Massimo Biondi

Psychological Stress and Neuroendocrine Function in Humans: The Last Two Decades of Research

This paper reviews experimental contributions published in the last two decades and exploring the effect of emotional stress on neuroendocrine function in healthy humans. Laboratory studies allow standardization of the stressor and better control for known confounding factors. Commonly used stressors are mental arithmetics, speech tasks, the Stroop test, videogame playing, films or videotapes and interviews. Little is known about the generalizability of laboratory results, with some studies suggesting great caution in extrapolating data to real-life stress conditions. Another strategy is studying the psychoendocrine reaction to real-life stressors, such as bereavement or anticipated loss, academic examinations, everyday work and parachute jumping. The effects of different stressors on neuroendocrine axes are reviewed, as well as the influence of gender, age, personality, coping style, social support, biological and nonbiological interventions. The subjective perception of the situation is probably a main determinant of the psychoendocrine response pattern. In fact, marked variability in individual responses to a variety of stressors has frequently been observed. Evidently, the ‘objective’ characteristics of a given event are not the only determinants of reaction to the event itself. According to a constructivistic perspective, every given stressor has a strictly personal and idiosyncratic meaning and loses its ‘objective’ characteristics. Of course, biological factors may also play a part. In any case, it is mandatory to overcome a rigid dichotomy between psychological and biological processes. Dualistic conceptions which imply a determination of the physical by the psychological or vice versa should give place to a systemic conception, which implies mutual, circular interactions.

Depression induced by treatment with interferon-alpha in patients affected by hepatitis C virus

BACKGROUND Several studies found a high incidence rate of neuro-psychiatric complications during long-term therapy with interferon alpha (IFNalpha), e.g. slowness, severe fatigue, hypersomnia, lethargy, depressed mood, mnemonic troubles, irritability, short temper, emotional lability, social withdrawal, and lack of concentration. The aim of this study was to examine the incidence of depressed mood and major depression in patients who were treated with IFNalpha. METHODS 30 patients, affected by chronic active C-hepatitis, have been evaluated at baseline and 3 months after IFNalpha treatment. The evaluation consisted of psychometric assessments employing the DSM-IV criteria and the Montgomery Asberg Depression Rating Scale (MADRS). RESULTS At end-point, 40.7% of the patients suffered from a full blown major depression, according to the DSM-IV criteria for major depression. IFNalpha treatment induced a significant increase in the MADRS score from baseline to 3 months later. The MADRS items which were significantly increased at end-point were: expressed and unexpressed sadness; irritability; insomnia; loss of appetite; and asthenia. DISCUSSION The results show that prolonged IFNalpha treatment may induce depressive symptoms and major depression in a considerable number of subjects.

Immunotherapy with interferon-alpha in patients affected by chronic hepatitis C induces an intercorrelated stimulation of the cytokine network and an increase in depressive and anxiety symptoms.

Immunotherapy with interferon-alpha (IFNalpha) may induce depressive symptoms, anxiety and major depression when administered for at least 1-3 months at a dose of 3-10 MUI daily, twice or three times a week. Previously, it has been shown that immunotherapy with interleukin-2 (IL-2) significantly induces the cytokine network, as measured by increases in serum IL-6, IL-10 and the IL-2 receptor (IL-2R), and that the immunotherapy-induced changes in the cytokine network are significantly correlated with the increases in depression ratings. The main aim of this study was to examine the effects of immunotherapy with IFNalpha on the cytokine network in relation to changes in depression and anxiety ratings. Fourteen patients, affected by chronic active C-hepatitis, were treated with IFNalpha (3-6 MUI s.c. three/six times a week for 6 months) and had measurements of serum IFN-gamma (IFNgamma), IL-2, IL-6, IL-6R, IL-8 and IL-10 before starting therapy and 2, 4, 16 and 24 weeks after immunotherapy with IFNalpha. Severity of depression and anxiety were measured with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A), respectively. Repeated measure (RM) design ANOVAs showed significantly higher MADRS and HAM-A scores 2-4 weeks and 4-6 months after starting IFNalpha-based immunotherapy than at baseline. RM design ANOVAs showed significantly higher serum IL-6 and IL-8 levels 2-4 weeks after starting IFNalpha-based immunotherapy and higher serum IL-10 levels 2-4 weeks and 4-6 months after starting therapy than at baseline. There were significant relationships between the IFNalpha-induced changes in serum IL-6 or IL-8 and the depression and anxiety scores. The findings show that IFNalpha-based immunotherapy induces the cytokine network and that IFNalpha-induced increases in IL-6 predicts the development of depressive symptoms. Depressive symptoms following IFNalpha treatment may be secondary to cytokine induction, including that of IL-6.

Increased 24‐hour urinary cortisol excretion in patients with post‐traumatic stress disorder and patients with major depression, but not h patients with fibromyalgia

There is now firm evidence that major depression is accompanied by increased baseline activity of the hypothalamic‐pituitary‐adrenal (HPA) axis, as assessed by means of 24‐h urinary cortisol (UC) excretion. Recently, there were some reports that fibromyalgia and post‐traumatic stress disorder (PTSD), two disorders which show a significant amplitude of depressive symptoms, are associated with changes in the baseline activity of the HPA axis, such as low 24‐h UC excretion. The aim of the present study was to examine 24‐h UC excretion in fibromyalgia and PTSD patients compared to normal controls and patients with major depression. In the three patient groups, severity of depressive symptoms was measured by means of the Hamilton Depression Rating Scale (HDRS) score. Severity of fibromyalgia was measured using a dolorimetrically obtained myalgic score, and severity of PTSD was assessed by means of factor analytical scores computed on the items of the Composite International Diagnostic Interview (CIDI), PTSD Module. Patients with PTSD and major depression had significantly higher 24‐h UC excretion than normal controls and fibromyalgia patients. At a threshold value of ≥240 μg/24 h, 80% of PTSD patients and 80% of depressed patients had increased 24‐h UC excretion with a specificity of 100%. There were no significant differences in 24‐h UC excretion either between fibromyalgia patients and normal controls, or between patients with major depression and PTSD patients. In the three patient groups, no significant correlations were found between 24‐h UC excretion and The HDRS score. In fibromyalgia, no significant correlations were found between 24‐h UC excretion and the myalgic score. In PTSD, no significant correlations were found between 24‐h UC excretion and severity of either depression‐avoidance or anxiety‐arousal symptoms. In conclusion, this study found increased 24‐h UC excretion in patients with PTSD comparable to that in patients with major depression, whereas in fibromyalgia no significant changes in 24‐h UC were found.

Psychological stress, neuroimmunomodulation, and susceptibility to infectious diseases in animals and man: a review.

This article reviews research on the role of psychological stress, personality, social support and other psychosocial factors in bacterial, viral and parasitic infections. After 100 years of research on man and animals, psychological stress is considered as a potential cofactor in the pathogenesis of infectious disease. Psychological stress seems able to alter the susceptibility of animals and man to infectious agents, influencing the onset, course and outcome of certain infectious pathologies. Many experiments have identified in neuroimmunomodulation the principal mediator of the alterations associated with conditions of stress. The development of psychoneuroimmunology has fostered in-depth study of the complex relationship between psychosocial factors, the central nervous system, the immune system and infectious disease. Although antimicrobial drugs have certainly remained the basis of all anti-infective therapy, this type of study has already led some authors to propose and experiment protocols of psychological intervention or psychoimmunotherapy in pathologies such as tuberculosis, or herpes simplex virus or human immunodeficiency virus infections. The psychoneuroimmunological approach to infectious diseases will probably grow in importance in the future not only in the setting of research in psychosomatic medicine but also in that of clinical microbiology.

Depression in cancer patients: a critical review

Cancer patients experience several stressors and emotional upheavals. Fear of death, interruption of life plans, changes in body image and self-esteem, changes in social role and lifestyle are all important issues to be faced. Moreover, Depressive Disorders may impact the course of the disease and compliance. The cost and prevalence, the impairment caused, and the diagnostic and therapeutic uncertainty surrounding depressive symptoms among cancer patients make these conditions a priority for research. In this article we discuss recent data, focusing on detection of Depressive Disorders, biological correlates, treatments and unmet needs of depressed cancer patients.

The influence of illness-related variables, personal resources and context-related factors on real-life functioning of people with schizophrenia.

In people suffering from schizophrenia, major areas of everyday life are impaired, including independent living, productive activities and social relationships. Enhanced understanding of factors that hinder real‐life functioning is vital for treatments to translate into more positive outcomes. The goal of the present study was to identify predictors of real‐life functioning in people with schizophrenia, and to assess their relative contribution. Based on previous literature and clinical experience, several factors were selected and grouped into three categories: illness‐related variables, personal resources and context‐related factors. Some of these variables were never investigated before in relationship with real‐life functioning. In 921 patients with schizophrenia living in the community, we found that variables relevant to the disease, personal resources and social context explain 53.8% of real‐life functioning variance in a structural equation model. Neurocognition exhibited the strongest, though indirect, association with real‐life functioning. Positive symptoms and disorganization, as well as avolition, proved to have significant direct and indirect effects, while depression had no significant association and poor emotional expression was only indirectly and weakly related to real‐life functioning. Availability of a disability pension and access to social and family incentives also showed a significant direct association with functioning. Social cognition, functional capacity, resilience, internalized stigma and engagement with mental health services served as mediators. The observed complex associations among investigated predictors, mediators and real‐life functioning strongly suggest that integrated and personalized programs should be provided as standard treatment to people with schizophrenia.

Treatment with interferon-alpha (IFNα) of hepatitis C patients induces lower serum dipeptidyl peptidase IV activity, which is related to IFNα-induced depressive and anxiety symptoms and immune activation

We have shown that treatment with interleukin-2 (IL-2) or interferon-α (IFNα) may induce depressive symptoms and activation of the cytokine network and that IL-2 treatment may diminish serum dipeptidyl pepdidase IV (DPP IV) activity.1–3 DPP IV (EC 3.4.14.5) is a membrane bound serine protease which catalyzes the cleavage of some cytokines and neuroactive peptides which modulate T cell activity.4 The aims of the present study were to examine the effects of IFNα-based immunotherapy on serum DPP IV activity in relation to induction of the inflammatory response system. In 18 patients with chronic active hepatitis C, we determined the Montgomery and Asberg Rating Scale (MADRS),5 the Hamilton Anxiety Rating Scale (HAM-A),6 serum DPP IV activity, the kynurenine/tryptophan (K/T) quotient, which is an indicator of cytokine (in particular IFN)-induced catabolism of tryptophan,7 and serum interleukin-8 (IL-8) before starting therapy and 2, 4, 16 and 24 weeks after immunotherapy with IFNα. IFNα-immunotherapy significantly suppressed serum DPP IV 2–4 weeks and 16–24 weeks after starting IFNα-based immunotherapy. The reduction in serum DPP IV activity was more pronounced 16–24 weeks after starting immunotherapy than after 2–4 weeks. The IFNα-induced suppression of serum DPP IV activity was significantly correlated to IFNα-induced increases in the MADRS and HAM-A and increases in the K/T quotient and serum IL-8. In conclusion, long-term immunotherapy with IFNα suppresses serum DPP IV activity and the immunotherapy-induced changes in DPP IV are related to increases in severity of depression, anxiety and activation of the inflammatory response system.

Deep transcranial magnetic stimulation as a treatment for psychiatric disorders: a comprehensive review.

Deep transcranial magnetic stimulation (TMS) is a technique of neuromodulation and neurostimulation based on the principle of electromagnetic induction of an electric field in the brain. The coil (H-coil) used in deep TMS is able to modulate cortical excitability up to a maximum depth of 6 cm and is therefore able not only to modulate the activity of the cerebral cortex but also the activity of deeper neural circuits. Deep TMS is largely used for the treatment of drug-resistant major depressive disorder (MDD) and is being tested to treat a very wide range of neurological, psychiatric and medical conditions. The aim of this review is to illustrate the biophysical principles of deep TMS, to explain the pathophysiological basis for its utilization in each psychiatric disorder (major depression, autism, bipolar depression, auditory hallucinations, negative symptoms of schizophrenia), to summarize the results presented thus far in the international scientific literature regarding the use of deep TMS in psychiatry, its side effects and its effects on cognitive functions.

Stressful Life events, social support, attachment security and alexithymia in vitiligo: A case-control study

Background: It has often been suggested that stress might trigger vitiligo. However, only one study supported this hypothesis, and no study explored the role of other personality or social factors. Methods: Out-patients experiencing a recent onset or exacerbation of vitiligo (n = 31) were compared with out-patients with skin conditions in which psychosomatic factors are commonly were regarded as negligible (n = 116). Stressful events during the last 12 months were assessed with Paykel’s Interview for Recent Life Events. Attachment style, alexithymia and social support were assessed with the ‘Experiences in Close Relationships’ questionnaire, the Toronto Alexithymia Scale (TAS-20), and the Multidimensional Scale of Perceived Social Support, respectively. Results: Cases and controls did not differ regarding the total number of events and the number of undesirable, uncontrollable or major events. Three or more uncontrollable events had occurred more frequently among cases than controls. Perceived social support was lower in cases than in controls. Cases scored higher than controls on anxious attachment, tended towards higher scores on avoidant attachment and were classified more often as insecure. Cases scored higher than controls on the TAS-20 and were classified more often as alexithymic or borderline alexithymic. The occurrence of many uncontrollable events, alexithymia and anxious attachment were associated with vitiligo also in multiple logistic regression analysis. Conclusions: These findings suggest that vulnerability to vitiligo is not increased by stressful events, except for many uncontrollable events. Alexithymia, insecure attachment and poor social support appear to increase susceptibility to vitiligo, possibly through deficits in emotion regulation or reduced ability to cope effectively with stress.