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The Neurobiology of Psychiatric Disorders: Insights from ECNP 2013

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 26th European College of Neuropsychopharmacology (ECNP)

Barcelona, Spain / October 5-9, 2013

Barcelona - ECNP is Europe’s leading interdisciplinary platform for the exchange of scientific research on the brain. During the 2013 congress, investigators from around the world shared current insights into the workings of the brain and disorders that can arise as a result of genetic, epigenetic and/or environmental insults, which may occur in utero and throughout a lifespan. By focusing on insults to the brain and neuropathologies, the hope is that new insights into psychiatric disorders may result, potentially leading to novel therapeutic targets and improved patient outcomes. This report summarizes selected highlights from presentations detailing experimental and clinical findings from across the field of neuroscience.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Among a number of sessions highlighted in this summary report are insights into pain processing in patients with a variety of mental disorders. Dr. Predrag Petrovic, Professor of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden set the stage by describing activation patterns in the brain that occur during placebo-induced analgesia (Abstract S.02.03). “Expectations are important in terms of how we experience pain and these expectations can be induced through verbal prompts as well as conditioning,” Dr. Petrovic said.

Imaging studies confirm that placebo analgesia involves both higher order cognitive networks and endogenous opioid systems. In particular, the rostral anterior cingulate cortex (rACC) and the brainstem are implicated in opioid analgesia, suggesting there is a related neural mechanism in both placebo and opioid-induced analgesia.  “We are postulating that the placebo effect is a general phenomenon where our belief system can change any experience in the human mind and that a common brain mechanism is involved in all types of placebo treatments,” he added.

This is particularly important for affective disorders, especially depression, where the placebo effect appears to be large. If so, knowing that the placebo effect is both real and is linked to other systems in the brain, including the endogenous opioid system, might open new pathways for more effective antidepressant therapy.

Implications in Pain

Findings indicate that learning of expectations is directly strengthened by the dopamine system. As noted by several conference speakers, evidence suggests that dopamine, along with serotonin, are both implicated in centralized pain processing, which explains why antidepressants have a role in the management of pain independent of their antidepressant effects. As discussed  by Rosemary Kluetsch, PhD candidate, Central Institute of Mental Health, Heidelberg University, Mannheim, Germany, (Abstract S.02.01), patients with Borderline Personality Disorder (BPD) have higher pain thresholds than normal and can tolerate significantly higher degrees of thermal stimulus than non-BPD counterparts. Interestingly, patients with anorexia nervosa also have high pain thresholds, as other speakers noted.

Focusing on the default mode network connectivity (DMN) during pain processing, Kluetsch showed that DMN connectivity was altered during painful stimuli in BPD patients and that the connectivity between different areas of the brain may reflect either altered cognition modulation of painful stimuli or diminished capacity for emotional regulation. Between 80 to 90% of BPD patients engage in non-suicidal self-injury but many patients do not report pain during self-injurious acts. As Kluetsch suggested, perhaps BPD patients evaluate painful stimuli differently than others possibly due to dissociative symptoms and less integration of what is happening to them.

Another syndrome in which chronic widespread pain may have real pathological underpinnings is fibromyalgia. Some experts still argue that fibromyalgia is a variant of depression or a psychological disorder, noted Dr. Claudia Sommer, Professor of Neurology, University of Wurzburg, Germany during her discussion on fibromyalgia (Abstract PL.03.01). In a case control study (Brain 2013:136:1857-67), Dr. Sommer and colleagues found that fibromyalgia patients had higher NPSI-G discriminative scores than patients with depression, as well as, healthy controls. The NPSI-G scale is the German version of the Neuropathic Pain Symptom Inventory. On quantitative sensory testing, fibromyalgia patients were significantly less sensitive to warmth and cold than depressed patients or healthy controls. Their response to electrical stimulation of small A-delta nerve fibres was significantly lower compared to both control groups as well.  Interestingly, fibromyalgia patients had significantly lower numbers of nerve fibres than both control groups on skin biopsy on average.

Thus, the function and morphology of small nerve fibres in fibromyalgia patients is clearly altered relative to controls, suggesting that small fibre pathology—and not depression or any other psychological condition—may contribute to the complex pathophysiology of pain in fibromyalgia.

Early Childhood Maltreatment

If underlying neuropathology appears to influence the development of psychiatric conditions, early childhood maltreatment appears to affect not only the lifetime risk of depression but the risk of recurrent and persistent depressive episodes, as well as poor response to treatment. Maltreatment in early childhood also potentially increases cardiovascular disease (CVD) risk later in adulthood. In a longitudinal prospective study of a birth cohort followed to age 32 years  (Arch Gen Psychiatry 2008;65(4):409-16), Dr. Andrea Danese, MRC Social Genetic and Developmental Psychiatry Centre, London, UK, found adults with current depression and a history of childhood maltreatment were more likely to have high C-reactive protein (CRP >3 mg/L) levels—a widely recognized marker of chronic inflammation—compared with depressed adults who had no history of childhood maltreatment (Abstract S.15.02).

Dr. Danese also suggested that among adults with a history of childhood abuse, chronic underlying inflammation might contribute to the increased risk of recurrent and persistent depressive episodes, as well as poorer treatment outcomes. “In some cases of treatment-resistant depression, anti-inflammatory medications given in combination with antidepressants may improve treatment response,” he added.

Underlying Stress Response

In explorations of how organisms respond and adapt to stress (Abstract S.11.02), Dr. Johannes Reul, Professorial Research Fellow in Neuroscience, University of Bristol, UK, noted that glucocorticoid (GC) hormones play a central role in the stress response and facilitate consolidation of memories of a stressful event so that individuals can learn and cope better with the same event the next time around.

For example, under normal conditions, animals subjected to the forced swim test (www.pnas.org/content/108/33/13806)will no longer struggle to escape the second time they are exposed because of a learned adaptive response. If, on the other hand, the GC receptor is blocked by a GC receptor antagonist given just prior to the forced swim test, the adaptive immobility response observed in animals under normal conditions is impaired during retest, as Dr. Reul observed.

Moreover, this impaired response occurs not just in the short-term but remains impaired over time. As Dr. Reul and colleagues pointed out in the same forced swim study, GC hormones released during a traumatic event activate glucocorticoid receptors that form complexes in dentate neurons which ultimately activate histone-modifying enzymes, epigenetic changes and induction of gene expression. These processes are associated with consolidation of stress-related behavioural responses including memory formation of a traumatic event and may help explain why stressful events have a long-lasting impact on stress-related memories such as those that occur in post-traumatic stress disorder (PTSD).

Viral Infections and Psychoses

Various viral infections have long been implicated in the etiology of psychoses, including schizophrenia and bipolar disorder, but the link between early infection and later psychosis has never been clear. As discussed by Dr. Herve Perron, CSO, GeNeuro, Geneva, Switzerland (Abstract S.15.04) that link might be the result of an ancient group of human endogenous retroviruses (HERVs) which are present—although in most individuals have been silenced—in every human genome.

One specific HERV, HERV-W, has been implicated in the etiology of both schizophrenia and bipolar disorder. In both disorders, Dr. Perron showed that expression of HERV-W envelop RNA was significantly increased compared with controls although the pattern of distribution was different in the two disorders (Transl Psychiatry 2012;2(12):E201). As he explained, the HERV-W envelop gene encodes a protein that is capable of initiating and perpetuating inflammatory and neurotoxic cascades. Once activated, HERV-W envelop expression may fluctuate but it remains elevated and can continue to fuel the pathogenesis of the underlying disorder, he noted.

Summary

ECNP 2013 provides a platform for scientists and clinicians to share novel ideas and explore new lines of research  that underlie the development of psychiatric disorders. It is a largely investigational meeting because the research presented goes into the origins of psychiatric disease and what might contribute to either its prevention or manifestation. Delegates can look forward to ECNP 2014 as another opportunity to raise the intellectual bar and bring new insights back to clinical practice. 

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