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1 AFFECTIVE DISORDERS IN INTELLECTUAL DISABILITIES DIAGNOSTIC PITTFALLS AND PHARMACOLOGICAL TREATMENT STRATEGIES Mental Health in Intellectual Disabilities (formerly MHMR), Antwerp, May 31th 2007 Prof.Dr. Willem M.A. Verhoeven Vincent van Gogh Institute for Psychiatry, NL-Venray

2 Prevalence of affective spectrum disorders (Bipolar)AffectiveAnxietyOCD Lund, 19851.72.0- Acta Psychiatr Scand Corbett, 19794.025.4- In: Psychiatric Illness and Mental Handicap Cooper & Bailey, 20016.07.22.5 Ir J Psychol Med Holden & Gitlesen, 200411259 J Intellect Disabil Res Cooper et al., 20076.63.80.7 Br J Psychiatry

3 DIMENSIONAL DIAGNOSTIC PROCEDURES AND FUNCTIONAL PHARMACOTHERAPY OF AFFECTIVE DISORDERS IN INTELLECTUAL DISABILITIES diagnostic procedures manifestations of depression unstable mood disorder behavioural phenotypes and depression pharmacotherapeutic strategies

4 DIAGNOSTIC INSTRUMENTS ICD-10 Guide for Mental Retardation DSM-IV ICD-10 Diagnostic Criteria for psychiatric disorders for use with adults with Learning Disabilities/Mental Retardation (DC-LD) Clinical Diagnosis

5 DIAGNOSTIC PROCEDURES REFERENCE COMPLAINT  VIDEO REGISTRATION + CONSENSUS MEETING  SPECIFICATION OF SYMPTOMATOLOGY  QUESTIONS: genetic etiology neurological examination epilepsy somatic examination course hereditary factors plasma concentrations psychotropics and anticonvulsants delirious state environmental variables results previous interventions attenuation of treatment effects tar dive behavioural effects of psychotropics and anticonvulsants  NEUROPSYCHIATRIC EXAMINATION  DIFFERENTIAL DIAGNOSIS DIAGNOSTIC HYPOTHESIS  TREATMENT ADVISE 

6 BEHAVIOURS, SIGNS AND SYMPTOMS OF DEPRESSION Level of intellectual disability (number of subjects) DiagnosisSevere/profound (n=15)Mild/moderate (n=7) Depressed affect156 Sleep disturbance (insomnia = 13; hypersomnia = 1)145 Appetite disturbance (decrease = 12; increase = 1)133 Loss of interest120 Social isolation110 Self-injurious behaviour105 Psychomotor agitation106 Aggression92 Irritability72 Lack of emotional response64 Screaming60 Stereotypical behaviour60 Psychomotor retardation53 Weight loss60 Anxiety56 Constipation50 Loss of energy52 Unreasonable self-reproachx3 Delusion (mood congruent)x2 Diurnal variation of moodx2 From: Tsiouris, JIDR, 2001

7 SYMPTOMS OF DEPRESSION IN INTELLECTUAL DISABILITIES MORE THAN 50%LESS THAN 50% irritabilitysomatic complaints depressed affectlack of emotional response tearfulnessdiurnal variation loss of interestpsychomotor retardation sleep disturbanceloss of appetite psychomotor agitationweight loss self-injurious behavioursuicidal ideation loss of energyobsessive-compulsive behaviour constipationeuphoria anxietylabile mood aggressionscreaming social isolationstereotyped behaviour antisocial behaviourvomiting decreased concentrationincontinence anhedoniaguilt feelings increased speechchange in sexual activities decreased appetitehallucinations withdrawn behaviourdelusions Adapted from Charlot et al. 1993; Meins, 1995; Marston et al., 1997

8 FUNCTIONAL DOMAINS OF DEPRESSIVE DISORDER (n=58) Domains mild/moderate (n=47)severe/profound (n=11) n%n% Affect Depressed affect3677436 Labile mood2247873 Dysphoria2043436 Tearfullness2247655 Anxieties2860764 Motivation Loss of energy3166327 Loss of interest2757218 Anhedonia71500 Withdrwan behaviour2757655 Motor Psychomotor retardation613218 Psychomotor agitation2655982 Stereotyped behaviour1736982 Irritability28601091 Screaming2247655 Aggression2655764 Impulsivity1021327 Self-injurious behaviour1838873 Vital Loss of appetite1838545 Sleep disturbances2043545 Diurnal variation81700 Verhoeven et al., 2004

9 SYMPTOMS (PRESENCE ≥50%) OF AFFECTIVE SPECTRUM DISORDERS* IN INTELLECTUAL DISABILITIES (n=285) depressionaffective spectrum (n=58)(n=136) psychomotor agitation++ stereotypies-+ aggression-+ self-injuries-+ anxieties++ irritability++ depressed mood+- mood swings++ dysphoria-+ loss of energy+- loss of interest+- withdrawn behaviour+- difficult to handle++ *depression, anxiety disorder, bipolar disorder and unstable mood disorder Verhoeven et al., The European Journal of Psychiatry, 18:49-53, 2004

10 UNSTABLE MOOD DISORDER Sollier (1901) "on voit des changements brusques d’humeur que rien ne paraît motiver, des actes bizarres et des mouvements capricieux" Duncan (1936) considerable degree of emotional instability that could not be considered as typical for bipolar affective disorder Verhoeven & Tuinier (1997): high prevalence of atypical bipolar and mood disorders with features like inactivity, lability and irritability  unstable mood disorder, characterized by an episodic pattern of disturbed mood, anxiety and behaviour

11 UNSTABLE MOOD DISORDER IN INTELLECTUAL DISABILITIES affective instability episodic motor inhibition or disinhibition irritability rapid mood changes unprovoked crying sleep disturbances Adapted from: Matson et al., 1991; Einfeld & Aman, 1995; Meins, 1994

12 DISORDERED STRESS FEEDBACK IN INTELLECTUAL DISABILITIES increased arousability anxiousness stereotyped behaviour avoidant behaviour irritability Adapted from: Einfeld & Aman, 1995

13 FUNCTIONAL DOMAINS OF UNSTABLE MOOD DISORDER (n=64) DomainsPresencePercentage mood rapide mood swings2234 mood swings4164 episodic dysphoria3756 anxiety anxieties3555 irritability3555 motor disorganized behaviour1727 hyperactivity3961 stereotypies3656 self-injuries2539 impulsivity2539 aggression3555 Verhoeven et al., 2001, 2004

14 UNSTABLE MOOD DISORDER (n=28) METHODS - 1 subjects: -18 male, 10 female -mean age: 37.3 year -mild to severe intellectual disabilities etiology: -unknown: 18 -perinatal complications: 6 -encephalitis postvaccinalis: 1 -specific syndromes: 6 diagnosis: -rapid or episodic fluctuations in behaviour -prominent mood deviations mostly with motor signs like self-injuries and aggression Verhoeven & Tuinier, JARID, 14:147-154, 2001

15 UNSTABLE MOOD DISORDER (n=28) METHODS - 2 previous psychiatric diagnoses: -mood disorder: 12 -(atypical) autism: 4 -psychotic disorder: 3 -panic disorder: 1 current medication: -anticonvulsants for epilepsy: 3 -anticonvulsants for behaviour control: 2 -antipsychotics: 20 -antidepressants: 6 -anxiolytics: 8 Verhoeven & Tuinier, 2001

16 UNSTABLE MOOD DISORDER (n=28) METHODS - 3 treatment: -valproic acid, starting at a daily dose of 300 mg -dosage adjustment over 6 weeks according to plasma concentration or clinical effect -concomitant medication unchanged 3 months prior and during the first 12 weeks of treatment Verhoeven & Tuinier, 2001

17 CYCLOTHYMIA AND UNSTABLE MOOD DISORDER cyclothymia: -persistent instability of mood, involving numerous periods of mild depression and mild elation -mood swings not related to life events unstable mood disorder: -long-lasting episodic disturbances in the mood, anxiety and motor domains main difference: -presence of elation in cyclothymia

18 CONCLUSIONS UNSTABLE MOOD DISORDER *often described as (atypical) bipolar disorder without, however, familial load *the here advocated unstable mood disorder resembles the description of the ICD-10 diagnosis cyclothymia but lacks episodes of elation *treatment effects of valproic acid at a mean daily dose level and mean plasma concentration of 1343 mg and 63 mg/l respectively *clinically relevant and sustained improvement both in terms of behaviour stability and symptom reduction in 68% of the subjects

19 RAPID CYCLING BIPOLAR AFFECTIVE DISORDER characteristics -symptomatology characterized by observable behaviours rather than by reports of subjective mood states -mostly family history with affective disorder -first episode affective disorder at or before age of 17 -gender differences not present -not associated with particular organic pathology treatment -mood stabilizers, preferably sodium valproate From: JIDR, 43, 349-359, 1999

20 EXAMPLES OF BEHAVIOURAL PHENOTYPES ASSOCIATED WITH AFFECTIVE DISORDERS VELO-CARDIO-FACIAL-SYNDROME (chromosome 22) - affective spectrum disorders KLINEFELTER SYNDROME (47XXY) - bipolar affective disorders PRADER-WILLI SYNDROME (chromosome 15) - bipolar (affective) disorders WOLFRAM SYNDROME CARRIERS (chromosome 4) - affective disorders - suicidal ideation FRAGILE-X SYNDROME CARRIERS (X-chromosome) - affective/anxiety disorders DOWN SYNDROME (trisomy-21) - affective disorders

21 EXAMPLES OF BEHAVIOURAL PHENOTYPES ASSOCIATED WITH AFFECTIVE DISORDERS DOWN SYNDROME (trisomy-21) atypical depression:social withdrawal reduced energy irritability psychomotor retardation regression of self-care hypochondriasis aggression sleep disturbances reduced speech auditory hallucinations From: Myers & Pueschel, 1995

22 PATIENTS WITH DOWN SYNDROME REFERRED FOR DEPRESSION (n=20) domainspresencepercentage motor disorganized behaviour315 obsessive-compulsive rituals630 stereotypies840 psychomotor-agitation735 psychomotor retardation525 impulsivity735 aggression945 self-injuries945 temper tantrums525 difficult to handle525 psychotic features confusion315 visual hallucinations210 auditory hallucinations315 delusional ideas15 paranoid ideation210 Verhoeven & Tuinier, 2002

23 PATIENTS WITH DOWN SYNDROME REFERRED FOR DEPRESSION (n=20) psychiatric diagnoses major depression8 unstable mood disorder5 self- injurious behaviour1 hypothyroidism2 obsessive compulsive disorder1 anxiety disorder1 Gilles de la Tourette1 no disorder1 Verhoeven & Tuinier, 2002

24 FUNCTIONAL DOMAINS OF DEPRESSIVE DISORDER IN PATIENTS TREATED WITH CITALOPRAM (N=20) Verhoeven et al. European Psychiatry, 16:104-108, 2001 domainspresencepercentage Affect Depressed affect735 Labile mood420 Dysphoria735 Tearfulness315 Anxieties945 Motivation Loss of energy735 Loss of interest315 Anhedonia15 Withdrawn behavior945 Motor Psychomotor retardation210 Psychomotor agitation735 Stereotyped behaviour735 Irritability945 Screaming15 Aggression735 Impulsivity630 Self-injurious behaviour630 Vital Loss of appetite15 Sleep disturbances315 Diurnal variations15

25 CITALOPRAM IN DEPRESSION Methods – 1 Verhoeven et al. European Psychiatry, 16:104-108, 2001 Subjects:10 male, 10 female mild to severe ID mean age: 36,9 years Etiology:unknown: 11 perinatal complications: 4 (meningo)-encephalitis: 2 rhesus antagonism: 1 specific syndromes: 2

26 CITALOPRAM IN DEPRESSION Methods – 2 Previous (psychiatric) diagnoses: -mood disorder: 4 -(atypical) autism: 2 -pychotic disorder: 1 -history of epilepsy: 4 -congenital cataract: 2 -Current medication: -anticonvulsants: 12 -antipsychotics: 11 -anxiolytics: 3

27 CITALOPRAM IN DEPRESSION Methods – 3 Treatment: -citalopram, starting at 20mg daily and kept stable during first 6 weeks -dose adjustment according to clinical response up to 60mg daily maximally -follow-up period 6 (n=11) to 12 (n=9) months -measurement of plasmaconcentrations of anticonvulsants, citalopram and desmethyl- citalopram

28 RESULTS AND CONCLUSIONS CITALOPRAM Verhoeven et al. European Psychiatry, 16:104-108, 2001 Results: -Daily dose range: 20-60mg; mean: 33mg -Plasmaconcentrations: 30-105 respectively 19-75µgr/l -Side effects: seizure: n=1; delirious state: n=1 -Marked improvement in 12 out of 20 patients -No relapse during long term treatment over >12 months -No pharmacokinetic drug-drug interactions Conclusion: -Well tolerated, safe and effective -Optimal dose: 20-30mg daily

29 RESULTS OF TREATMENT WITH SSRI’S IN INTELLECTUAL DISABILITIES -Studies:c ase reports only -Compounds:fluoxetine (19), sertraline (7), paroxetine (5), citalopram(1), fluvoxamine (1) -Indications:depressive and obsessive-compulsive disorders, maladaptive behaviours -Conclusions:results questionable because of publication bias; sometimes deterioration of behaviour; anxiety as target symptom virtually absent -Note:over 15 years tenfold increase of prescription of SSRI’s Verhoeven & Tuinier, 2005 In: Trends in Serotonin Uptake Inhibitor Research Nova Science Publishers, Inc, New York.

30 CONCLUSIONS * increased vulnerability for stress-related disorders in ID *categorical diagnostic systems, particularly DSM-IV, are not appropriate in ID *dimensional diagnostic approach is necessary for delineation of atypical manifestations of affective disorders, unstable mood disorder and psychopathological phenotypes *symptom profile and course of disease (rapid cycling!) determine choice of pharmacological strategy; antidepressant and/or mood stabilizer compounds of first choice: antidepressants: citalopram, nortriptyline; mood stabilizers: valproic acid, lithium


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