Updates in Psychodermatology

J. Jewel Shim, MD, FACLP, FAPA Assistant Chief, Department of Kaiser Oakland/East Bay Associate Clinical Professor University of California, San Francisco CLP 2018 Disclosure: J. Jewel Shim, MD, FACLP, FAPA

With respect to the following presentation, there has been no relevant (direct or indirect) financial relationship between the party listed above (and/or spouse/partner) and any for-profit company which could be considered a conflict of interest. “. . .one is more conscious of the skin than any other organ, it occupies an important place in the consciousness, not alone as an abstract idea, but because it is the site of many sensations – heat, cold, touch, , itching, sexual and lustful. . .” Joseph V. Klauder, “Psychogenic Aspects of Skin Diseases” 1936 Agenda

• Introduction, Dr. Jewel Shim • Skin picking and self injurious behavior in the elderly, Dr. Zeba Hafeez • Delusions of infestation, Dr. Aum Pathare • Dermatologic side effects of psychotropic medications, Dr. Jason Caplan • Psychiatric manifestations of skin diseases and their treatment, Dr. Mark Rapp Psychodermatology

• A not well understood field of psychiatry • 18% dermatologists • 21% psychiatrists • Psychiatric disease may either be the cause or be the result of a dermatological disorder • 1/3 of patients have psychiatric disorder • Delusional parasitosis • , vulgaris

Brown et al., 2015, Nowak and Wong, 2016, Gupta and Gupta, 2014 The skin and the nervous system: A common origin • Differentiation early in embryonic development • Endoderm • Mesoderm • Ectoderm • Nervous system • Skin, hair, nails

Jaffernany and Franca, 2016 The skin

• The body’s largest organ • Large sensory organ • Immune organ • A canvas for emotions • , anxiety • Happiness, excitement • Fear • Anger • Sexual arousal • Barrier between self and the world • Protective, immunologic • Psychological • Sense of self • “thick” vs. “thin” skin

Gupta and Gupta, 2014, Jafferany and Franca, 2016 A Brief History of Psychodermatology

• Archetype of a psychosomatic illness • Confluence of three different medical disciplines • Psychiatry • Neurology • Dermatology • The “brain-skin axis” • Hippocrates (460-377 BC) described people who pulled out their hair when emotionally stressed • Aristotle (384-322 BC) Mind and body are two complementary entities

Franca, et al., 2017, Jafferany and Franca, 2016 History of Psychodermatology (cont)

• Starting in the 18th century, various physicians described the condition of delusional parasitosis • Robert Willan (1757-1812) • Thibierge Georges (1856-1926) “acarophobia” • Karl Axel Ekbom (1907-1977) – “dermatozoic delusion” (Ekbom’s syndrome) • J. Walter Wilson, Hiram E. Miller (1946) “delusional parasitosis” • described • Enrico Morselli (1852-1929) “dysmorphophobia” • Pierre Janet (1959-1947) “l’obsession de la honte du corps” • Sigmund Freud (1856-1939) “The Wolfman” • G.A. Ladee (1966)“dermatologic ”

Franca et al., 2017, Franca et al., 2016

Classification of psychiatric dermatoses

• Four categories • Primary psychiatric disorders • Secondary psychiatric disorders • Psychophysiologic disorders • Cutaneous sensory disorders

Brown, et al., 2015 Primary Psychiatric Disorders • Psychiatric symptoms are primary • Skin manifestations are secondary • Self induced as a result of the psychiatric illness • Reflective of underlying psychiatric disorder • Not explained by a primary pathological skin condition • Examples • Delusional infestation/delusional parasitosis • Neurotic excoriations • artefacta (factitious dermatitis) • • Onychotillomania • Onychophagia • Body dysmorphic disorder Brown, et al., 2015 Secondary Psychiatric Disorders

• Occur as a consequence of the skin condition • • Anxiety • Social • Treating the dermatological disorder associated with improvement of psychiatric symptoms

Brown et al., 2015 Secondary Psychiatric Disorders

• Examples • Psoriasis • Atopic dermatitis • Acne vulgaris • Vitiligo • Psychophysiologic Disorders • Skin disorders exacerbated by psychological factors • Stress • Anxiety • Emotional volatility • Not all dermatoses are worsened by stress • Stress responders • Nonstress responders

Brown et al., 2015 Psychophysiologic Disorders

• Examples • Psoriasis • Atopic dermatitis • Acne vulgaris • • Lichen simplex chronicus • Seborrheic dermatitis • Hyperhidrosis Psychophysiologic disorders

• Treatment of psychological symptoms correlate with improvement • Perception of symptom severity • Compliance with treatment • Quality of life • Improvements are independent of actual changes in clinical severity • Antidepressants effective • SSRIs • TCAs • Psychotropic medications may also cause/worsen skin disorders Brown et al., 2015 Cutaneous Sensory Disorders (CSD)

• Unpleasant cutaneous sensory disturbances • Pain • Burning • Itching • Stinging • Not due to a primary skin disease • No known neurological or medical disorder • Confined to specific location, (face, scalp, perineum) • Greater density of epidermal innervation • More susceptible to disagreeable cutaneous sensations

Brown et al., 2015, Gupta and Gupta, 2014 CSD

• Examples • Stomatodynia • Glossodynia • Vulvodinia • Scrotodynia CSD

• Comorbid psychiatric illness may exacerbate symptoms through heightened awareness • Often improve with treatment of the psychiatric disorder • Pts with no identifiable mental health disorder may also benefit from treatment of dermatoses. • SNRI • TCAs • Analgesic • Antipruritic • CBT Brown et al., 2015 Skin Picking Disorder Self-injurious Behavior in the Elderly Zeba Hasan Hafeez, MD Staff Psychiatrist Kaiser Permanente, Santa Rosa Adjunct Faculty, Touro University CLP 2018 Disclosure: Zeba Hasan Hafeez, MD

With respect to the following presentation, there has been no relevant (direct or indirect) financial relationship between the party listed above (and/or spouse/partner) and any for- profit company which could be considered a conflict of interest.

2 Pathological Skin Picking

• Intentional, repetitive scratching or picking normal skin or skin with minor blemishes, scabs or insect bites.

• Noticeable injury and functional impairment.

3 Background

• Erasmus Wilson (1875) coined the term neurotic excoriations (1).

• Self excoriation triggered by a disturbing/ pruritic sensation (2).

• Itch –scratch cycle can cause a chronic dermatitis in some individuals (3). Skin Picking/ DSM - 5

• Obsessive – compulsive and related disorders. Diagnostic Criteria of Skin Picking Disorder DSM-5

A) Recurrent skin picking resulting in skin lesions B) Repeated attempts to decrease or stop skin picking C) The skin picking causes clinically significant distress or impairment in social, occupational, or other important areas of functioning D) The skin picking is not attributable to the direct physiological effects of a substance (e.g., cocaine) or another medical condition (e.g., scabies) E) The skin picking is not better explained by symptoms of another (e.g., skin picking due to delusions or tactile hallucinations in a psychotic disorder, attempts to improve a perceived defect or flaw in appearance in body dysmorphic disorder, in stereotypic , or intention to harm oneself in non-suicidal self injury Epidemiology

• 2 % of patients presenting at dermatology clinics (4).

• Middle aged female (average age of onset between 30 and 50 years) (5). Treatment of SPD

• Benzodiazepines (6,3), • Amitriptyline 50-75 mg daily (6) • Open trials, small double-blind studies demonstrated efficacy of SSRIs, doxepin, clomipramine, naltrexone, olanzapine, pimozide (5, 7, 8) • N-Acetylcysteine (antioxidant, cysteine pro drug) (9) • Topiramate (10) Neurocognitive findings in SPD

• Response inhibition is dependent on the integrity of the right frontal gyrus , anterior cingulate cortices, and connecting white-matter tracts • Disconnectivity in white-matter tracts connecting neural regions involved in motor generation and suppression • Phenomenological overlap between SPD and trichotillomania (11) fMRI Imaging in SPD

• Eighteen participants with SPD and 15 matched healthy controls undertook an executive planning task (Tower of London) during functional magnetic resonance imaging (fMRI).

• Results :The SPD group had marked functional under activation in bilateral dorsal striatum (maximal in right caudate), bilateral anterior cingulate and right medial frontal regions (12). Pruritus in Elderly

• Physical changes; dryness due to the absence of fatty acids.

• Impaired hydration & barrier function. Other Changes

• Pigmentary changes (rubbing, scratching, solar damage)

• Changes in lifestyle and psychological state Stereotypic Behaviors in

• Patting, rubbing, scratching, picking, placing nonfood items in the mouth, verbalizations (counting or repetitive sounds) Consequences

• Skin can get damaged

• Irritate or agitate others in a facility setting

• Caregiver stress (13,14)

14 Study of 141 Patients with Dementia

• 79 had repetitive behaviors ( typically presented in early stages of dementia) (15)

• Increased prevalence in dementia affecting frontal lobe compared to Alzheimer’s disease (16)

15 Conclusion of other Studies

Combined damage to the following may cause these behavioral disorders(17). • Frontal lobe • Caudate nucleus • Globus pallidus Conclusion of other Studies

Complex stereotypic behaviors are a core feature of the dementing syndrome in FTD ; may reflect early and specific deficits in orbitofrontal circuitry and basal ganglia (18). Self-injurious Behavior (SIB) in the Elderly • Poorly understood phenomenon

• Growing clinical problem affecting elderly patients Self-injurious Behavior (SIB) in Psychiatric disorders • • Mental retardation • Tourette's syndrome • Acute psychotic episodes, • Borderline • Psychiatric Syndromes(Elderly)

• • Dementia • Delusions • Mood disorders associated with general medical conditions (18) Case Report

• A 70 year old woman developed delusions of parasitosis with onset of hyperthyroidism

• Remitted with treatment compliance

• Also treated with pimozide 2 mg/day for 20 months (19) Cross-sectional Study of 110 Nursing Home Patients with Dementia • SIB was observed in 22% of patients • Pinching, scratching oneself , banging one's fist against objects most frequently reported • Combination of two types of SIB seen in five patients Cross-Sectional Study, Contd.

• Modestly related to aimless repetitive behavior and aggression

• No association found between SIB and apathy (20) Associations of SIB

• Prescribed psychotropics (i.e. benzodiazepines) • Immobility • Restraints (21) Neurochemical Hypotheses for SIB

• Based on animal models and drug responses • Low levels of serotonin in the central nervous system associated with impulsive, aggressive, and self-mutilating behavior (18) Neurochemical Hypotheses, SIB

• D1 dopamine supersensitivity hypothesis is based on neuropathological findings (Lesch- Nyhan syndrome pts & animal model testing:rats & monkeys • Endorphin hypothesis: endogenously high CSF levels of opioids may create an opioid- analgesic state which eliminates the motivation to terminate self abuse (18) 26 Neurotransmitters

• Dementia (AD, vascular or substance induced) is associated with pathology of noradrenergic, dopaminergic , serotonergic & cholinergic systems • Decreased serotonin levels in FTD

• Decreased acetylcholine levels in AD

27 Treatment

28 Case Reports

• Stereotypic, Repetitive Movements in Dementia Treated with Buspirone (21)

29 Dopamine Hypothesis

• Neuroleptics commonly used to manage SIB (especially ). Case Reports

SIB associated with Dementia effectively treated: • Risperidone • Thioridazine • Pimozide • Fluphenazine (18) Divalproex

• Retrospective study of 13 patients treated over a 2-year period showed that all had decline in agitation scores (22) • Efficacious for labile, impulsive/ disinhibited brain injury patients (another case series of 29 patients(13 to 89 years) (23) Other Treatment Options

• Lamotrigine (24) • Carbamazapine (25) • Gabapentin (26) • Naltrexone and Naloxone (case studies especially in the developmentally disabled) (18) Non Pharmalcologic Therapies

• Electroconvulsive therapy (27)

• Light therapy improves sleep and decreases agitation (Alzheimer’s disease/ related (28) Non Pharmalcologic Therapies

Humor therapy (29) Music therapy (30) Massage therapy Foot massage and slow stroke massage (31,32) CASE REPORT

A 74 year old patient with a diagnosis of mixed dementia with comorbid depression whose skin picking was successfully treated with fluvoxamine is presented (33).

33) Hafeez ZH. Resolution of Pathological Skin Picking With Fluvoxamine in a 74-Year-Old Dementia Patient. Prim Care Companion CNS Disord. 2016; 18(1) History

• Pt was initially seen at age 71

• For 5-6 months she had been picking the skin of her hands, scalp, chest, arms. Caused sores on face if she got hold of a tweezer.

• MMSE 18/30. 37 Examination

Multiple excoriated, crusted papules, plaques on hands, upper chest, back and scalp

38 MRI Brain (Age 71)

Acute lacunar infarct (left basal ganglia). Small vessel ischemic disease in deep white matter. Moderate ventriculomegaly with central and cortical atrophy. Progression of Dementia

• At age 74

• MMSE was 8/30

40 Previous Ineffective Trials

Sertraline, Duloxetine (increased picking) Escitalopram (dystonia) Fluoxetine (hallucinations) Venlafaxine and donepezil (poorly tolerated) Seroquel and olanzapine ( not helpful) Memantine Treatment

Her relentless skin picking finally decreased after starting fluvoxamine 25 mg twice a day.

Eventually resolved when the dose was increased to 75 mg twice a day Follow up

• The dose of fluvoxamine was subsequently increased to help with agitation although skin picking had resolved.

43 Fluvoxamine

• Binds to presynaptic transporter (SERT) • Role of Serotonin 5HT1-A autoreceptor desensization • Increased sensitivity of D2- like receptors in the nucleus accumbens (33) • Sigma -1 receptors exert potent modulations on neurotransmitters (glutamatergic, noradrenergic, dopaminergic serotonergic and cholinergic systems) • Affinity with Sigma-1-receptors exceeds that of 44 other SSRIs (34) References

1) Odlaug BL, Grant JE: Pathologic skin picking, in Trichotillomania, Skin Picking, and Other Body-Focused Repetitive Behaviors. Edited by Grant JE, Stein DJ, Woods DW, Keuthen NJ Washington, DC, American Psychiatric Publishing, Inc, 2012, pp 21–41 2)Arnold LM, McElroy SL, Mutasim DF, Dwight MM, Lamerson CL, Morris EM. Characteristics of 34 adults with psychogenic excoriations. J Clin Psychiatry. 1998;59:509–14 3)Gupta MA, Gupta AK, Haberman HF. The self-inflicted dermatoses: a critical review. Gen Hosp 4) Griesemer RD, Nadelson T: Emotional aspects of cutaneous disease. In Fitzpatrick TB, Eisen HZ, Wolff K, Freedberg IM, Austen KF (Eds), Dermatology in General Medicine. New York, McGraw-Hill, 1979, pp 1353-1363 5)Gupta MA, Gupta AK, Haberman HF. Neurotic excoriations: a review and some new perspectives .Compr Psychiatry. 1986 Jul-Aug;27(4):381-6 Psychiatry. 1987;9:45–52 6) Fisher BK, Pearce KI: Neurotic excoriations: A personality evaluation. Cutis 1974, 14:251-254 7) Arnold LM, Auchenbach MB, McElroy SL. Psychogenic excoriation. Clinical features, proposed diagnostic criteria, epidemiology and approaches to treatment. CNS Drugs. 2001;15(5):351-9 8) Koblenzer CS, Gupta R. Neurotic Excoriations and Dermatitis Artefacta, Semin Cutan Med Surg, 2013, 32:95-100 45 References

9)Grant JE, Chamberlain SR, Redden SA, et al . N-Acetylcysteine in the Treatment of Excoriation DisorderA Randomized Clinical Trial. JAMA Psychiatry. 2016;73(5):490-496. 10) Jafferany M, Osuagwu FC. Use of Topiramate in Skin-Picking Disorder: A Pilot Study. Prim Care Companion CNS Disord. 2017 Jan 26;19(1). 11)Grant JE, Odlaug BL, Hampshire A et al. White Matter Abnormalities in Skin Picking Disorder: A Diffusion Tensor Imaging Study. Neuropsychophrmacology. 2013 Apr; 38(5): 763– 769 12)Odlaug B L, Hampshire A, Chamberlain SR Grant JE et al. Abnormal brain activation in excoriation (skin-picking) disorder: evidence from an executive planning fMRI study.B J

Psychiatry. 2016 Feb; 2082): 168–174. 13) Johansson K, Aignmark K, Norberg A: Narratives of care providers concerning picking behavior among institutionalized dementia sufferers. Geriatr Nurs, 1999; 20:29—33 14) Neistein S, Siegal AP: Agitation, pacing, restlessness. Int Psychogeriatr.1996;8 Suppl 3:399-402. 15)Hwang P, Tsai SJ, Yang CH, et al: Repetitive phenomena in dementia. Int J Psychiatry Med 2000; 30(2):165—171 46 References

16) Ames D, Cummings JL, Wirshing WC, et al: Repetitive and compulsive behavior in frontal lobe degenerations. J Neuropsychiatry Clin Neurosci 1994; 6:100—113 17)Nyatsanza S, Shetty T, Gregory C, et al: A study of stereotypic behaviors in Alzheimer’s disease and frontal and temporal variant . J Neurol Neurosurg Psychiatry 2003; 74:1398—1402 18)Warnock JK, Burke WJ, Huerter C, Self-Injurious Behavior in Elderly Patients With Dementia Four Case Reports. Am J Geriatr Psychiatry 1999; 7:166–170 19)Ozten E, Tufan AE, Cerit C, Sayar H, Ulubil IY. Delusional parasitosis with hyperthyroidism in an 20) de Jonghe-Rouleau AP, Pot AM, de Jonghe JF. Self-injurious behaviour in nursing home residents with dementia. Int J Geriatr Psychiatry. 2005 Jul;20(7):651-7 21) Helvink B, Holroyd S, Buspirone for Stereotypic Movements in Elderly With Cognitive Impairment. The Journal of Neuropsychiatry and Clinical Neurosciences 2006; 18:242–244). 22). Kunik ME, Puryear L, Orengo CA, et al: The efficacy and tolerability of divalproex sodium in elderly demented patients with behavioral disturbances. Int J Geriatr Psychiatry 1998; 13:29–34. 23)Chatham Showalter PE, Kimmel DNJ. Agitated symptom response to divalproex following acute brain injury. Neuropsychiatry Clin Neurosci. 2000 ;12(3):395-7. 47 References

24) Ng B, Camacho A, Bardwell W, Sewell DD. Lamotrigine for agitation in older patients with dementia.Int Psychogeriatr. 2009 Fe b;21(1):207-8. Epub 2008 Oct 6. 25)Alexopoulous GS, Silver JM, Kahn DA, et al (eds): Treatment of agitation in older persons with dementia. Post-Graduate Medicine. A Special Report. 1998; 4:1–88. 26)Kim Y, Wilkins KM, Tampi RR. Use of gabapentin in the treatment of behavioral and psychological symptoms of dementia: a review of the evidence. Drugs Aging. 2008;25(3):187- 96. 27)Acharya D, Harper DG, Achtyes ED, Seiner SJ, Mahdasian JA, Nykamp LJ, Adkison L, et al. Safety and utility of acute electroconvulsive therapy for agitation and aggression in dementia Int J Geriatr Psychiatry, 2014 .May 16. doi: 10.1002/gps.4137. 28)Hanford N, Figueiro M. Light therapy and Alzheimer's disease and related dementia: past, present, and future. J Alzheimers Dis. 2013;33(4):913-22. 29)Low LF, Goodenough B, Fletcher J, Xu K, Casey AN, Chenoweth L, Fleming R, Spitzer P, Bell JP, Brodaty H.The effects of humor therapy on nursing home residents measured using observational methods: the SMILE cluster randomized trial. J Am Med Dir Assoc. 2014 Aug;15(8):564-9. Epub 2014 May 9.

48 References

30)Vink AC, Zuidersma M, Boersma F, de Jonge P, Zuidema SU, Slaets JP. The effect of music therapy compared with general recreational activities in reducing agitation in people with dementia: a randomised controlled trial. Int J Geriatr Psychiatry. 2013 Oct;28(10):1031-8. 31)Rowe M, Alfred D. The effectiveness of slow-stroke massage in diffusing agitated behaviors in individuals with Alzheimer's disease.J Gerontol Nurs. 1999 Jun;25(6):22-34. 32)Moyle W, Johnston AN, O'Dwyer ST. Australas J Ageing. Exploring the effect of foot massage on agitated behaviours in older people with dementia: a pilot study. 2011 Sep;30(3):159-61. 33) Hafeez ZH. Resolution of Pathological Skin Picking With Fluvoxamine in a 74-Year-Old Dementia Patient. Prim Care Companion CNS Disord. 2016; 18(1) 34) Ishikawa M , Ishiwata K, Ishii K, Kimura Y, Sakata M, Naganawa M, Oda K, Miyatake R et al. High occupancy of sigma-1 receptors in the human brain after single oral administration of fluvoxamine: a positron emission tomography study using [11C]SA4503.Biol Psychiatry. 2007 Oct 15;62(8):878-83.

49 Delusions of Infestation

Aum Pathare, M.D. Assistant Professor of Psychiatry Penn State Health

ACADEMY OF CONSULTATION-LIAISON PSYCHIATRY Psychiatrists Providing Collaborative Care Bridging Physical and Mental Health CLP 2018 Disclosure: Aum Pathare, MD

With respect to the following presentation, there has been no relevant (direct or indirect) financial relationship between the party listed above (and/or spouse/partner) and any for-profit company which could be considered a conflict of interest.

Academy of Consultation-Liaison Psychiatry His durance in these prisons (he being a gentleman of a high spirit and hot head) was the procatractique cause of his deliration or madnesse; which was not outragious, for he would discourse rationally enough and be very facetious company, but he grew to have a phancy that his perspiration turned to flies, and sometimes to bees- ad coetera sobrius; and he had a timber versatile built in Mr. Hart's garden (opposite to St. James's parke) to try the experiment. He would turne it to the sun, and sitt towards it; then he had his fox-tayles there to chase away and massacre all the flies and bees that were to be found there, and then shutt his chassees. Now this experiment was only to be tryed in warme weather, and some flies would lye so close in the cranies and the cloath (with which it was hung) that they would not presently shew themselves. A quarter of an hower after perhaps, a fly or two, or more, might be drawen-out of the lurking holes by the warmeth; and then he would crye out, 'Doe not you see it apparently that these come from me ?’ ‘Twas the strangest sort of madnes that ever found in any one: talke of any thing els, his discourse would be very ingeniose and pleasant. James Harrington after Sir Peter Lely, ca.1658, National Portrait Gallery, London -Aubrey, John. Brief Lives. Oxford: Clarendon Press, 1898. Pg. 292

Academy of Consultation-Liaison Psychiatry Outline

. History, Names, and Basic Concepts . The clinical picture . Epidemiology . Classification and Type of DI . Pathogenesis . Diagnosing DI . Treatment and Outcome . Psychiatric Therapy other than . Special Therapeutic Issues: Ethics and law . Summary

Academy of Consultation-Liaison Psychiatry History, Names, and Basic Concepts

. Magnan & Saury (1889): signe de Magnan/cocaine bugs . Thieberge (1894): Les acarophobes (scabies) . Perrin (1896): Des névrodermies parasitophobiques (First specimens) . Giacardy (1923): Shared delusions of parasitosis . Macnamara (1928): Cutaneous hallucinations . Ekbom (1938): Der präsenile Dermatozoenwahn- First described as a distinct disorder . Riding and Munro (1975): First response to pimozide . Musalek (1989): Interdisciplinary study/SPECT . Trabert (1995): Epidemiological metanalysis of 1223 cases . Lepping et al (2007): Systematic review of antipsychotics in DI . Huber (2008): Structural MRI study . Freudenmann: Delusions of infestation and specimen sign . Davis et al (2010s): Incidence, prevalence and characteristics

Academy of Consultation-Liaison Psychiatry The Clinical Picture Classic patients: • Isolated middle-aged to elderly woman with no psychiatric history, grossly normal cognition and social function • Older patient with a neurocognitive disorder and sensory impairment, may display paranoia • Young male patient with sudden and transient symptoms secondary to use of cannabis, amphetamines, or cocaine

Research and theories: • Self-examination • Pictures and videos • Theories about life cycle

Healthcare: • Initial Contact: Primary care 71%, Public Health 9%, Dermatologists 6%1 • Lack of findings/lack of effect of treatment problem with either the doctor, tests or medications • Doctor shopping • Tests Treatment

Academy of Consultation-Liaison Psychiatry 1Trabert, W. 1993. Delusional parasitosis. Studies on frequency, classification and prognosis. Dissertation. Universitat des Saarlandes, Homburg/Saar, Germany Specimens: • Proof of infestation  handled without disgust or anxiety • Frequencies vary greatly (between 4% in India and 92% in Argentina) • Patient-provided specimens- 13% contained insects, but only 1% of an infesting species • Biopsies show dermatitis 61%; excoriation/ulceration/erosion in 48%; and nonspecific dermal inflammation in 31% • Unexplained dermopathy CDC found no evidence of an infectious process, including B. burgdorferi antibodies. Lesions were ‘most consistent with excoriations or chronic irritation, some with evidence of secondary infection’, solar elastosis in 51% of cases. Hair analysis in a subgroup of 40 (35%) cases showed use of illicit drugs in 50% of cases (opiates and benzodiazepines > cannabinoids > amphetamines > other)

Self-treatment: • ~ 80% of patients with intensive self-cleaning • The most common complications of self-therapy are skin lesion related to irritation/secondary infection (17% - 63%) • Desperate patients also become susceptible to unscrupulous providers/fad treatments

Freudenmann R and Lepping P. (2009). Delusional Infestation. Clinical Microbiology Reviews, 22(4) 690–732. DOI:10.1128/CMR.00018-09 Academy of Consultation-Liaison Psychiatry Pathogens: • Insects 63-84%; worms 11-14%; bacteria 2-20%; and fungi 1-6% • The syndrome (delusional theme) has remained stable over time, although the alleged pathogens(contents), are influenced by culture • Transmission from other humans (50%), plants/ garden/part of the patient's home (33%), and animals/pets (17%) • Localizations of infestation are the skin of the hands, arms, feet, lower legs, scalp, the upper back and breast region, genitals, nose, eyes ears, mouth, gastrointestinal tract • 71-91% experience an infestation of the body before that of the environment, but later believe their environment was affected in some way1 • Patients reporting bugs were more likely to be given a final diagnosis of or found to have a medical diagnosis, whereas patients noting fibers were more likely to have a somatoform disorder2 • Indescribable or very large agents indicate intoxication, delirium/neurocognitive disorder or schizophrenia

1Freudenmann R and Lepping P. (2009). Delusional Infestation. Clinical Microbiology Reviews, 22(4) 690–732. DOI:10.1128/CMR.00018-09 2Reichenberg J, Magid M, Jesser C, et al. (2013). Patients labeled with delusions of parasitosis compose a heterogeneous group: A retrospective study from a referral center. American Academy of Consultation-Liaison Psychiatry Journal of Clinical Dermatology,68(1), 41-46. DOI:10.1016/j.jaad.2012.08.006 Epidemiology

• The mean age at DI diagnosis was 61.5-64.5 years (median 69 years; range 12-93 years) • Most recent age and sex-adjusted DI prevalence 27.3 per 100,000 person-years (prior accounts note 1.9/100,000 person-years; and 6/1,000,000 person-years; v/s 3.7/100,000 for ; one Indian study noted 0.5% prevalence) • The age- and sex-adjusted incidence was 1.9/100,000 person-years. The incidence of DI increased over the four decades from 1. 6 (1976) to 2. 6/100,000 person-years (2010) • Female : Male ratio ranges 1.33-2.5:1, although excess risk for females exists only over 45 years of age and in primary, not secondary, forms of DI. The higher number of males up to 40 years is correlated with intoxication. • Average duration of illness 3.13 years • 47-77 % of patients are isolated; ~69.8% of being unmarried, divorced, or widowed • 33% self-described as disabled; 28% were retired; and 26% were employed in the largest sample • Shared DI 8-49% (14.4% in the largest sample)

Academy of Consultation-Liaison Psychiatry Types of DI

Primary: 8-88% (~40%) . Cannot be explained by any other condition and has been described as monosymptomatic, circumscript, or isolated . Depression, if present, must be secondary to the delusion and have a shorter duration

Secondary: . All other forms of DI are secondary to another disorder, illness, or cause . Substances: 22-30% positive for substances. Amphetamines and cannabis were the most commonly used drugs. Cannabis was the most common , followed by amphetamines and cocaine through 3 studies. Recreational drugs may contribute more commonly to the development of DI in younger patients

Academy of Consultation-Liaison Psychiatry Pathogenesis

Academy of Consultation-Liaison Psychiatry Freudenmann R and Lepping P. (2009). Delusional Infestation. Clinical Microbiology Reviews, 22(4) 690–732. DOI:10.1128/CMR.00018-09 Genetics/Heredity: • Patients with DI have twice as more affected relatives than controls, but only for psychiatric disorders without a specific association • Family history of DI in 15% of the cases in another study

Role of the Dopaminergic System: • Polymorphisms in the gene encoding the presynaptic dopamine transporter was associated with delusional disorder • Long alleles in exon 3 of the dopamine receptor D4 (DRD4) gene were associated with delusional severity in psychotic and delusional disorders • Secondary DI/Treatment by blocking Dopamine

Neuroimaging: • Structural and functional neuroimaging: Pneumencephalography with cortical/subcortical atrophy and dilatation of third and lateral ventricles in ~75% • Structural cranial MRI study by Huber’s group showed mainly vascular lesions of the basal ganglia with a predominant bilateral affection of the striatum disordered striato-thalamo-cortical loop (connection to OCD?) • Structural MRI and voxel-based morphometry by Freudenmann showed lower gray matter volume in DI patients compared to controls in the left medial, lateral and right superior frontal, left anterior cingulate,right striatal areas, higher white matter volume in right middle cingulate, left frontal opercular and bilateral striatal regions, supporting disrupted prefrontal control over somato-sensory representations

Academy of Consultation-Liaison Psychiatry Freudenmann R and Lepping P. (2009). Delusional Infestation. Clinical Microbiology Reviews, 22(4) 690–732. DOI:10.1128/CMR.00018-09 Diagnosing Delusions

• Cognitive v/s Sensoralist approach Disturbed reasoning and judgment (100%) v/s tactile symptoms (82%)

• Impossible to exclude every organism

• Psychiatrists required to judge opinions about areas outside their expertise

• Focusing on impossible content- pitfall?

• For DI: Examine the line of reasoning, proofs of infestation, and response to tests

Academy of Consultation-Liaison Psychiatry Minimal Criteria (Freudenmann and Lepping, 2009) DSM 5: Delusional Disorder 1. Conviction of being infested by pathogens (small, A. The presence of one (or more) delusions with a duration of 1 vivid, inanimate [rare], often “new to science”) month or longer. without any medical or microbiological evidence for B. Criterion A for schizophrenia has never been met. Note: this, ranging from overvalued ideas to a fixed, Hallucinations, if present, are not prominent and are related to unshakable belief. the delusional theme (e.g., the sensation of being infested with insects associated with delusions of infestation). 2. Abnormal sensations in the skin explained by the first C. Apart from the impact of the delusion(s) or its ramifications, criterion (usually meeting criteria of qualitatively functioning is not markedly impaired, and behavior is not abnormal sensations) i.e., without delusions of obviously bizarre or odd. control or so-called passivity phenomena, except in D. If manic or major depressive episodes have occurred, these have cases secondary to schizophrenia). been brief relative to the duration of the delusional periods. 3. Additional symptoms: additional facultative psychotic E. The disturbance is not attributable to the physiological effects of and nonpsychotic symptoms, e.g., visual illusions or a substance or another medical condition and is not better hallucinations, may be present. explained by another mental disorder, such as body dysmorphic 4. Location: (on, in, or under the) skin, but all parts of disorder or obsessive-compulsive disorder. Somatic type: The the body may be infested central theme of the delusion involves bodily functions or 5. Duration: typically months or years (chronic), ranging sensations. Somatic delusions can occur in several forms. Most from minutes (if secondary to toxic psychosis or common is the belief that the individual emits a foul odor; that delirium) to years. there is an infestation of insects on or in the skin; that there is an internal parasite; that certain parts of the body are misshapen or ugly; or that parts of the body are not functioning.

Academy of Consultation-Liaison Psychiatry Additional considerations

Other diagnoses: • Psychiatric diagnoses in addition to delusional infestation in 74% • Depression 45%> anxiety 19% = drug dependence/abuse 19% • In 4%, this additional psychiatric diagnosis was believed to account for the delusional state • Abnormal personality traits uncommon • Impaired Quality of life 81%

Differential i. Dermatitis artefacta ii. Psychogenic excoriation iii. Senile pruritus: Senile pruritus is frequent in the elderly (with no psychotic symptoms) iv. Medication adverse effects v. Other medical conditions

Academy of Consultation-Liaison Psychiatry Approach

1. Take time; take a careful history, including trips to tropical resorts 2. Perform the diagnostic investigations needed 3. Examine all specimens carefully 4. Acknowledge the patient's suffering 5. Paraphrase the symptoms 6. Indicate that you are familiar with the problem 7. Answer that you did not find any pathogens so far, but you are sure that the patient really suffers from the perceptions 8. Indicate that this may be due to over activity in the nervous system and to normal neuron-adaptive processes in the brain 9. Try to introduce antipsychotics as the only substances helpful against these processes, as suggested by current research 10. Use the names “unexplained dermopathy” or “Ekbom's syndrome” if the patients asks for the diagnosis 11. Introduce antipsychotics as helpful against the patient's distress and itching (antihistaminic component of many antipsychotics) 12. Do not try to convince the patient or question the patient's beliefs 13. Do not use words like “delusion(al),” “psychotic,” “psychological,” “psychiatric,” etc. 14. Do not use phrases like “calm down” (“be happy it's not infectious,” “it is only psychogenic,” etc.); this will upset the patient 15. Do not simply prescribe an because different approaches are needed according to the type of DI 16. Do not prescribe antibiotics or any other anti-infective without a real infection (further reinforcing the delusion) 17. Do not overlook frank aggression against other health care professionals 18. Do not forget to ask patients with despair and signs of manifest depression about suicidal ideation and to evaluate any risk to others Freudenmann and Lepping (2009) Academy of Consultation-Liaison Psychiatry General Considerations • Set realistic goals for treatment • Avoid constant questioning of beliefs, premature psychiatric referral or treatment • Local treatment of skin lesions- light dressings to avoid itch-scratch-itch, non-sedating antihistamines against pruritus, treatment of secondary infection • Treat underlying medical conditions • Reduce maintaining factors- social isolation, sensory impairment • Management in psychiatry is possible for ~7.5% of patients • ~ 9% of patients with mixed DI gained full insight with sufficient psychiatric therapy • Setting: Dermatology (11%) v/s Psychiatry (56%) v/s Combined therapy (60%), but no conclusive evidence for the superiority of any setting

Academy of Consultation-Liaison Psychiatry General principles for use of antipsychotics

• Lack of randomized controlled trials with adequate sample sizes • Evidence is limited to small open and retrospective trials, surveys, and case studies (level of evidence between IIa and IV) according to the (AHCPR) • With antipsychotics, rate of full remission increased from 33.9% to 51.9%, as did the rate of response from 28.5% to 31.5%. Rate of nonresponse decreased from 37.5% to 16.5% (publication bias) • Relatively smaller doses of antipsychotics compared to other psychotic disorders • Zomer et al. recommend continuing the antipsychotic for 6 weeks after symptom dissolution and then tapering it off, but low-dose maintenance therapy appears reasonable • More than 25% of patients may relapse within the first 4 months of stopping treatment

Academy of Consultation-Liaison Psychiatry Freudenmann R and Lepping P. (2009). Delusional Infestation. Clinical Microbiology Reviews, 22(4) 690–732. DOI:10.1128/CMR.00018-09 Pimozide and Typicals

• Before specific use of pimozide, the disorder was considered almost untreatable • Pimozide showed a response in 94% of cases, with full remission in 45% • Cochrane reviews failed to find controlled trials with pimozide for DI and for any delusional disorder • Srinivasan (1994) indicated that a good outcome is not a substance-specific effect of pimozide but probably a class effect relating to antidopaminergic medication • First response in 1-4 weeks; maximum effect of treatment in 2-8 weeks (Secondary 3 weeks; Primary 10 weeks) • Individual case reports with typical antipsychotics do not allow further statistics, but they show that a variety of antipsychotic substances have been used for DI • Limited data suggest that depot antipsychotics (Haloperidol, cisflupenthixol, fluphenazine, fluspirilene have been used) might be a treatment option in cases with transient or persistent insight into the illness, but conclusive evidence for superiority of this approach is lacking

Academy of Consultation-Liaison Psychiatry Atypical Antipsychotics

Case-based meta-analysis • 69% of the patients responded or remitted with the use of the first atypical antipsychotic; 75% responded after therapy switches • The rate of full remissions only 37% • First effects were noted after 1.5 weeks, on average, and the maximum effect was observed after 6 weeks (later in primary than in secondary DI) • If a treatment of more than 8 weeks could be established, all cases responded at least partially • Risperidone (69% partial or full remission), and olanzapine (72%) were the most widely used atypical antipsychotics Depot atypical antipsychotics • The first atypical antipsychotic available as a depot for intramuscular injection is risperidone, limited to two cases, which both fully remitted

Academy of Consultation-Liaison Psychiatry Comparing typical and atypical antipsychotics for treatment of DI

• 37% of cases became asymptomatic with atypical antipsychotics v/s 52% with typical antipsychotics • Full remission in primary DI- 25% with atypical v/s 51% typical • Highest remission rate (73%) was seen with typical depot, followed by an open trial using pimozide (64%) • The rates of response (including partial remission) similar with atypical (75%) v/s typical antipsychotics (84%) • The lowest rate of nonresponse or cases left unchanged was seen with atypical antipsychotics (5%) v/s 17% with typicals

Academy of Consultation-Liaison Psychiatry Other modalities

• Antidepressants: Depressive symptoms within primary DI v/s other depressive disorders • , with or without confrontational denial was helpful in 10-45% of cases, particularly suggestion, in cases with a “shakable conviction” • Prefrontal leucotomy (neurosurgery of the cerebral white matter) was effective and, furthermore, led to a remission in other people involved in an SPD in one case • 20 published cases treated with ECT since 1949, mainly for DI secondary to severe depression. The response rate was superior to that for antipsychotic treatment in the largest sample

Academy of Consultation-Liaison Psychiatry Settings and Strategies

. Specialized joint clinics for DI (although evidence for the superiority is mixed ) best placed in dermatology clinics with a well-planned “disappearance” of psychiatry is needed in advertisements, letterheads, websites, and initial patient contact . Thorough counselling of patients with regard to indication, dosage and side-effects of psychotropic agents can improve adherence to medication up to 59 % . A case series with high rates of engagement (88%) with antipsychotics used the following approach- involve the relatives who ensure regular follow-up; stay in telephone contact with patients and their families; personally meet patients when they come in for studies

Academy of Consultation-Liaison Psychiatry Ethical Perspectives

Not reinforcing the Maintaining a fiduciary delusion through tests or Disclosing a diagnosis relationship treatment/ not providing may precipitate hostility ambiguous diagnosis

Narrative based Limited disclosure of approach antipsychotic treatment

Mostow et al (2013) Academy of Consultation-Liaison Psychiatry ALTERNATIVELY • Several authors suggest that non-disclosure of the diagnosis of DP/DI or treatment targets of delusions helps-invoking therapeutic privilege • Disclosure of the diagnosis  Risk of non-improvement and NOT worsening

3 main strategies a) The Stress Strategy: Specifically for Morgellons (Sandoz et al), the psychiatric treatment is disclosed as aimed towards the secondary issues associated with the condition, when in fact it is the primary treatment b) The Empirical Strategy: This strategy consists of telling the patient that a certain pharmaceutical has helped others with similar ailments but that its mechanism is unclear. Alluding to an unknown cause or somatic symptoms is untruthful, as the treatment is aimed towards a delusion c) The Euphemistic Strategy: Some suggest usage of oversensitivity/over activity in the nervous system; referring to the medication as neuroleptics; and to give the diagnosis of unexplained dermopathy/Ekbom’s syndrome; and claiming to use antipsychotics for their antipruritic effect. The physician could appear to exploit the patient’s lack of expertise by misleading them about the primary effect

• Right to refuse treatment  decision-making capacity must be assessed independently of the diagnosis IF incapacitated  Surrogate (practicality?) • Capacitated Obligation to disclose the possibility of delusions and pharmacological treatment • Time-limited trial + open minded attitude towards the possibility that the DP/DI diagnosis may be wrong Consent + Autonomy

Academy of Consultation-Liaison Psychiatry Söderfeldt et al (2013) DI and the Law

Three types of presentations 1. Evaluative, in which a diagnosis of DI would affect the proceedings of a case. Examples include hearings for competency and appealing involuntary commitment, denial of child custody, or denial of Disabilities Insurance Benefits (DIB) or supplemental Security Income (SSI) 2. ‘Delusions of Crime’, in which a claimant with DI sues another party based on the false beliefs, such as suits against doctors who failed to treat an ‘infestation’.* 3. ‘Crimes of delusion’, in which a person in DI is accused of committing a crime (arson, murder, etc.)that likely would not have occurred had they not been delusional

*Patients referred to the clinic for DI were 300 times more likely to require a physician to contact the hospital’s legal counsel compared with other patients in the practice

Academy of Consultation-Liaison Psychiatry Summary

• Primary v/s Secondary DI • Shared DI- may have implications for CPS, communication with family, and treatment targets • Diagnose delusions (Data to the contrary; falsifiable explanations v/s infestation) • Basic dermatological workup + empathic validation builds rapport • Avoid non-disclosure use the idea of time limited trial after establishing rapport • Subset of patients may need surrogate if incapacitated • Data for antipsychotics limited BUT potent dopamine blocking agents show some effect • Continue treatment for at least 6 weeks, although maintenance most likely needed • Identify and treat associated symptoms

Academy of Consultation-Liaison Psychiatry Academy of Consultation-Liaison Psychiatry Spain Rodriguez, 1970 References 1. Freudenmann R, Kölle M, Schönfeldt-Lecuona C, et al. (2010) Delusional Parasitosis and the Revisited: The International Perspective. Acta Dermato-Venereologica, 90(5), 517-554. DOI: 10.2340/00015555-0909 2. P. Lepping and R. W. Freudenmann. (2007). Delusional parasitosis: a new pathway for diagnosis and treatment. Clinical and Experimental Dermatology, 33, 113–117. DOI:10.1111/j.1365-2230.2007.02635.x 3. M. Huber a, E. Kirchler a, M. Karner. (2007). Delusional parasitosis and the dopamine transporter. A new insight of etiology? Medical Hypotheses (2007) 68, 1351–1358. DOI:10.1016/j.mehy.2006.07.061 4. Bewley A, Lepping P, Freundenmann R. (2010). Delusional parasitosis: time to call it delusional infestation. British Journal of Dermatology, 163, 1–2. DOI:10.1111/j.1365-2133.2010.09841.x 5. Fabbro S, Aultman J, and Mostow E. (2013). Delusions of parasitosis: Ethical and clinical considerations. Journal of American Academy of Dermatology,69(1), 156-159. DOI:10.1016/j.jaad.2013.02.012 6. Hebbar S, Ahuja N & Chandrasekaran R. (1999). High prevalence of delusional parasitosis in an Indian setting. Indian Journal of Psychiatry, 41 (2), 136-139. PMCID:PMC2962837 7. Middelveen M, Fesler M, Stricker R. (2018). History of Morgellons disease: from delusion to definition. Clinical, Cosmetic and Investigational Dermatology, 71–90. DOI:10.2147/CCID.S152343 8. Lepping P, Huber M, Freudenmann R. (2015). How to approach delusional infestation. The BMJ, 350. DOI: 10.1136/bmj.h1328 9. Söderfeldt Y, Groß D. (2014). Information, Consent and Treatment of Patients with Morgellons Disease: An Ethical Perspective. American Journal of Clinical Dermatology, 15, 71-76. DOI:10.1007/s40257-014-0071-y 10. Pearson ML, Selby JV, Katz KA, Cantrell V, Braden CR,Parise ME, et al. Clinical, epidemiologic, histopathologic and molecular features of an unexplained dermopathy PLosONE 2012; 7: e29908. 11. Kohorst J, Bailey C, Andersen L. (2018). Prevalence of Delusional Infestation-A Population-Based Study. JAMA Dermatology,154(5), 615-617. DOI: 10.1001/jamadermatol.2018.0004 12. Ahmad K and Ramsay B. (2009). Delusional Parasitosis: Lessons Learnt. Acta Dermato-Venereologica, 154(5),615-617. DOI:10.1001/jamadermatol.2018.0004 13. Lyell A. (1983). Editorial: Delusions of parasitosis. Journal of the American Academy of Dermatology, 8(6),895-897. DOI: 10.1016/S0190-9622(83)80024-3 14. Lyell A. (1983). The Michelson Lecture: Delusions of parasitosis. British Journal of Dermatology 108(4), 485-499. PMID:6838775 15. R. Healy, R. Taylor, S. Dhoat et al. (2009). Management of patients with delusional parasitosis in a joint dermatology ⁄ liaison psychiatry clinic. British Journal of Dermatology,161(1), 197–199. DOI: 10.1111/j.1365-2133.2009.09183.x 16. Reichenberg J, Magid M, Jesser C, et al. (2013). Patients labeled with delusions of parasitosis compose a heterogeneous group: A retrospective study from a referral center. American Journal of Clinical Dermatology,68(1), 41-46. DOI:10.1016/j.jaad.2012.08.006 17. S. Wong and A. Bewley. (2011). Patients with delusional infestation (delusional parasitosis) often require prolonged treatment as recurrence of symptoms after cessation of treatment is common: an observational study. British Association of Dermatologists,165(4), 893–896. DOI:10.1111/j.1365-2133.2011.10426.x 18. Slaughter J, Zanol K, Rezvani H, Flax J. (1998). Psychogenic parasitosis: A case series and literature review. Psychosomatics: The Journal of Consultation-Liaison Psychiatry, 39(6),491-500. DOI:10.1016/S0033-3182(98)71281-2 19. Musalek M, Grünberger J, Lesch OM, Linzmayer L, et al. Psychopathology of patients with delusions of ectoparasitic infestation. Der Nervenarzt,59(10),603-9. PMID: 3237267 20. Wolfgang Trabert. (1999). Shared Psychotic Disorder in Delusional Parasitosis. Psychopathology 32(1),30-4. DOI:10.1159/000029063 21. Srinivasan T, Suresh T, Jayaram V, et al. (1994). Nature and Treatment of Delusional Parasitosis: A Different Experience in India. International Journal of Dermatology, 33(12). PMID:7883408 22. Bostwick J. (2011). Editorials- Taming hornets: the therapeutic relationship in successful treatment of delusional infestation. General Hospital Psychiatry, 33(6), 533–534. DOI: 10.1016/j.genhosppsych.2011.07.002 23. Musalek M and Kutzer E. (1990). The Frequency of Shared Delusions in Delusions of Infestation. European Archives of Psychiatry and Neurological Sciences,239(4), 263-266. PMID:2138550 24. Ekbom K, Yorston G, Miesch M, Pleasance S, Rubbert S. (2003). Classic Text No. 54-The Pre-Senile Delusion of Infestation. History of Psychiatry, 14/2, 229–256. DOI:10.1177/0957154X030142007 25. Zomer, S. F., R. F. De Wit, J. E. Van Bronswijk, G. Nabarro, and W. A. Van Vloten. 1998. Delusions of parasitosis. A psychiatric disorder to be treated by dermatologists? An analysis of 33 patients. Br. J. Dermatol. 138:1030–1032. 26. Jaspers, K. 1973. Allgemeine Psychopathologie, 9th ed. Springer, Heidelberg,Germany. 27. Bhatia, M. S., R. K. Gautam, S. Shome, and G. K. Bedi. 1994. Delusional parasitosis with trichotillomania. J. Indian Med. Assoc. 92:389. 28. Wilson, J. W., and H. E. Miller. 1946. Delusions of parasitosis (acarophobia). Arch. Dermatol. 54:39–56. 29. Zanol, K., J. Slaughter, and R. Hall. 1998. An approach to the treatment of psychogenic parasitosis. Int. J. Dermatol. 37:56–63. 24. Kimsey, L. (2016). Delusional Infestation and Chronic Pruritus: A Review. Acta Dermato-Venereologica, 96, 298–302. DOI: 10.2340/00015555-2236 25. Wykoff, R. (1987). Reviews of Infectious Diseases. Oxford University Press, JSTOR Vol. 9, No. 3, pp. 433-437. https://www.jstor.org/stable/4454119 26. Trabert, W. (1995). 100 Years of delusional parasitosis. Meta-analysis of 1,223 case reports. Psychopathology, 28, 238-46. DOI: 10.1159/000284934 27. Trabert, W. 1993. Delusional parasitosis. Studies on frequency, classification and prognosis. Dissertation. Universitat des Saarlandes, Homburg/Saar, Germany 28. Shah R, Taylor R and Bewley A. (2017). Exploring the Psychological Profile of Patients with Delusional Infestation. Acta Dermato-Venereologica, 97, 98–101. DOI: 10.2340/00015555-2423

Academy of Consultation-Liaison Psychiatry 29. Sandoz A, LoPiccolo M, Kusnir D. (2008). A clinical paradigm of delusions of parasitosis. American Academy of Dermatology, 59(4), 698-704. DOI: 10.1016/j.jaad.2008.06.033 30. Wolf RC, Huber M, Depping MS, et al. (2013) Abnormal gray and white matter volume in delusional infestation. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 46,19-24. DOI: 10.1016/j.pnpbp.2013.06.004 31. Lepping P, Noorthoorn EO, Kemperman PMJH et al. (2017). An international study of the prevalence of substance use in patients with delusional infestation. Journal of American Academy of Dermatology, 77(4), 778-779. DOI: 10.1016/j.jaad.2017.06.024. 32. Lepping P, Russell I and Freudenmann R. (2007) Antipsychotic treatment of primary delusional parasitosis. British Journal of Psychiatry, 191, 198- 205. DOI: 10.1192/bjp.bp.106.029660 33. Bailey C, Andersen L, Lowe G. (2014). A population-based study of the incidence of delusional infestation in Olmsted County, Minnesota, 1976–2010*. British Journal of Dermatology, 170, 1130-1135. DOI: 10.1111/bjd.12848 34. Hirjak D, Huber M, Kirchler E et al. (2017). Cortical features of distinct developmental trajectories in patients with delusional infestation. Progress in Neuro-Psycho-pharmacology & Biological Psychiatry 76, 72-79. DOI: 10.1016/j.pnpbp.2017.02.018 35. A. Ahmed and A. Bewley. (2013). Delusional infestation and patient adherence to treatment: an observational study. British Journal of Dermatology169, 607-610. DOI:10.1111/bjd.12392 36. R.W. Freudenmann, P. Lepping, M. Huber et al. (2012). Delusional infestation and the specimen sign: A European multicenter study in 148 consecutive cases. British Association of Dermatologists. 167, 247–251. DOI:10.1111/j.1365- 2133.2012.10995.x 37. Rishniw M, Lepping P, Freudenmann P. (2014). Delusional infestation by proxy — What should veterinarians do? Veterinary Wellness, The Canadian Veterinary Journal, 55,887-891. PMID: 25183897 38. Freudenmann R and Lepping P. (2009). Delusional Infestation. Clinical Microbiology Reviews, 22(4) 690–732. DOI:10.1128/CMR.00018-09 39. Foster A, Hylwa S, Bury J. (2012). Delusional infestation: Clinical presentation in 147 patients seen at Mayo Clinic. Journal of American Academy of Dermatology, 67(4),673. DOI: 10.1016/j.jaad.2011.12.012 40. Hylwa S, Foster A, Bury J, et al. (2012) Delusional Infestation is Typically Comorbid with Other Psychiatric Diagnoses: Review of 54 Patients Receiving Psychiatric Evaluation at Mayo Clinic. Psychosomatics: The Journal of Consultation-Liaison Psychiatry, 53(3), 258–265. DOI: 10.1016/j.psym.2011.11.003 41. Marshall C, Williams V, Ellis C, Taylor E et al. (2016). Delusional infestation may be caused by recreational drug usage in some patients, but they may not disclose their habit. Clinical and Experimental Dermatology, 42, 41-45. DOI:10.1111/ced.12999 42. Freudenmann R, Kölle M, Huwe A. (2010) Delusional infestation: Neural correlates and antipsychotic therapy investigated by multimodal neuroimaging. Progress in Neuro-Psychopharmacology & Biological Psychiatry,34, 1215-1222. DOI:10.1016/j.pnpbp.2010.06.022 43. Vulink N. (2016). Delusional Infestation: State of the Art. Acta Dermato-Venereologica Suppl 217,58-63. DOI: 10.2340/00015555-2412 44. Huber M, Lepping P, Pycha R. (2011) Delusional infestation: treatment outcome with antipsychotics in 17 consecutive patients (using standardized reporting criteria). General Hospital Psychiatry, 33, 604–611. DOI: 10.1016/j.genhosppsych.2011.05.013 45. Hylwa S, Bury J, Davis M. (2011) Delusional Infestation, Including Delusions of Parasitosis- Results of Histologic Examination of Skin Biopsy and Patient-Provided Skin Specimens. Archives of Dermatology.147(9), 1041-1045. DOI:10.1001/archdermatol.2011.114 46. Matan Shelomi.(2015). Delusional infestation/parasitosis and the law: a review, , Crime & Law, 21(8), 747-763, DOI: 10.1080/1068316X.2015.1038265 47. Serretti, A., R. Lilli, C. Lorenzi, E. Lattuada, and E. Smeraldi. 2001. DRD4 exon 3 variants associated with delusional symptomatology in major psychoses: a study on 2,011 affected subjects. Am. J. Med. Genet.105:283–290.

Academy of Consultation-Liaison Psychiatry Psychiatric Manifestations of Skin Diseases and Their Treatment Mark A. Rapp, M.D. Associate Professor, Director Consultation- Liaison Psychiatry Penn State Health CLP 2018 Disclosure: Mark A. Rapp, MD

With respect to the following presentation, there has been no relevant (direct or indirect) financial relationship between the party listed above (and/or spouse/partner) and any for- profit company which could be considered a conflict of interest. Psychophysiological disorders

• Include those disorders where there is thought to be a bidirectional relationship between stress and skin disease

• Psychophysiologic disorders are associated with with skin problems that are not directly connected to the mind but that react to emotional states, such as stress.

• Treatment implications of this relationship?

Koo J, Lebwohl A. Psychodermatology: The Mind and Skin Connection. Am Fam Physician. 2001 Dec 1;64(11):1873-8. What dermatologists think:

• Survey-based study of 102 (of 237) dermatologists responding from the Washington State Dermatology Association database

• 42% of 102 responding, practicing dermatologists said they were very comfortable treating psychocutaneous disorders

• Acne (most), atopic dermatitis and psoriasis were reported as most common diagnoses associated with psychiatric manifestations

Jafferany M, Vander Stoep A, Dumitrescu A, Hornung R. The Knowledge, awareness, and practice patterns of dermatologists toward psychocutaneous disorders: results of a survey study. Int J Dermatol. 2010 Jul;49(7):784 What dermatologists think:

• 68% reported referring patients with cutaneous disorders with psychologic components to psychiatrists at least once a month, 10.7% of these referrals for depression associated with chronic skin diseases

• 32% reported having no education or training in psychodermatology; 42% reported no formal training or CME in their professional life on cutaneous disorders with psychologic components; 17% reported no interest in attending CME education on the topic

Jafferany M, Vander Stoep A, Dumitrescu A, Hornung R. The Knowledge, awareness, and practice patterns of dermatologists toward psychocutaneous disorders: results of a survey study. Int J Dermatol. 2010 Jul;49(7):784 Higher rate of dermatological disease among psychiatric patients:

• Analytic cross-sectional study of 200 outpatients with primary psychiatric disorders and 200 age- and sex- matched controls free of primary psychiatric disorders

• Psychiatric disorders included schizophrenia (76), depression (67), anxiety disorders (15), other mood disorders (25), OCD (17). Not randomized.

• Increased prevalence of skin diseases in general in psychiatric patients: 71.5% versus 22%, P<0.001

Moftah N, Kamel A, Attia H, El-Baz M, El-Moty H. Skin diseases in patients with primary psychiatric conditions: A hospital bed study. J Epidemiol Glob Health. 2013 Sep;3(3):131-8. doi: 10.1016/j.jegh.2013.03.005. Epub 2013 May 9. Psychiatric illness and skin disease:

• Australian study N=6630 restricted to women, 3 surveys, aged 22-27 at time of first survey: multivariate longitudinal analysis to avoid confounding of skin disease-psychological morbidity relationship

• Depression symptoms and stress (but not anxiety ) were significantly associated with skin problems

• Skin problems in the previous 12 months: 24.2% at initial survey (22-27 years); 23.9% second (25-30); 24.3 % (28-33).

• Women reporting prevalent skin problems had the highest level of depression in all three surveys; intermittent had the second highest. (P<0.001)

• Women who never reported having skin problems clearly and consistently had the lowest levels of stress (P<0.001)

• Women who never recorded skin problems (all three surveys) had the lowest proportion of reported intense anxiety (not significant on analysis)

Magin P, Sibbritt D, Bailey K. The Relationship Between Psychiatric Illnesses and Skin Disease. A Longitudinal Analysis of Young Australian Women. Arch Dermatol. 2009 Aug;145(8):896-902. doi: 10.1001/archdermatol.2009.155. Acne

• Acne affects >85% of teenagers, significant impact on quality of life. Adolescent acne can affect self-image, assertiveness, and the formation of friendships1

• Young men with severe scarring acne are at particular risk of depression and suicide

• Acne patients report greater levels of anxiety and depression than other medical populations, including cancer patients and other dermatology patients.2

• Only patients with severe psoriasis reported more depression and suicidal ideation than mild-to-moderate acne patients, among dermatological conditions. Severe acne may be worse.

• Both generic and disease-related quality of life impaired in acne versus general population

• With generic quality-of-life instruments, deficits as great as those reported by those with chronic, debilitating asthma, epilepsy, diabetes or arthritis

• With disease-specific instruments, older patients reported greater effect on quality of life

1. Reddy M, Chaturvedi S. Psychosocial Issues in Dermatology. EMJ Dermatology. 2017;5[1]:83-89 2. Hanna S, Sharma J, Klotz J. Acne vulgaris- more than skin deep. Dermatol Online J. 2003 Aug;9(3):8. Acne

• N=19, volunteer university students with minimum on Leeds acne scale 0.5. Stress assesses with Perceived Stress Scale questionnaire. Excluded those on isoretinoin. Logistic regression.

• Increased acne severity was significantly associated with increased stress levels (p <0.01), while self-assessed changes in diet quality was the only other significant variable (p = 0.02)

• Patients with acne may experience worsening fo the disease during examinations

• Worsening acne highly correlated with worsening stress

Chiu A, Chon S, Kimball A. The response of Skin Disease to Stress. Arch Dermatol. 2003; 139:897-900. Does treating acne reduce psychiatric morbidity?

• yes Does treating acne reduce psychiatric morbidity?

• Acne severity has been correlated with psychiatric comorbidity

• Depression, anxiety and overall psychiatric morbidity have been found to improve when acne is treated

Margin P, Adams J, Heading G, Pond D, Smith W. Psychological Sequelae of acne vulgaris: results of a qualitative study. Can Fam Physician. 2006 Aug;52:978-979. Does treating acne reduce psychiatric morbidity?

• Acne severity has been correlated with psychiatric comorbidity1

• Depression, anxiety and overall psychiatric morbidity have been found to improve when acne is treated (especially with isoretinoin therapy)1

• Substantial improvement in measurements of quality of life and self-esteem documented with treatment with isoretinoin. 2

• Clinical and patient assessed outcomes of physical and psychological measures were significantly better with isoretinoin treatment. 2

1. Margin P, Adams J, Heading G, Pond D, Smith W. Psychological Sequelae of acne vulgaris: results of a qualitative study. Can Fam Physician. 2006 Aug;52:978-979 2. Hanna S, Sharma J, Klotz J. Acne vulgaris- more than skin deep. Dermatol Online J. 2003 Aug;9(3):8 Controversy over isoretinoin treatment

• Possible induction of depressive symptoms by isoretinoin treatment for acne first reported in 1983

• FDA issued a warning regarding possible association of isoretinoin treatment with depression, psychosis and suicide

• Several studies suggesting this association

Huang YC, Cheng YC. Isoretinoin treatment for acne and risk of depression: A systematic review and meta-analysis. J Am Acad Dermatol. 2017 Jun;76(6):1068-1076.e9. doi: 10.1016/j.jaad.2016.12.028. Epub 2017 Mar 11. HOWEVER,

• A large, population-based study found acne alone to be significantly associated with depression and suicidal ideation. 1

• No significant difference found between isoretinoin versus treatment-as-usual (antibiotics, hormonal, physical and topical treatments) on mood, quality of life, suicidality.2

1. Huang YC, Cheng YC. Isoretinoin treatment for acne and risk of depression: A systematic review and meta-analysis. J Am Acad Dermatol. 2017 Jun;76(6):1068-1076.e9. doi: 10.1016/j.jaad.2016.12.028. Epub 2017 Mar 11 2. Hanna S, Sharma J, Klotz J. Acne vulgaris- more than skin deep. Dermatol Online J. 2003 Aug;9(3):8. Meta-anaylsis: isoretinoin treatment for acne:

Huang YC, Cheng YC. Isoretinoin treatment for acne and risk of depression: A systematic review and meta

• Reviewed literature from inception to the end of September 2016, including 31 studies (but no RTCs), pooled results of 1411 patients

• The prevalence of depression after isoretinoin treatment significantly declined (the mean depression scores decreased from baseline but were not significantly different from other therapies)

• Isoretinoin treatment does not appear to be associated with increased risk of depression. The treatment of acne appears to ameliorate depressive symptoms.

• If there is a link between isoretinoin and depression, no predictive test exists for quantifying the level of risk to patients Psoriasis: a more protean skin disease

• Quality of life may be severely affected by the chronicity and visibility of psoriasis as well as the need for lifelong treatment

• Five dimensions of the stigma associated with psoriasis have been identified:

1. Anticipation of rejection

2. Feelings of being flawed

3. Sensitivity to the attitudes of society

4. Guilt and shame

5. Secretiveness

• Depressive symptoms and suicidal ideation was frequently associated with psoriasis

• Psychological and social factors in addition to the primary dermatologic factors

Basavaraj K, Navya M, Rashmi R. Relevance of psychiatry in dermatology: Present concepts. Indian J Psychiatry. 2010 Jul-Sep; 52(3): 270–275. doi: [10.4103/0019-5545.70992] Stigma Associated with Psoriasis

• N=524 psoriasis patients (from one academic and three community Dutch hospitals, and the Dutch Psoriasis Foundation) by survey, multiple regression analysis. Patients 18+ with confirmed diagnosis. Impact of Chronic Skin Disease on Daily Life questionnaire, validated instrument.

• Reactions of disgust or aversion, negative comments, avoidance of contact = enacted stigma

• Contributes to disability, depression and reduced quality of life in psoriasis

• 73% experienced stigmatization, correlating with all five categories of predictor variables (sociodemographic, disease-related, personality, illness cognition and social support); 61.9% stared at; 44.9% perceived others thought they were contagious; only 6.7% had severe disease

• Stigmatization was associated with higher impact on daily life; lower education; higher disease visibility; having a type D personality [inclined towards both negative affectivity and social inhibition]; and not having a partner.

• Type D personalty correlates with poorer physical and psychological and social functioning in other healthy and patient samples, including two studies in psoriasis. Strong correlation with increased cardiovascular morbidity and mortality.

• The subjective experience of disease impact is generally more important than disease severity

• Patients whose psoriasis is not adequately controlled may be more affected by stigmatization

• ”As stress can be a trigger for psoriasis exacerbation, this can become a vicious, self-perpetuating cycle.”

Beugen, S. , Middendorp, H. , Ferwerda, M. , Smit, J. , Zeeuwen‐Franssen, M. , Kroft, E. , Jong, E. , Donders, A. , Kerkhof, P. and Evers, A. (2017), Predictors of perceived stigmatization in patients with psoriasis. Br J Dermatol, 176: 687 Morbidity from psoriasis

• Increasing severity of psoriasis is associated with increased risk of depression and anxiety diagnoses, as well as suicidality

• Chart review of 146042 patients with mild-, 3956 patients with severe psoriasis, and 766950 patients without psoriasis (five controls without psoriasis from the same practices and similar cohort entry dates per psoriasis patient)

• Psoriasis is associated with impairments in health-related quality of life even in mild cases and is associated with excess cardiovascular risk and mortality in patients with more severe disease.

Kurd SK, Troxel AB, Crits-Christoph P, Gelfand JM. The risk of Depression, Anxiety and Suicidality in Patients With Psoriasis: A Population-Based Cohort Study. Arch Dermatol. 2010 Aug;146(8):891-5. doi: 10.1001/archdermatol.2010.186. Suicide and psoriasis

• N=330,207 from systematic review and meta analysis

• Patients with psoriasis have a significantly higher likelihood of suicidal ideation (suicidal ideation OR 2.05, 95% CI 1.54-2.74), suicide attempts and completed suicides. Among patients with psoriasis, those who are younger and whose psoriasis is more severe are at particular risk for suicidality.

• Suicidal behaviors (pooled attempts and completed suicides) OR1.26, 95% CI 1.13-1.40.

• Patients with psoriasis were more likely to attempt suicide OR 1.32 (95% CI 1.14-1.54) and complete suicide OR 1.20 (95% CI 1.04-1.39), than those without psoriasis

• More severe psoriasis and younger age were associated with greater likelihood of suicidality.

Singh S, Taylor C, Kornmehl H, Armstrong AW. Psoriasis and suicidality: A systematic review and meta-analysis. J Am Acad Dermatol. 2017 Sep;77(3):425-440.e2. doi: 10.1016/j.jaad.2017.05.019. Systemic disease with cutaneous manifestations

• Psoriasis affects 2% of the world’s population

• Joint involvement appears in 40% of patients

• In 20% of patients, it is intense, debilitating and disabling.1

• The risk of new-onset depression in psoriasis is mediated primarily by comorbidities, except in younger individuals with severe psoriasis (N35,001 mild and 7510 severe psoriasis cases from Danish cohort of ~5 million). 2

1. Carneiro C, Chaves M, Verardino G, Drummond A, Ramos-e-Silva M, Carneiro S. Fatigue in Psoriasis with Arthritis. Skinmed. 2011 Jan-Feb;9(1):34-7. 2. Jensen P, Ahlehoff O, Egeberg A, Gislason G, Hansen PR, Skov L. Psoriasis and New-onset Depression: A Danish Nationwide Cohort Study. Acta Derm Venereol. 2016 Jan;96(1):39-42. doi: 10.2340/00015555-2183. Psoriasis and psychoneuroimmunology

• Psychosocial stress is a known precipitant and exacerbant of mood disorders, but can also stimulate a peripheral and CNS inflammatory response through a complex loop.1

• Stress-induced inflammation involves activation of the hypothalamic pituitary adrenal (HPA) axis via CRH and the sympathetic nervous system, which leads to increased in levels of nuclear factor kappa B (NF-kappaB) and the release of inflammatory mediators and cytokines that can access the CNS and affect monoamine metabolism.1

• Signaling back to brain via vagus nerve, soluble cytokines (IL- 1, IL-6, TNF- ). 2

1 Moynihan J, Rieder E, Tausk F. Psychoneuroimmunology: the example of psoriasis. G Ital Dermatol Venereol. 2010 Apr; 145(2): 221–228. 2. Tausk F, Elenkov I, Moynihan J. Psychoneuroimmunology. Dermatol Ther. 2008 Jan-Feb;21(1):22-31. doi: 10.1111/j.1529-8019.2008.00166.x. Environment

STRESS

Locus Paraventricular nucleus Ceruleus of hypothalamus

CRH

Anterior Pituitary

ACTH

Norepinephrine Adrenals

glucocorticoids

MORE inflammation LESS Inflammation

Macrophag Psoriatic es skin TNF-훂, IL-1, IL6, back to brain, causing sickness behavior

After J. Moynihan, E. Rieder, F. Tausk .Psychoneuroimmunology: the example of psoriasis. G Ital Dermatol Venereol. 2010 Apr; 145(2): 221–228. Environment

STRESS

Locus Paraventricular nucleus Ceruleus of hypothalamus

CRH

Anterior Pituitary

ACTH Norepinephrine Adrenals

glucocorticoids

MORE inflammation LESS Inflammation

Macrophag Psoriatic es skin TNF-훂, IL-1, IL6, back to brain, causing sickness behavior Psychiatric effects of treatment of psoriasis • Steroid treatment is suspect because corticosteroids are highly psychoactive

• Some reported effects (depression and suicide) from several biologicals that interfere with immunity, BUT

• Study with N= 414, using self-administered Psoriasis Area and Severity Index (SAPASI) and 12-item General Health Questionnaire (GHQ-12); proportion of patients who became GHQ-12 non-cases much higher in patients with improvement of greater than or equal to 50% in symptoms, compared to patients with no improvement or worsening (70% and 32%, respectively).

• Non-cases became cases 20.4% in people with no improvement or worsening (versus 3.1% in people with improvement of greater than or equal to 50%).

• The effect of clinical improvement on psychological distress was stronger than the effect of worsening.

• In contrast, one-third of people with complete clearance of their psoriasis still presented psychological problems at follow up.

Sampogna F, Tabolli S, Abeni D; IDI Multipurpose Psoriasis Research on Vital Experiences (IMPROVE) investigators. The impact of changes in clinical severity of psychiatric morbidity in patients with psoriasis: a follow Biologicals for psoriasis

• Most studies of biological therapies shows reduction in mood symptoms.

• Little signal for suicide and depression arising from these drugs; most studies show net reduction, correlating with efficacy of treatment. • Moderate-to-severe psoriasis patients in PSOLAR (N=7490), using Hospital Anxiety and Depression Scale- depression (HADS-D)

• Compared with conventional therapies, biologics appear to be associated with a lower incidence of depressive symptoms among patients with psoriasis (HR, 0.76; 95% CI, 0.59-0.98). P=0.0367

• Only adalimumab signficantly lowered the risk for depressive symptoms (HR, 0.63; 95% CI, 0.46-0.86); P= 0.0034

• In the pivotal clinical trials for adalimumab, entanercept, ustekinusab, and infliximab, depressive symptoms decreased.

• Dysregulated systemic inflammation may promote depression

Strober B, Gooderham M, de Jong EMGJ, Kimball AB, Langley RG, Lakdawala N, Goyal K, Lawson F, Langholff W, Hopkins L, Fakharzadeh S, Srivastava B, Menter A. Depressive symptoms, depression, and the effect of biology therapy among patients in Psoriasis • N= 980

• The results suggest that biologics [etanercept, adalimumab, golimumab, and ustekinumbab] may be associated with reduced rates of depression and , and a reduced rate of regular antidepressant use in psoriasis patients.

Wu CY, Chang YT, Juan CK, Shen JL, Lin YP, Shieh JJ, Liu HN, Chen YJ. Depression and Insomnia in Patients with Psoriasis and Psoriatic Arthritis Taking Tumor Necrosis Factor An Psychological and psychiatric treatment in psoriasis

• N=38 subjects with moderate-to-severe psoriasis and depressive and/or mood disorders, treated with anti-TNF- agents. Retrospective study.

• Patients treated with escitalopram had a reduction of psycho- diagnostic test scores that measure depression and anxiety levels as well as the values of pruritus.

• Psychological interventions and antidepressant medications may improve perceived symptom severity, quality of life and major compliance to the treatment in selected patients suffering from psoriasis and mood disturbance, without a clinician necessarily being able to see an impact on psoriasis severity.

D'Erme AM, Zanieri F, Campolmi E, Santosuosso U, Betti S, Agnoletti AF, Cossidente A, Lotti T. Therapeutic implications of adding the psychotropic drug escitalopram in the treatment of patients suffering from moderate Other interventions:

• , support groups, biofeedback, , guided imagery, progressive muscle relaxation, cognitive- behavioral therapy and other psychotherapy

• Online interactive YP Face IT, seven-week program for skin conditions including injuries and burns affecting appearance, shown to decrease and increase assertiveness and social skills.1

• Internet-based psoriasis CBT exists.2

1. Clay R. The link between skin and psychology. Monitor on Psychology. Feb 2015, Vol 46, No. 2, p56 2. 2. Beugen, S. , Middendorp, H. , Ferwerda, M. , Smit, J. , Zeeuwen‐Franssen, M. , Kroft, E. , Jong, E. , Donders, A. , Kerkhof, P. and Evers, A. (2017), Predictors of perceived stigmatization in patients with psoriasis. Br J Dermatol, 176: 687 Take home:

• Skin diseases are common in psychiatric populations

• Psychiatric morbidities are common in psychophysiological skin diseases

• Treatment of skin diseases appears to do more good than harm despite our suspicions

• Psychiatric treatment appears to have some benefit Consultation: Should my patient with psychiatric history/symptoms get indicated treatment of skin disease with suspect drugs?

• Generally a qualified yes.

• Conflation of morbidity of disease with morbidity of treatment.

• Reasonable vigilance.

• Problem of lore. Selected bibliography: 1.Basavaraj K, Navya M, Rashmi R. Relevance of psychiatry in dermatology: Present concepts. Indian J Psychiatry. 2010 Jul-Sep; 52(3): 270–275. doi: [10.4103/0019-5545.70992] 2.Beugen, S. , Middendorp, H. , Ferwerda, M. , Smit, J. , Zeeuwen‐Franssen, M. , Kroft, E. , Jong, E. , Donders, A. , Kerkhof, P. and Evers, A. (2017), Predictors of perceived stigmatization in patients with psoriasis. Br J Dermatol, 176: 687-694. doi:10.1111/bjd.14875 3.Bewley A. The neglected psychological aspects of skin disease. BMJ. 2017 Jul 6;358:j3208. doi: 10.1136/bmj.j3208. 4.Carneiro C, Chaves M, Verardino G, Drummond A, Ramos-e-Silva M, Carneiro S. Fatigue in Psoriasis with Arthritis. Skinmed. 2011 Jan-Feb;9(1):34-7. 5.Castela E, Archier E, Devaux S, Gallini A, Aractingi S, Cribier B, Jullien D, Aubin F, Bachelez H, Joly P, Le Maître M, Misery L, Richard MA, Paul C, Ortonne JP. Topical corticosteroids in plaque psoriasis: a systematic review of risk of adrenal axis suppression and skin atrophy. J Eur Acad Dermatol Venereol. 2012 May;26 Suppl 3:47-51. doi: 10.1111/j 1468-3083.2012.04523.x. 6.Chiu A, Chon S, Kimball A. The response of Skin Disease to Stress. Arch Dermatol. 2003; 139:897-900. 7.Clay R. The link between skin and psychology. Monitor on Psychology. Feb 2015, Vol 46, No. 2, p56 8.D'Erme AM, Zanieri F, Campolmi E, Santosuosso U, Betti S, Agnoletti AF, Cossidente A, Lotti T. Therapeutic implications of adding the psychotropic drug escitalopram in the treatment of patients suffering from moderate-severe psoriasis and psychiatric comorbidity: a retrospective study. J Eur Acad Dermatol Venereol. 2014 Feb;28(2):246-9. doi: 10.1111/j. 1468-3083.2012.04690.x. Epub 2012 Sep 11. 9.Ellard R, Ahmed A, Shah R, Bewley A. Suicide and depression in a patient with psoriasis receiving adalimumab: the role of the dermatologist. Clin Exp Dermatol. 2014 Jul;39(5):624-7. doi: 10.1111/ced.12351. 10.Fleming P, Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, Siu S, Kraft J, Lynde C, Pope JE, Keeling S, Dutz J, Bessette L, Bissonnette R, Haraoui B, Gulliver WP. Effects of biologics on depressive symptoms in patients with psoriasis: a systematic review. J Eur Acad Dermatol Venereol. 2015 Jun;29(6):1063-70. doi: 10.1111/jdv.12909. Epub 2014 Dec 10. 11.Gooderham M, Gavino-Velasco J, Clifford C, MacPherson A, Krasnoshtein F, Papp K. A Review of Psoriasis, Therapies, and Suicide. J Cutan Med Surg. 2016 Jul;20(4):293-303. doi: 10.1177/1203475416648323. Epub 2016 May 5. 12.Hanna S, Sharma J, Klotz J. Acne vulgaris- more than skin deep. Dermatol Online J. 2003 Aug;9(3):8. 13.Honeyman J. Psychoneuroimmunology and the Skin. Acta Derm Venereol 2106; Suppl 217: 38-46. 14.Huang YC, Cheng YC. Isoretinoin treatment for acne and risk of depression: A systematic review and meta-analysis. J Am Acad Dermatol. 2017 Jun;76(6):1068-1076.e9. doi: 10.1016/j.jaad.2016.12.028. Epub 2017 Mar 11. 15.Innamorati M, Quinto RM, Imperatori C, Lora V, Graceffa D, Fabbricatore M, Lester D, Contardi A, Bonifati C. Health-related quality of life and its association with alexithymia and difficulties in emotion regulation in patients with psoriasis. Compr Psychiatry. 2016 Oct;70:200-8. doi: 10.1016/j.comppsych.2016.08.001. Epub 2016 Aug 3. 16.Jafferany M, Vander Stoep A, Dumitrescu A, Hornung R. The Knowledge, awareness, and practice patterns of dermatologists toward psychocutaneous disorders: results of a survey study. Int J Dermatol. 2010 Jul;49(7):784-9. doi: 10.1111/j.1365-4632.2009.04372.x. 17.Jensen P, Ahlehoff O, Egeberg A, Gislason G, Hansen PR, Skov L. Psoriasis and New-onset Depression: A Danish Nationwide Cohort Study. Acta Derm Venereol. 2016 Jan;96(1):39-42. doi: 10.2340/00015555-2183. 18.Koo J, Lebwohl A. Psychodermatology: The Mind and Skin Connection. Am Fam Physician. 2001 Dec 1;64(11):1873-8. 19.Kurd SK, Troxel AB, Crits-Christoph P, Gelfand JM. The risk of Depression, Anxiety and Suicidality in Patients With Psoriasis: A Population-Based Cohort Study. Arch Dermatol. 2010 Aug;146(8):891-5. doi: 10.1001/archdermatol.2010.186. 20.Lebwohl MG, Papp KA, Marangell LB, Koo J, Blauvelt A, Gooderham M, Wu JJ, Rastogi S, Harris S, Pillai R, Israel RJ. Psychiatric adverse events during treatment with brodalumab: Analysis of psoriasis clinical trials. J Am Acad Dermatol. 2018 Jan;78(1):81-89.e5. doi: 10.1016/j.jaad.2017.08.024. Epub 2017 Oct 3. 21.Magin P, Sibbritt D, Bailey K. The Relationship Between Psychiatric Illnesses and Skin Disease. A Longitudinal Analysis of Young Australian Women. Arch Dermatol. 2009 Aug;145(8):896-902. doi: 10.1001/archdermatol.2009.155. 22.Margin P, Adams J, Heading G, Pond D, Smith W. Psychological Sequelae of acne vulgaris: results of a qualitative study. Can Fam Physician. 2006 Aug;52:978-979. 23.Moftah N, Kamel A, Attia H, El-Baz M, El-Moty H. Skin diseases in patients with primary psychiatric conditions: A hospital bed study. J Epidemiol Glob Health. 2013 Sep;3(3):131-8. doi: 10.1016/j.jegh.2013.03.005. Epub 2013 May 9. 24.Moynihan J, Rieder E, Tausk F. Psychoneuroimmunology: the example of psoriasis. G Ital Dermatol Venereol. 2010 Apr; 145(2): 221–228. 25.Reddy M, Chaturvedi S. Psychosocial Issues in Dermatology. EMJ Dermatology. 2017;5[1]:83-89 26.Sampogna F, Tabolli S, Abeni D; IDI Multipurpose Psoriasis Research on Vital Experiences (IMPROVE) investigators. The impact of changes in clinical severity of psychiatric morbidity in patients with psoriasis: a follow-up study. Br J Dermatol. 2007 Sep;157(3):508-13. Epub 2007 Jul 11. 27.Singh S, Taylor C, Kornmehl H, Armstrong AW. Psoriasis and suicidality: A systematic review and meta-analysis. J Am Acad Dermatol. 2017 Sep;77(3):425-440.e2. doi: 10.1016/j.jaad.2017.05.019. 28.Strober B, Gooderham M, de Jong EMGJ, Kimball AB, Langley RG, Lakdawala N, Goyal K, Lawson F, Langholff W, Hopkins L, Fakharzadeh S, Srivastava B, Menter A. Depressive symptoms, depression, and the effect of biology therapy among patients in Psoriasis Longitudinal Assessment and Registry (PSOLAR). J Am Acad Dermatol. 2018 Jan;78(1):70-80. doi: 10.1016/j.jaad.2017.08.051. Epub 2017 Nov 6. 29.Tausk F, Elenkov I, Moynihan J. Psychoneuroimmunology. Dermatol Ther. 2008 Jan-Feb;21(1):22-31. doi: 10.1111/j.1529-8019.2008.00166.x. 30.Walsh JA, McFadden ML, Morgan MD, Sawitzke AD, Duffin KC, Krueger GG, Clegg DO. Work Productivity Loss and Fatigue in Psoriatic Arthritis. J Rheumatol. 2014 Aug;41(8):1670-4. doi: 10.3899/jrheum.140259. Epub 2014 Jul 15. 31.Wu CY, Chang YT, Juan CK, Shen JL, Lin YP, Shieh JJ, Liu HN, Chen YJ. Depression and Insomnia in Patients with Psoriasis and Psoriatic Arthritis Taking Tumor Necrosis Factor Antagonists. Medicine (Baltimore). 2016 May;95(22):e3816. doi: 10.1097/MD.0000000000003816. Dermatologic Side Effects of Psychotropic Medications

Jason P. Caplan, MD, FACLP Professor of Psychiatry – Creighton University School of Medicine Chair of Psychiatry – St. Joseph’s Hospital and Medical Center Phoenix, AZ

ACADEMY OF CONSULTATION-LIAISON PSYCHIATRY Psychiatrists Providing Collaborative Care Bridging Physical and Mental Health CLP 2018 Disclosure: Jason P. Caplan, MD

Avanir Acadia Myriad Neurocrine Otsuka Company Pharmaceuticals Pharmaceuticals Genetics Biosciences Pharmaceuticals Employment Management Independent Contractor Consulting I I Speaking & Teaching I I D I Board, Panel or Committee Membership

D – Relationship is considered directly relevant to the presentation I – Relationship is NOT considered directly relevant to the presentation

Academy of Consultation-Liaison Psychiatry Dermatologic Side Effects of Psychotropics

. 0.1% incidence across all classes

. Mood stabilizers – 0.22% . Tricyclics – 0.07% . SSRIs – 0.05% . SGAs – 0.03% . FGAs – 0.028%

Academy of Consultation-Liaison Psychiatry So why should we care…?

. Cutaneous drug reactions are more commonly Type B reactions (idiosyncratic, unpredictable, often involving a metabolic or genetic predisposition) vs. Type A reactions (predictable, dose-dependent, reproducible, spanning the population) . These reactions include the potential fatal TEN/SJS . But more commonly, when a rash develops in the hospital, never underestimate…

Academy of Consultation-Liaison Psychiatry The race to blame the psychotropic

Academy of Consultation-Liaison Psychiatry Risk Factors

. Winter season . Female . HLA Subtype . Increased age . Multiple co-occurring illnesses

Academy of Consultation-Liaison Psychiatry Winter Season

. Lowest exposure to UV light . Role of vitamin D in – Cutaneous immune function – Cellular differentiation

Academy of Consultation-Liaison Psychiatry Women

. Adverse cutaneous drug reactions 50% more common than in men . Among psychotropics, most pronounced with – AEDs – SSRIs . Thought to be a result of: – More active immune system – Greater likelihood of reporting – Hormonal factors

Academy of Consultation-Liaison Psychiatry Increased Age

. Less efficient metabolism (hepatic and renal) . Higher rates of polypharmacy

Academy of Consultation-Liaison Psychiatry Co-occurring Illnesses

. Diseases affecting metabolism . Other drugs affecting metabolism . Alteration of immune response to drugs

. Of psychiatric diagnoses, highest rates of cutaneous reactions seen in: – Substance use disorders – Depression –

Academy of Consultation-Liaison Psychiatry HLA Status

. HLA-B 1502 – 100 times more susceptible to carbamazepine-induced epidermal necrolysis – 5 times more susceptible to lamotrigine-induced epidermal necrolysis – 7-16% allele frequencies in: . Malaysian . Thai . Vietnamese . Chinese . Philippino populations – Black box warning on carbamazepine – Warning on oxcarbazepine

Academy of Consultation-Liaison Psychiatry Carbamazepine

Academy of Consultation-Liaison Psychiatry 12 Oxcarbazepine

Academy of Consultation-Liaison Psychiatry 13 HLA Status

. HLA-A 3101 – 9 times more susceptible to carbamazepine-induced epidermal necrolysis . 10-15% allele frequency in: – Japanese – Native American – Indian – Arabic – Han Chinese – Korean – European populations

Academy of Consultation-Liaison Psychiatry 14 Types of Reaction

. Exanthematous eruptions . Urticaria . Fixed drug eruptions . Drug-induced hypersensitivity syndrome . Epidermal necrolysis

Academy of Consultation-Liaison Psychiatry Exanthematous Eruptions

. 51-95% of drug reactions . Diffuse . Erythematous . Macules and papules (no blisters or pustules) . Symmetric . Usually start on the trunk . Within 10 days of drug

. Carbamazepine and barbiturates have idiosyncratic pattern of starting on the face and spreading to the trunk

Academy of Consultation-Liaison Psychiatry Urticaria

. Minutes to hours after initiation . Transient pruritic papules and plaques . Anywhere on the body . Can progress to anaphylaxis and angioedema

Academy of Consultation-Liaison Psychiatry Fixed drug eruptions

. Solitary, sharply demarcated lesions . Red to purple . 30mins to 8 hours after dose . Fixed because they recur at the same site with additional exposure . Mucocutaneous or flexor surfaces

Academy of Consultation-Liaison Psychiatry Drug-induced Hypersensitivity Syndrome (DIHS)

. Macular eruption . Fever . Lymphadenopathy . Organ involvement (usually liver) . Eosinophilia in 30% . Facial edema in 25% . 2-6 weeks after initiation . 1-4 cases per 10,000 for carbamazepine . 10% mortality rate (fulminant hepatitis)

Academy of Consultation-Liaison Psychiatry Epidermal Necrolysis

. Stevens-Johnson Syndrome (SJS) – <10% of body area . Toxic Epidermal Necrolysis (TEN) – >30% of body area

. Average time of onset 16 days . <2.5% of cases after day 32

Academy of Consultation-Liaison Psychiatry SJS/TEN

. Fever . Flu-like symptoms . Dusky red macules . Evolves to bullae . Evolves to necrosis and detachment of epidermis and mucous membranes

. 5-30% mortality depending on extent of skin involved

Academy of Consultation-Liaison Psychiatry Academy of Consultation-Liaison Psychiatry 22 Academy of Consultation-Liaison Psychiatry 23 Academy of Consultation-Liaison Psychiatry 24 SJS/TEN

. Carbamazepine – 67.8% of cases (0.23% of carbamazepine exposures) . Lamotrigine – 10.4% of cases (0.08% of lamotrigine exposures) . Phenobarbital – 0.9 % of cases

Academy of Consultation-Liaison Psychiatry Mitigation

. Education, education, education . Start low and go slow . Simultaneous use of VPA with lamotrigine increases risk of rash 60%

Academy of Consultation-Liaison Psychiatry Restart

. There are proposed strategies for reintroduction of lamotrigine or carbamazepine in a patient that has developed a rash . Given the potential risks, recommendation is to avoid restarting the drug unless the benefits clearly outweigh the potential risks

Academy of Consultation-Liaison Psychiatry Antidepressants

. SSRIs – Petechiae/ecchymosis – Photoinduced cutaneous reaction – Pigmentation changes with long-term use – Alopecia – Hyperhydrosis . SNRIs – Hyperhydrosis . TCAs – Angioedema

Academy of Consultation-Liaison Psychiatry Neuroleptics

. Pigmentation changes . Photosensitivity

. Brown discoloration of sun-exposed areas (face, neck, dorsum of hands, lower legs), progresses to darker blue/grey color . Most prominent with chlorpromazine and risperidone

Academy of Consultation-Liaison Psychiatry Sedative-hypnotics

. Exanthematous eruption . Alprazolam – 4% . Chlordiazepoxide – 0.42% . Diazepam – 0.38%

. Can also occur with barbiturates, but in those cases can (rarely) progress to epidermal necrolysis

Academy of Consultation-Liaison Psychiatry