Differential diagnosis and comorbidity in patients with ADHD

Differential diagnosis and comorbidity in patients with ADHD Andrej Kastelic Global Addiction Association President EUROPAD General Secretary SEEA net President Center for Treatment of Drug Addiction University Psychiatric Clinic Ljubljana, Slovenia E-mail: andrej. kastelic@psih-klinika. si Global Addiction 2015

ATTENTION DEFICIT HYPERACTIVITY DISORDER Jamie Oliver Paris Hilton Michael Phelps Justin Timberlake

Heritability in the Range of Schizophrenia and Height 1. Hudziak JJ, et al. Am Acad of Child and Adolesc Psychiatry 2000; 39(4): 469 -476. 2. Faraone SV, et al. Biol Psychiatry 1998; 44: 951 -958.

Symptoms • Core symptoms inatention impulsivness over-activity INATENTION IMPULSIVNESS OVER-ACTIVITY

• In children ADHD is 3 -5 times more comon in boys than girls. In adults it is more closer to even, incresing in women and decreasing in men. • The prevalence of ADHD in adults declines with age. Partly due to age related the client in the symptoms, tough some patients with ADHD in childhood meet fewer criteria as adults but have persistent symptoms - ADHD in partial remission under DSM 5. • Over - activity in adulthood declines more than attention deficit. There is more anxiety, attention deficit, presents more as inability to fulfill the tasks. Problems with employment, finances, interpersonal relationships including workplace, partnerships, divorces and specially as comorbidity of psychiatric disorders (depression, anxiety, substance abuse, including smoking). Volkow N. D, Swanson J. M. Adult Attention Deficit-Hyperactivity Disorder. New Enlg J Med 2013; 369: 1935 -44.

Long term outcome without treatment Shaw et al. BMC Medicine 2012, 10: 99, available at: http//www. biomedcentral. com/1741 -7015/10/99

Increased Risk of Traffic Violations and Accidents Subjects Receiving Citation for Any Traffic Violation (%) Findings from driving records obtained from the state 90 department of motor vehicles 80 ADHD (n=25) 70 60 50 Control (n=23) ** **p ≤ 0. 01 40 30 20 ** 10 0 Traffic Violations Speeding Violations 1. Barkley et al. Pediatrics 1996; 98: 1089– 95. Drunk Driving License Suspended Crashed as Driver

Increased Risk for Employment Problems • Individuals with ADHD are 3 times more likely to be fired from a job than individuals without ADHD • ADHD patients change their jobs at a rate of 2– 3 times within a 10 -year period • ADHD patients have lower work performance ratings than employees without ADHD 1. Barkley. J Clin Psychiatry 2002; 63: 10– 15.

Other Consequences of ADHD Outcomes of ADHD on Major Life Activities Patients (%) *** 1. Barkley et al. J Am Acad Child Adolesc Psych 2006; 45: 192– 202. ***p<0. 001 **p<0. 01 **

Why Should Adult Mental Health Services be Interested in ADHD? • ADHD is a common behavioural disorder associated with significant adult psychopathology, social and academic impairments and the risk for negative long–term outcomes 1, 2 • ADHD symptoms persist into adult life and cause significant clinical impairments 1 • The main clinical issue is recognition of the disorder in adults and quantifying the load on adult psychopathology 1 • ADHD is a treatable condition 1 1. Asherson et al. Br J Psychiatry 2007; 190: 4– 5. 2. Antshel et al. BMC Med 2011; 9: 72.

Treatment outcome Shaw et al. BMC Medicine 2012, 10: 99, available at: http//www. biomedcentral. com/1741 -7015/10/99

Key Principles • ADHD in adults is no more difficult to diagnose and treat than other common mental health disorders 1 • ADHD in adults is a symptomatic disorder (not just about behaviour)1, 2 • ADHD in adults is often misdiagnosed for other common adult mental health disorders 1, 2 • ADHD in adults is in most cases treatable 1 1. Asherson. 1 st European Network Adult ADHD Conference. London, 2011. 2. Kooij et al. BMC Psychiatry 2010; 10: 67.

Assesment • Psychiatric History • Somatic histroy • Screening for most common comorbid disorders • Screening for special and general learning difficulties • Family history • Substance abuse • Forensic history 1. Asherson. 1 st European Network Adult ADHD Conference. London, 2011.

simptom nepozornost otroci • Odkrenljivost • Ne morejo dokončati dela • Kot da ne slišijo, ko se jim govori odrasli • Neorganizira nost • Slabo razporejajo s časom • Se izgubljajo v razgovoru, ker ne morejo slediti, saj se okoli njih dogaja toliko drugega

Symptoms of ADHD • Anxiety: 1 – Ceaseless thoughts, avoidance behaviour • Depression: 1 – Unstable mood, impatience, irritability, initial insomnia, low selfesteem • Personality disorder: 1 – Antisocial, borderline, emotionally unstable, poor social interactions, impulsive, adulthood instability trait-like quality • Hypomania, bipolar ll disorder, cyclothymia: 2 – Differentiated by grandiosity, clear focus of thoughts, episodic, reduced need for sleep, psychosis 1. Asherson. 1 st European Network Adult ADHD Conference. London, 2011. 2. Babcock and Ornstein. Postgraduate Medicine. 2009; 121(3): 73 -82.

Overlapping Neurodevelopmental Disorders • Dyslexia (overlapping genetic risk factors)1 • Specific and general learning difficulties (overlapping genetic risk factors, inattention)1 • Pervasive developmental disorder 1 • Dyspraxia 1 • Tic disorders/Tourette's disorder 1 • Speech problems 2 • Autism spectrum disorder 1 1. Kooij et al. BMC Psychiatry 2010; 10: 67 2. Tannock et al J Abnl Child Psychol, 2000; 28(3): 237– 252

ADHD in population with substance abuse disorders and incarterated population is about 25% - significantly higher than in general population. Philipsen A, Heslinger B, tebartz van Elst. Attention Deficit Hyperactivity Disorder in Adulthood; Diagnosis, Etiology and Therapy. Dtsch Arztebl Int 2008; 105(17): 311 -7

Medication for ADHD and criminality: Observational Swedish data base analysis 1. Rate of Crime Over 4 Years in Swedish ADHD Subjects Aged >15 years (N=25, 656) Subjects committing crime Male ADHD Subjects Female ADHD subjects ADHD 36. 6% 15. 4% General population 8. 9% 2. 2% 2. Hazard Ratio for Conviction for Any Crime During ADHD Medication (2006– 2009) vs. Non. Medication Periods Treatment Men (N=16, 087) Hazard Ratio (95%CI) Women (N=9, 569) Hazard Ratio (95%CI) All medications 0. 68 (0. 63– 0. 73) 0. 59 (0. 50– 0. 70) Stimulants 0. 66 (0. 61– 0. 71) N/A Atomoxetine 0. 76 (0. 63– 0. 91) N/A Crimes occurred less often during medication periods (men 32% reduction, women 41% reduction); however, the observational nature of the data cannot confirm a causal relationship with ADHD medication and other factors co-occuring with medication may play a role Lichtenstein et al. N Engl J Med. 2012; 367: 2006 -14.

High comorbidity of mental health disorders (80%): • depression (40 -60%), • anxiety (20 -60%) • substance abuse disorders (50 -60%). Philipsen A, Heslinger B, tebartz van Elst. Attention Deficit Hyperactivity Disorder in Adulthood; Diagnosis, Etiology and Therapy. Dtsch Arztebl Int 2008; 105(17): 311 -7

DD: Depression specially with cognitive disfunction but no continuity of symptoms. Borderline personality disorder – high overlaping the symptoms: • Impulsivity and emotional instability • Anxiety offten followed by autoagressive/self-harming behaviour, suicidal ideation or PTSD. Philipsen A, Heslinger B, tebartz van Elst. Attention Deficit Hyperactivity Disorder in Adulthood; Diagnosis, Etiology and Therapy. Dtsch Arztebl Int 2008; 105(17): 311 -7

ADHD and Depressive Mood Symptoms ADHD Mood Disorder Chronic mood instability Mood instability only during episode No anhedonia, no appetite disturbances Neurovegetative symptoms present Usually responds to control of symptoms and improvement in level of function Episodes of depression, requiring separate treatment of depression 1. Amons. J Affective Disord 2006; 91: 251– 5. 2. Kooij et al. J Attention Disord 2012; 16: 3 S– 19 S.

ADHD and Bipolar Disorder ADHD Bipolar Disorder Early childhood onset 1 Adolescent or adult onset 1 Trait-like, no change from pre-morbid state 1 Episodic course, change from pre-morbid state 1 Excitable, but not grandiose/elated Grandiose/elated 2 Reports being unable to function 1 Reports high level function 1 Chronic low self-esteem 2 Episodes of depression 1 Usually possesses insight, complains of changeable moods Trend to lack of insight 1 Difficulty sleeping 2 Reduced need for sleep 2 Complains of being unable to concentrate/focus 1 Subjective sense of sharpened mental abilities 1 Restless (fidgety, difficult being still)1 Overactivity, often linked to unrealistic ideas/plans 1 1. APA. DSM-IV-TR. APA 2000. 2. Kooij et al. J Att Dis 2012; 16: 3 S– 19 S.

ADHD and Anxiety ADHD Anxiety Disorder Ceaseless mental activity 1 Anxious worrying (might look like obsessive thought processes [OCD])2 Motor restlessness 1 Nervous tension 2 Family history of ADHD 2 Family history of anxiety–depression 2 Avoids frustrating situations: Shopping, social situations, queueing, travelling Phobic avoidance 2 Easily feeling overwhelmed 3 Easily becoming anxious 2 Forgetfulness 2 Hypervigilant No somatic symptoms 1 Somatic symptoms 1 Improved by stimulants 4 Exacerbated by stimulants 4 1. Kooij et al. J Att Dis 2012; 16: 3 S– 19 S. 2. APA. DSM-IV-TR. APA 2000 3. Reimherr et al Biol Psychiatry 2005; 58: 125– 131. 4. Ritalin SPC

ADHD and Personality Disorder ADHD Borderline Personality Disorder Childhood/adolescent onset 1 Early adult/adolescent onset 1 Defined by impairment 2 Chronic-like trait 1 Pervasive across situations 2 Affective lability (can be severe)4 Affective lability 3 Impulsive 3 Inattention 3 Frantic efforts to avoid real or imagined abandonment 4 Recurrent suicidal behaviour 4 1. APA. DSM-IV-TR. APA 2000. 2. Miller et al. J Clin Psychiatr 2008; 69: 1477– 84. 3. Distel et al. Am J Med Genet 2011; 156: 817– 25. 4. Kooij et al. J Att Dis 2012: 16(5 S): 3 S– 19 S.

Conclusions • ADHD is a neurobiological condition characterised by persistent patterns of inattention and/or hyperactivity, impulsiveness, and impairment in executive functioning • ADHD symptoms persist into adult life and cause significant clinical, social, economic, psychological, and functional impairment • ADHD in adults is often associated with a number of comorbidities • Diagnosis of ADHD in adults is a multifaceted process • Clinicians should carefully consider comorbidities and medical rule-outs • ADHD in adults is a treatable condition

ADHD, SUBSTANCE USE DISORDERS AND TREATMENT Andrej Kastelic Global Addiction Association President EUROPAD General Secretary SEEA net President Center for Treatment of Drug Addiction University Psychiatric Clinic Ljubljana, Slovenia E-mail: andrej. kastelic@psih-klinika. si Global Addiction 2015

• Curr Opin Psychiatry. 2011 Jul; 24(4): 280 -5. doi: 10. 1097/YCO. 0 b 013 e 328345 c 956. The intersection of attention-deficit/hyperactivity disorder and substance abuse. Wilens TE, Morrison NR.

• • Substance abuse disorders (SUD) are the most common co-morbidity disorder. Nicotine dependence in Germany is 27 %, about 40 % in the USA (1). Second most common disorder is the harmful use of alcohol. In general, patients with ADHD are twice as much at risk of development of drug dependence (2). Co-morbidity of drug dependence is between 45 and 70 % (22 -24) and one third of those addicted to alcohol has ADHD. (3, 4). 15 -25 % of adults with SUD fulfill criteria for ADHD. The most common illicit drug is cannabis – 21 %. Cocaine - 11 -35 % (5, 6). SUD with ADHD patients start earlier, course of the disease is more serious and the prognosis is worse. 1. 2. Philipsen A, Heslinger B, tebartz van Elst. Attention Deficit Hyperactivity Disorder in Adulthood; Diagnosis, Etiology and Therapy. Dtsch Arztebl Int 2008; 105(17): 311 -7 Huss M. Abschlussbericht and des Bundesministerium fur Gesundheit und Soziale Sicherung (BMGS). Bonn: 2004.

simptom nepozornost otroci • Odkrenljivost • Ne morejo dokončati dela • Kot da ne slišijo, ko se jim govori odrasli • Neorganizira nost • Slabo razporejajo s časom • Se izgubljajo v razgovoru, ker ne morejo slediti, saj se okoli njih dogaja toliko drugega

Increased Lifetime Substance Abuse Lifetime history of psychoactive substance *** use disorder Lifetime Rate (%) of Substance Abuse in Referred Adults 60 55% 50 ***p=0. 001 40 30 27% 20 10 0 Control (n=262) 1. Biederman et al. Biol Psychiatry 1998; 44: 269– 73. ADHD (n=239)

• ADHD and SUD share common neurobiological mechanisms and treatment of ADHD decreases craving and relapse rate. Frodl T. Comorbidity of ADHD and substance disorder (SUD): a neuroimaging perspective. J Atten Disord. 2010 Sep; 14(2): 109 -20.

Brain Networks Implicated in ADHD 1. Liston et al. Biol Psychiatry 2011; 69: 1168– 77.

ADHD and Substance Misuse • Reason for the relationship: – High stimulus seeking behaviour: • Inherent component of ADHD (e. g. novelty seeking) • Shared genetic risk – Impaired social/academic/work function: • Secondary consequence of psychosocial impairments – Relief from symptoms: • Self-treatment of symptoms (e. g. cannabis, alcohol, cocaine) 1. Arias et al. Addictive Behaviors 2008; 33(9): 1199– 207. 2. Asherson. 1 st European Network Adult ADHD Conference. London, 2011.

75 % patients with ADHD in childhood have ADHD in adolescence and 50 % in adulthood (1). 66 % children with ADHD have in adulthood at least clnical significant symptom of mental health disorders (2). 25 -50 % adolescents with SUD have ADHD. 40 -50% those smoking marihuana have ADHD. Adults with ADHD and SUD have more serious symptoms of those disordes and have started using PAS when they were younger (3). 1. 2. 3. Timoty E, Wilens M. D, R. Morrison N. The Intersection of Attention-deficit/Hyperactivity Disorder and Substance Abuse. Curr Opin Psychiatry. 2011 July; 24(4): 208 -285 Kolar et. al. Treatment of adults with ADHD. Neuropsychiatric Disease and Treatment 2008; 4(2): 389 -403 Wilens T, R Morrison N. Substance-use disorders in adolescents and adults with ADHD: focus on treatment. Neuropsychiatry (London). August 2012; 2(4): 301 -312

Understanding reasons for using PAS is important for treating these patients. Wilson JJ, Levin FR. Attention deficit hyperactivity disorder (ADHD) and substance use disorders. Curr Psychiatry Rep. 2001 December; 3(6): 497 -506.

• Children with ADHD and comorbid conduct or bipolar disorder have the worst prognosis for SUD (1). • Those without these disorders have a moderate risk (2). • There is not much research about the role of ADHD and comorbid SUD in women (3). 1. 2. 3. Brook DW, Brook JS, Zhang C, Koppel J. Association between attention-deficit/hyoeractivity disorder in adolescence and substance use disorder in adulthood. Arch Pediatr Adolesc Med. 2010 Oct; 164(10): 930 -4. Wilens TE. Attention-deficit/hyperactivity disorder and the substance use disorders: the nature of the relationship, subtypes at risk, and treatment issues. Psychiatr Clin North Am. 2004 Jun; 27(2): 283 -301. Lynskey MT, Hall W. Attention deficit hyperactivity disorder and substance use disorder: Is there a causal link? Addiction. 2001 Jun; 96(6): 815 -22.

• • 1. 2. In many patients with SUD ADHD was not recognized or diagnosed. In the group of patients with SUD 54 % had symptoms of ADHD in childhood and it was related to the earlier use of alcohol and other PAS (1). Because ADHD symptoms express earlier as SUD there is a small possibility that the SUD cause ADHD (2). ADHD is a significant risk factor for starting smoking before 15 years and when associated behavioral disorders or mood disorders are particularly risky. Early exposure to nicotine may make the brain more susceptible to subsequent behavioral and emotional disorders and PAS abuse. Hypothesis of selfmedication is of course linked to the fact that ADHD often associated with a loss of motivation, failure as are important factors for the abuse of drugs (2). Ohlmeier et. al. Alcohol and drug dependence in adults with attention-deficit/hyperactivity disorder: Data from Germany. Eur J Psychiat 2011. Vol 25. N 3: 150 -163. Timoty E, Wilens M. D, R. Morrison N. The Intersection of Attention-deficit/Hyperactivity Disorder and Substance Abuse. Curr Opin Psychiatry. 2011 July; 24(4): 208 -285

• As ADHD is recognized ahead of PAS abuse it can be successfully treated and so the possibility of the development of SUD and also ADHD in adulthood may be reduced (1). • Persons who abuse drugs are more often hospitalized and have worse outcomes in ADHD in this population (2). • Wilens et. al have demonstrated significant reduction in ADHD symptoms in adults with alcohol dependence but no effect on alcohol consumption (3). 1. Wilson JJ, Levin FR. Attention deficit hyperactivity disorder (ADHD) and substance use disorders. Curr Psychiatry Rep. 2001 December; 3(6): 497 -506. 2. Thurstone C et. al. J Am Acat Child Adolesc Psychiatry 2010, 49: 573 -582 3. Wilens et. al. Drug Alcohol Depend 2008, 96: 145 -154

Atomoxetine in adult patients with ADHD and co-morbid alcohol abuse treated for 12 weeks: LYBY ADHD Investigator Symptom Rating Scale (AISRS) Changes from Baseline 0 40. 6 40. 1 19. 0 18. 7 21. 4 Randomised (n=147) -2 Placebo (n=75) -4 Atomoxetine (n=72) -6 -8 p=0. 009 -10 p=0. 013 -12 -14 -16 Effect Size: 0. 48 p=0. 007 -18 Total Score Hyperactive/ Impulsive Subscale Wilens et al. Drug Alcohol Depend 2008; 96: 145 -54. Inattentive Subscale

Atomoxetine efficacy in adult ADHD and co-morbid alcohol use disorders: alcohol use Cumulative Heavy Drinking Days • No worsening of alcohol abuse in patients treated with atomoxetine Recurrent Heavy Drinking 35 30 Randomised (n=147) Atomoxetine (N=72) 25 Placebo (N=75) 20 15 10 5 0 0 20 40 60 • This post-hoc analysis demonstrated robust effects of atomoxetine for reducing ADHD symptoms in adult ADHD patients with comorbid p=0. 0230 alcohol-use disorder and Event ratio=0. 737 suggests a positive effect on reducing cumulative heavy drinking events 80 100 over time Follow-up Time (Days) Wilens et al. Drug Alcohol Depend 2008; 96: 145 -54.

• Because of high incidence of ADHD in SUD population we should always have in mind the possibility of ADHD. • Correlates with worse quality of life(1). • All patients with SUD should be screened for ADHD as soon as their PAS use is stabilisied (2). 1. Fatseas M, Debrabant R, Auriacombe M. The diagnostic accuracy of attention-deficit/hyperactivity disorder in adults with substance use disorders. Curr Opin Psychiatry. 2012 May; 25(3): 219 -25. 2. Matthys F, Joostens P, Van den Brink W, Sabbe B. Summary of the practice guideline for the diagnosis and treatment of ADHD in adolescents and adults with addictions. Ned Tijdschr Geneeskd. 2013; 157(24): A 6025.

• Stabilisation of PAS use is priority though the treatment should be integrative and complex including pharmacotherapy starting with less adictive medications like atomoxetin or bupropion and if these are not affective start using stimulants. Wilens TE. Impact of ADHD and its treatment on substance abuse in adults. J Clin Psychiatry. 2004; 65 Suppl 3: 38 -45.

Dopamine Concentration as % of Baseline Methylphenidate Increase Dopamine Levels in Rat Nucleus Accumbens and Striatum * * * Time (hours) Methylphenidate 3 mg/kg i. p *p<. 05, overall concentration during 4 -hour time period vs. baseline Bymaster et al. Neuropsychopharmacology 2002; 27(5): 699 -711.

Dopamine Concentration as % of Baseline Atomoxetine Does Not Increase Dopamine Levels in Rat Nucleus Accumbens and Striatum * Time (hours) Atomoxetine 3 mg/kg i. p for PFC and n. A; 10 mg/kg i. p for striatum *p<. 05, overall concentration during 4 -hours time period vs. baseline Bymaster et al. Neuropsychopharmacology 2002; 27(5): 699 -711.

Proposed Effects of Atomoxetine in Brain Regional Catecholamine Neurotransmissiona post parietal NE prefrontal cortex NE & DA striatum nucleus accumbens amygdala NE hippocampus Regions potentially affected by atomoxetine’s action on the NE transporter a. Based on rat studies Bymaster et al. Neuropsychopharmacology 2002; 27(5): 699 -711.

• Early beginning of treatment of ADHD delays the start of drug abuse. But the treatment should not be was interrupted prematurely in adolescence (1). An extensive meta-analysis has clearly shown that if treatment with stimulants begun in childhood is less possibility of 27% of stimulant abuse in adulthood (Wilens et al 2003). • If the treatment is started only in adolescence, the possibility of SUD is increased to 44% (Collins et al. 2008). • It was also shown that abuse of stimulants in connection with the development of antisocial personality disorder. 1. Bejerot S, Ryden EM, Arlinde CM. Two-year outcome of treatment with central stimulant medication in adult attention -deficit/hyperactivity disorder: a prospective study. J Clin Psychiatry. 2010 Dec; 71(12): 1590 -7.

• There is a constant concern about the abuse and misuse of the stimulant prescribed to treat ADHD. The vast majority of patients use medicament for the treatment of ADHD properly. • But a significant proportion reports pressures to approve or sold medicines that have been prescribed to them (1, 2). 1. 2. Mc. Cabe SE, Knight JR, Teter CJ, Wechser H. Non-medical use of perscription stimulants among US college students: prevalence and correlates from a national survey. Addiction. 2005; 99(1): 96 -106. Teter CJ. Mc. Cabe SE, La. Grange K, Cranford JA, Boyd CJ. Illicit use of specific perscription stimulants among college students: prevalence, motives, and routes of administration. Pharmacotherapy. 2006; 26(10): 1501 -1510.

• Around 5% of students abuse stimulants for help with the study. More for improve cognitive functions than to achieve euphoria (1). The effect of 20 mg MPH on long-term memory and understanding of the information did not differ from placebo effect. Amphetamine does not affect short-term memory, long term memory improves, but only when new knowledge already is there. The reason that some students abuse them is to increase in the concentration (58 %), attention (43 %) and feel euphoria (43 %). 1. Wilens TE, Adler LA, Adamson J, et. al. Misuse and diversion of stimulants perscribed for ADHD: a systematic review of the literature. J Am Acad Child Adolesc Psychiatry. 2008 Jan; 47(1): 21 -31.

The link between the core ADHD symptoms and the prefrontal cortex Stahl SM et al. Stahl’s Illustrated. Attention Deficit Hyperactivity Disorder. Cambridge University Press. 2009