the influence of one system on the other has evolved in an intricate manner to help sense danger and to mount an appropriate adaptive response. Over recent decades, reasonable evidence has emerged that these brain-to-immune interactions are highly modulated by psychological factors which influence immunity and immune system-mediated disease.

Depressive disorders and immunity: 20 years of progress and discovery.

Since the inception of Brain, Behavior and Immunity twenty years ago, many exciting developments have occurred regarding the relationship between depression and the immune system. These developments have increasingly put the field of psychoneuroimmunology into a clinical context with important translational implications. Initial studies focused on the impact of depression on relatively narrowly defined immunologic endpoints, which ultimately found their relevance in studies examining the effect of depression on immunologically-based diseases including infectious illnesses, autoimmune disorders, and cancer as well as more recently cardiovascular disease. Mechanistic studies have also greatly contributed to an understanding of those facets of depression, which might mediate these effects. More recently, the reciprocal influences of the immune system on the brain and behavior including depression have taken center stage. Increasing data now indicate that activated inflammatory processes can influence multiple aspects of CNS function including neurotransmitter metabolism, neuroendocrine function, and information processing leading to behavioral changes in humans that bespeak depression. These latter developments have intrigued scientists investigating the pathophysiology of depression and warrant consideration as some of the most exciting new developments in psychiatry in the past 20 years. What the future holds is a world of promise as multiple translational targets derived from the cytokine model of depression work their way into the clinical arena as drug targets for further development. Moreover, the work has served to instantiate brain-immune interactions as an essential component in psychiatric and medical co-morbidities and their impact on health and illness.

Protein hormones and immunity.

A number of observations and discoveries over the past 20 years support the concept of important physiological interactions between the endocrine and immune systems. The best known pathway for transmission of information from the immune system to the neuroendocrine system is humoral in the form of cytokines, although neural transmission via the afferent vagus is well documented also. In the other direction, efferent signals from the nervous system to the immune system are conveyed by both the neuroendocrine and autonomic nervous systems. Communication is possible because the nervous and immune systems share a common biochemical language involving shared ligands and receptors, including neurotransmitters, neuropeptides, growth factors, neuroendocrine hormones and cytokines. This means that the brain functions as an immune-regulating organ participating in immune responses. A great deal of evidence has accumulated and confirmed that hormones secreted by the neuroendocrine system play an important role in communication and regulation of the cells of the immune system. Among protein hormones, this has been most clearly documented for prolactin (PRL), growth hormone (GH), and insulin-like growth factor-1 (IGF-I), but significant influences on immunity by thyroid-stimulating hormone (TSH) have also been demonstrated. Here we review evidence obtained during the past 20 years to clearly demonstrate that neuroendocrine protein hormones influence immunity and that immune processes affect the neuroendocrine system. New findings highlight a previously undiscovered route of communication between the immune and endocrine systems that is now known to occur at the cellular level. This communication system is activated when inflammatory processes induced by proinflammatory cytokines antagonize the function of a variety of hormones, which then causes endocrine resistance in both the periphery and brain. Homeostasis during inflammation is achieved by a balance between cytokines and endocrine hormones.

[Immunology in schizophrenic disorders]. / Immunologische Aspekte bei schizophrenen Störungen.

This manuscript deals with whether immune-mediated mechanisms of inflammation contribute to the pathogenesis of schizophrenia. A model is presented which integrates psychoneuroimmunologic findings and actual results from pharmacological, neurochemical, and genetic studies in schizophrenia. A pivotal role in the neurobiology of schizophrenia is played by dopaminergic neurotransmission, which is modulated by influences of the glutamatergic system. The decreased function of the glutamate system described in schizophrenia seems primarily mediated by N-methyl-D-aspartate (NMDA) receptor antagonism. Kynurenine acid is the only known endogenous NMDA receptor antagonist. In higher concentrations it blocks the NMDA receptor, but in lower concentrations it blocks the nicotinergic acetylcholin receptor, which has a prominent role in cognitive functions. Therefore, higher levels of kynurenine acid may explain psychotic symptoms and cognitive dysfunction. Several findings point out that prenatal infection, associated with an early sensitisation of the immune system, may result in an imbalance of the immune response (type 1 vs type 2) in schizophrenia. This immune constellation leads to inhibition of the enzyme indoleamin dioxigenase (IDO). It and tryptophane 2,3-dioxygenase (TDO) both catalyse the degradation from tryptophan to kynurenine. Due to the inhibition of IDO, tryptophan is metabolised to kynurenine primarily by TDO. In the CNS, TDO is located only in astrocytes, which are in particular activated in schizophrenia and in which kynurenine acid is the final product and can not be further metabolised. Therefore kynurenine acid accumulates in the CNS of schizophrenics and - due to its NMDA-antagonistic properties - leads to cognitive dysfunction and psychotic symptoms. This model describes the pathway of immune-mediated glutamatergic-dopaminergic dysregulation, which may lead to the clinical symptoms of schizophrenia. Therapeutic consequences (e.g. cyclo-oxygenase-2 inhibitors) are discussed.