Psychiatric Manifestations of Celiac Disease

Venkatesh Handratta MS, MD Assistant Professor Department of Psychiatry Medstar Georgetown University Hospital

OBJECTIVES The objective of this talk is for the audience to understand the psychological and psychiatric impact of CD in adults.

1. The impact of CD in adults on physical, social and emotional factors

2. Pathophysiology of psychiatric comorbidities the role of serotonin and inflammation

3. Psychiatric co-morbidies associated with CD

4. When to refer the patient to see a psychiatrist

5. When medication use is appropriate

PSYCHIATRIC SYMPTOMS AND DISORDERS ASSOCIATED WITH CD

A wide range of psychiatric symptoms and disorders have been associated with CD.

1.  Anxiety disorders

2.  Depressive and mood disorders

3.  Attention Deficit Hyperactivity Disorder (ADHD)

4.  Autism spectrum disorders

5.  Schizophrenia

ANXIETY DISORDERS

  Levels of anxiety (REACTIVE ANXIETY) appear to increase prior to CD diagnosis, although a diagnosis may be associated with feelings of relief.

  Problems with buying and preparing food, plus the associated expense, within a family group may also contribute to anxiety.

Ref: Ciacci C et al. Psychological dimensions of celiac disease: Toward an integratedapproach.Dig Dis Sci 2002; 47: 2082–2087.

Addolorato G et al. Anxiety but not depression decreases in coeliac patients after one-year gluten-free diet: A longitudinal study. Scand J Gastroenterol 2001; 36: 502–506.

Hauser W et al. Anxiety and depression in adult patients with celiac disease on a gluten-free diet. World J Gastroenterol 2010; 16: 2780.

  Increased concerns about the impact of the disease on socializing with friends and having to abstain from activities.

  Adults with CD also express a sense of loneliness and invisibility, especially when socializing with others.

  Frustration and isolation are the most common negative emotions.

Ref:

HallertC,Granno C, etal. Livingwithcoeliac disease: Controlled study of the burden of illness. Scand J Gastroenterol 2002; 37: 39–42.

Zarkadas M et al. Living with coeliac disease and a gluten-free diet: A Canadian per- spective. J Hum Nutr Diet 2013; 26: 10–23.

Taylor E et al. Coeliac disease: The path to diagnosis and the reality of living with the disease. J Hum Nutr Diet 2013; 26: 340–348.

MECHANISMS EXPLAINING PSYCHOLOGICAL MORBIDITIES

  Disease symptoms can be associated with a decreased sensation of generalized well-being.

  Cerebral hypoperfusion in some brain regions could be secondary to vitamin deficiency due to malabsorption or hyperhomocysteinemia, which might, by damaging the blood-brain barrier, expose neuronal tissue to neuroirritative metabolites.

Ref: Addolorato G et al. Regional cerebral hypoperfusion in patients with celiac disease. Am J Med 2004; 116: 312–317.

Hallert C et al. Clinical trial: B vitamins improve health in patients with coeliac disease living on a gluten-free diet. Aliment Pharmacol Ther 2009; 29: 811–816.

Ferretti A et al. The role of hyperhomocysteinemia in neurological features associated with coeliac disease. Med Hypotheses 2013; 81: 524–531.

Ref: Kurppa K et al. Celiac disease and health-related quality of life. Expert Rev Gastroenterol Hepatol 2011; 5: 83–90.

Autoimmune Theory:

  Association of CD with thyroid disease can represent a significant risk factor for depression and panic disorders.

  There is an elevated risk of depression in patients who have both CD and type I diabetes.

Ref: Garud S et al. Interaction between psychiatric and autoimmune disorders in coeliac disease patients in the Northeastern United States. Aliment Pharmacol Ther 2009; 29: 898–905.

Carta MG et al. Association between panic disorder, major depressive disorder and celiac disease: a possible role of thyroid autoimmunity. J Psychosom Res 2002; 53: 789–793.

  Depression and anxiety may be associated with other factors including an unsatisfactory sexual life, fatigue and poor quality of sleep.

  Defect in tryptophan metabolism can also cause sleep problems and insomnia can be a risk factor for depression and anxiety.

Ref: Ciacci C et al. Self-rated quality of life in celiac disease. Dig Dis Sci 2003; 48: 2216–2220.

Siniscalchi M et al. Fatigue in adult coeliac disease. Aliment Pharmacol Ther 2005; 22: 489– 494.

  CD has been linked to a number of neurological disorders: ataxia, neuropathy, epilepsy, and headaches, which can cause significant functional impairment and cause reactive depression and anxiety.

Ref: Hadjivassiliou M et al. Gluten ataxia in perspective: Epidemiology, genetic susceptibility and clinical characteristics. Brain 2003; 126: 685–691.

Ludvigsson JF et al. A population- based study of coeliac disease, neurodegenerative and neuroinflammatory diseases. Aliment Pharmacol Ther 2007; 25: 1317–1327.

Ludvigsson J et al. Increased risk of epilepsy in biopsy-verified celiac disease: A population- based cohort study. Neurology 2012; 78: 1401–1407.

Hadjivassiliou M et al. Headache and CNS white matter abnormalities associated with gluten sensitivity. Neurology 2001; 56: 385–388.

Rodrigo L et al. Prevalence of celiac disease in multiple sclerosis. BMC Neurol 2011; 11: 31.

FATIGUE There is good evidence to show that fatigue

is a common clinical presentation in patients with CD. Therefore serological screening for CD is now recommended in the workup of chronic fatigue. Ref:

Di Lazzaro V et al. Tired legs—a gut diagnosis. Lancet 2010; 376: 1798.

Skowera A et al. High prevalence of serum markers of coeliac disease in patients with chronic fatigue syndrome. J Clin Pathol 2001; 54: 335–336.

Carnevale V et al. Tiredness: A fea- ture of coeliac disease. Age Ageing 2000; 29: 462–463.

Sanders DS et al. A primary care cross-sectional study of undiagnosed adult coeliac disease. Eur J Gastroenterol Hepatol 2003; 15: 407–413.

EVIDENCE SUPPORTING A ROLE FOR SEROTONIN IN DEPRESSION INCLUDES…

  Lowered CSF and brain concentrations of the serotonin catabolite 5-HIAA is observed in depressed patients and particularly in depressive suicides.

  Increased susceptibility to depression is associated with polymorphisms in the serotonin transporter.

Ref:

Owens, M.J et al. (1994) Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 40, 288-295

Pezawas, L. et al. (2005) 5-HTTLPR polymorphism impacts human cingulate amygdala interactions: a genetic susceptibility mechanism for depression. Nat Neurosci 8, 828-834

In parallel with this, a significant increase in major serotonin and dopamine metabolite concentrations in the brain has been reported after one year on a gluten-free diet.

Pynnönen et al. observed that the majority of adolescents with celiac disease had depressive and behavioral symptoms before their diagnosis, and that celiac disease patients with depression (all girls) had significantly lower pre-diet tryptophan/ CAA ratios and free tryptophan concentrations and significantly higher biopsy morning prolactin levels.

Ref: Gluten-free diet may alleviate depressive and behavioral symptoms in adolescents with celiac disease: a prospective follow-up case-series study Päivi A Pynnönen,

Erkki T Isometsä, Matti A Verkasalo, Seppo A Kähkönen, Ilkka Sipilä, Erkki Savilahti and Veikko A Aalberg. BMC Psychiatry 2005, 5:14

Adolescents with celiac disease showed improvement in psychiatric symptoms after starting a gluten-free diet, and this improvement coincided with a significant decrease in celiac disease activity and in prolactin levels, and with a significant increase in serum concentrations of L-tyrosine and other CAAs.

Ref: Hallert C et al: Improvement in central monoamine metabolism in adult coeliac patient starting a gluten free diet. Psychol Med 1983, 13:267-271.

Tryptophan metabolism in the central nervous system: medical implications. P. Ruddick, Andrew K. et al. Lowry. Expert reviews in molecular medicine Vol. 8; Issue 20; August 2006

It is of theoretical interest that increased production of interferon-γ (IFN-γ), known to be the predominant cytokine produced by gluten-specific T-cells in active celiac disease, can suppress serotonin function both directly and indirectly by enhancing tryptophan and serotonin turnover.

Ref:

Sollid LM: Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunology 2002, 2:647-655.

Brown RR: Metabolism and biology of tryptophan. In Recent Advances in Tryptophan Research: Tryptophan and Serotonin Pathways

Fillippini GA et al., New York: Plenum; 1996:15-25.

Bonaccorso S et al: Psychological and behavioural effects of interferons. Curr Opin Psychiatry 2000, 13:673-677.

STRESS  AND  DEPRESSION    According to research data TDO expression and

activity can be increased by stress-related glucocorticoid hormones via actions at both transcriptional and translational levels.

Ref: Badawy, A.A. et al. (1989) Liver tryptophan pyrrolase. A major determinant of the lower brain 5-hydroxytryptamine concentration in alcohol-preferring C57BL mice. Biochem J 264, 597-599

Schimke, R.T et al. (1965) The roles of synthesis and degradation in the control of rat liver tryptophan pyrrolase. J Biol Chem 240, 322-331

Greengard, O et al. (1963) Relation of cortisone and synthesis of ribonucleic acid to induced and developmental enzyme formation. J Biol Chem 238, 1548-1551

Mangoni, A. (1974) The “kynurenine shunt” and depression. Adv Biochem Psychopharmacol 11, 293-298

HOW TO INHIBIT TDO

Peripheral TDO activity is inversely related to brain tryptophan concentrations and that brain tryptophan concentrations can be dramatically increased by inhibiting TDO activity.  

Ref:    

Salter,  M.  et  al.  (1995)  The  effects  of  a  novel  and  selec:ve  inhibitor  of  tryptophan  2,3-­‐dioxygenase  on  tryptophan  and  serotonin  metabolism  in  the  rat.  Biochem  Pharmacol  49,  1435-­‐1442  

 

USE  OF  ANTIDEPRESSANTS  In addition, several antidepressant drugs including imipramine, tranylcypramine, lofepramine, desmethylimipramine, paroxetine, fluoxetine and others have been shown to inhibit TDO activity – effects that are likely to increase plasma and brain tryptophan concentrations and to increase the rate of serotonin biosynthesis in the brain. Ref:

Badawy, A.A. et al. (1991). Biochem Pharmacol 42, 921-929, Badawy, A.A et al. (1991). Br J Pharmacol 102, 429-433, Bano, S. et al. (2003). J Coll Physicians Surg Pak 13, 5-10, Badawy, A.-B. et al. (1996) J Neurochem 66, 436-437, Badawy, A.A et al. (1982). Br J Pharmacol 77, 59-67, Salter, M. et al. (1995). Neuropharmacology 34, 217-227

 

CONCLUSION First line intervention should be for the patient to be referred to see a psychologist as motivational enhancement will help with dietary adherence which is an important step towards recovery.

If the patient experiences symptoms of depression or anxiety In spite of being compliant with the dietary recommendations, then its advisable for the patient to be referred to see a psychiatrist.

•  Once the patient has been referred to a psychiatrist, the most important thing is to use a medication that does not interfere with other meds and have minimal side effects.

•  Try to prevent polypharmacy to prevent side effects and polypharmacy can also cause a sense of psychological stress like lack of control and feeling of inadequacy.

•  Try to involve the patient in their own treatment, as recovery is a team effort.

THANK YOU