Inflammation, Autoimmunity, Bipolarity and Psychosis

Transcription

1 Inflammation, Autoimmunity, Bipolarity and Psychosis An humoral perspective Dr. Giulio Perugi Institute of Behavioral Sciences G De Lisio, Pisa, Italy Department of Clinical and Experimental Medicine, University of Pisa, Italy giulio. perugi@med.unipi.it

2 Overlap across the 3 DSM-IV psychosis diagnoses Symptoms Psychosocial functioning Familial lineage Overlapping genetic determinants across psychoses Scant evidence for distinct phenotypic clustering around traditional phenomenological diagnoses 2

3 .the Kraepelinian dychotomy has been usefull for a hundred years. Now it is time to move on.

4 Will we still use the term schizophrenia in 2030? The clinical evidence supports the possibility that what we have labelled schizophrenia for the past century may be many different disorders with different outcomes

5 Pisa Observational Study Sample: 347 patients Bipolar Disorder DSM-IV(DB) 207 (59.7%) DB I 140 (40.3%) DB II/CICLOTIMIA Objectives: - Prevalence of physical illness (PI) - Relationships between physical comorbidity and clinical features of BD

6 Lifetime Comorbid Physical Illness in 201 Bipolar Patients ,8 43,8 37,3 Metabolic Cardiovascular Autoimmune/allergic 35 Altro 25 20, % of comorbid physical illness

7 Autoimmune-Allergic Diseases 9,3% % of autoimmune-allergic diseaeses

8 Multiple logistic regression backward procedure of clinical features of BD on the presence of comorbid Autoimmune diseases Variables in equation Wald p OR (95% CI) Gender Female ( ) Bipolar I disorder ( ) Psychotic features ( )

9 Interestingly, the lifetime prevalence of cancer and neoplastic diseases was very low: 1 patient (.3%) reported Lung Adenocarcinoma and 2 (.6%) patients Bowel Cancer. Perugi et al. JAD, 2014

10 Key Words Neuroinflammation Psychoneuroimmunology Astrocyte Microglia Cytokines Oxidative stress

11 Allostatic load and neuro-progression of Bipolar Disorder - Glucocorticoids, Oxidative stress, Inflammation and decrease expression of Neuroprotective factors interact in nonlinear manner.

12 Neuroprogression: - Shortening of the interval with each recurrence - Cognitive deterioration Allostatic Load: - Proinflammatory Cytokines, corticosteroids, neurotrophins, mitochondrial energy generation, oxidative stress and neurogenesis

13 Autoimmunity and Psychiatric Symptoms Neuropsychiatric syndromes have been described in many autoimmune diseases, both systemic and organ-specific Stojanovich, 2007; Lass 2008

14 - Psychosis has been associated with genetic markers of the immune system and with excess autoreactivity and other immune alterations - The associations could also be caused by shared genetic factors or common etiologic components, such as infections. Infections can induce the development of autoimmune diseases and autoantibodies, possibly affecting the brain

15 - Autoimmune diseases (in patients and first degree relatives) predicted raised risk of psychosis - Bipolar Disorder is predicted by: - Guillaine-Barrè - Crohn s disease - Autoimmune epatitis - Perniciosus anemia (FH)

16 raised macrophage/monocyte inflammatory activation patterns (monocytosis, high-inflammatory gene expression, raised glucocorticoid receptor β/glucocorticoid receptor α ratio, high levels of proinflammatory and anti-inflammatory monocyte/macrophage derived cytokines in serum/plasma), reduced T cell numbers/proliferation, and TH1 skewing.

17 Immune mediate model of psychosis Bergink, 2013

18 infection-induced developmental neuroinflammation may be pathologically relevant beyond the antenatal and neonatal periods, and may contribute to disease progression associated with the gradual development of full-blown Schizophrenic Disease..exposure to prenatal immune challenge primes early pre- and postnatal alterations in peripheral and central inflammatory response systems, which in turn may disrupt the normal development and maturation of neuronal systems from juvenile to adult stages of life.

19 Autoantibodies and psychoses Autoantibodiesi antireceptors: NMDA AMPA VGKC GABAb GAD (...) Antibodies anti-nmdar e anti-vgkcrhave been described in patients with affective and non affective psychoses

20 Increased Prevalence of Diverse NMDA Glutamate Receptor Antibodies in Patients With an Initial Diagnosis of Schizophrenia: Specific Relevance of IgG NR1a Antibodies for Distinction From N -Methyl-D-Aspartate Glutamate Receptor Encephalitis Steinar J JAMA Psychiatry 2013 RESULTS: Anti-NMDAR antibodies: 9,9% Schizophrenia 2,8% MD 0% BLPD 0,4% controls 2 patients initially classified as having catatonic or disorganized schizophrenia reclassified as misdiagnosed NMDA-R encephalitis (specific IgG NR1a antibodies). In all other seropositive cases, the antibodies consisted of classes IgA and/or IgM or were directed against NR1a/NR2b (not against NR1a alone).

21 One day, I woke up in a strange hospital room, strapped to my bed, under guard, and unable to move or speak. My medical records from a month-long hospital stay of which I have no memory showed psychosis, violence, and dangerous instability. As weeks ticked by and I moved inexplicably from violence to catatonia,.. The exhausted doctors were ready to commit me to the psychiatric ward, in effect condemning me to a lifetime of institutions,.. one simple sketch, became key to diagnosing me with a newly discovered autoimmune disease in which my body was attacking my brain, an illness now thought to be the cause of demonic possessions..

22 Psychiatrists may encounter patients with autoimmune encephalitis in any number of settings, including emergency departments, inpatient units, consultation-liaison services, and outpatient offices Chapman, Am J Psychiatry 2011

23 Patient cohort: 91 women and girls, 9 men (range 5-76 years Symptom presentation / hospital admission (77% psychiatric, 23 % neuropsichiatric) Paranoid thoughts, visual or auditory hallucinations Prodromal symptoms Headache Low-grade fever Non-specific viral-like illness (86% of patients) Bizzarre personality changes, memory problems (all patients) Unresponsiveness (decreased consciousness, n= 88) Dyskinesia, movement disorders (n=86) Seizures (n=76) Autonomic instability (n=69) Central hypoventilation (n=66) Cardiac dysrhythmias (n=37) Time (weeks) Dalmau et al., 2008

24 Immunotherapy First line Corticosteroids Intravenuous Ig Plasma exchange Treatment Second line (in pts without tumors or tardive diagnosis) Rituximab Ciclofosfamide Antipsychotics (clozapine), lithium, ECT (?) when psychiatric manifestations are severe and predominants Dalmau, 2008; Florance, 2009.

25 Pharmachotherapy and inflammation Antidepressants: may decrease TNF-α and IL-6 (Kenis e Maes 2002), pro-inflammatory action, long-term use (Lee 2007) Mood Stabilizers: Lithium, Valproate, Carbamazepine, Lamotrigine may include COX-2 inhibition and reductions in inflammatory cytokines (Basselin, 2010), Atypical Antipsychotis: antagonism D2/5HT reduces the activity of cpla2, PGE2, TNF-α, IL-6 (Qu, 2003)

26 Lithium and inflammation Lithium treated subjects low levels of proinflamatory factors: IL-2, IL-6,IL-10, IFN-gamma Attenuates pro-inflammatory milieu in bipolar disorder (opposite effect in HC) In MDD treatment response may be predicted by baseline levels of IL-6, TNF-alfa levels are related with changes in depressive symptoms Goldesteein et al., J Clin Psych; 70 (8): ; 2009.

27 Is it possible that we have looked in the wrong place the answers to the pathogenesis and treatment of some mental disorders? If certain psychotic disorders were not primary brain diseases, but systemic disorders affecting the brain only in a secondarily? A NEW ROAD MAP: THINKING AND LINKING RATHER THAN NAMING AND BLAMING

28 THANK YOU The greatest mistake in the treatment of diseases is that there are physicians for the body and physicians for the soul, although the two cannot be separated. (Plato) Questions & Comments