An open-label prospective effectiveness-study: Effectiveness of one-year pharmacological treatment of adult attention-deficit/ hyperactivity disorder (ADHD) Dawn E. Peleikis ᵃ, MD, PhD and Mats Fredriksen ᵇ, MD, PhD ᵃ Department of Psychiatry, Akershus University Hospital, Norway ᵇ Division of Mental Health and Addiction, Vestfold Hospital Trust, Norway International Conference on Hospice and Palliative Care Orlando, Florida, USA August 31-September 02, 2015

Disclosure Dr. Peleikis has nothing to disclose Dr. Fredriksen has nothing to disclose

Treatment or‘Palliation’of ADHD ADHD is not considered as a life-threatening disorder, but increased mortality is found (Dalsgaard, 2015) Only symptomatic relief - from distressing symptoms and impaired functioning - on current medications – Aspects of a palliative aim – Improves quality of life – Support patients and their family in living & coping

ADHD - Diagnose and Core Symptoms DSM-IV (Text Revision): ADHD Attention-Deficit /Hyperactivity Disorder – DSM-IV TR: The Diagnostic and Statistical Manual of Mental Disorder - Fourth Edition Text Revision (American Psychiatric Association, 2000) Core symptoms: – Inattention – Hyperactivity - Impulsivity Nevrodevelopmental – and biological pedriatric psychiatric disorder – High heritability - shown in twin and family studies (70-80%) – High prevalence of persistence into adulthood

Melchior Adam Weikard Der Philosophische Arzt 1775

Background Increasing rate of referred and treated adults with ADHD ( Hannås, 2012) Increased consumption of ADHD drugs in Western Europe Childhood ADHD persists into adult ADHD in 50-65% (Faraone, 2006) Worldwide prevalence of adult ADHD: 2-5% (Simon, 2009; Barkley, 2010) Comorbid psychiatric disorders : Common in ADHD (70-80%) (Torgersen, 2006; Sobanski, 2007)

Treatment of adult ADHD Non-medicational treatment Psychosocial – Psycho-education – Structured forms of psychotherapy cognitiv behavioral therapy Group therapy – In addition Individual plans Solution focused treatment Habilitation or fascilitation Alternatives? – Diets? Medications Centralstimulants Methylfenidate Short- or long-acting Amphetamines Short- or long-acting Non-stimulants Atomoxetine Buproprione Antidepressives (TCA, MAO) Reboxetine Antihypertensives (clonidine, guanfacine) Modafinile

Gap of Knowledge Is there any clinical relevant evidence for long-term efficacy of ADHD-medication? – Randomized controlled trials (RCTs) had documented short-term efficacy (4-10weeks, a few up to 6 months) (Faraone, 2010; Torgersen, 2008; Fredriksen, 2012) – Small groups and many drop-outs – Few trials examined more than one drug – Selection bias

Aims of the Study A prospective observational study of a clinical relevant sample (real life patients with comorbidities, poly pharmacy) without blinded randomization Long time follow-up: one-year Treated with medication according to current guidelines Standardized evaluation to compare with other studies and to be able to generalize the results

Study Sample Inclusion: – Previously not medicated patients referred to a specialized Out-patient Clinic for diagnostic and treatment of ADHD – Fulfill the diagnostic criteria for ADHD (DSM-IV-TR) assessed by a board certified psychiatrist Exclusion: – Previously medicated for ADHD – Patients not allowed to use stimulants or atomoxetine due to other medical conditions – Comorbid acute psychosis or current substance use or dependence with immediate need of other treatment – Intelligence quotient below 2 SD (standard deviations) on the Wechsler Adult Intelligence Scale IV – Autism Spectrum Disorder

Study Flowchart

Methods Design: Prospective observational study for 12 months of adults with ADHD who receive ADHD-medication first time Sample: N=250 included, previously unmedicated Outcome measures: Repeated measures of self-rated ADHD- symptoms by the ASRS, clinical rated changes of global symptoms and functioning (GAF), and clinical rated respons (CGI-I), and self-rated general psychological distress or symptoms (SCL-90R, GSI), and side-effects Other variables: comorbide mental disorders by structural clinical interview (MINI), side-effects (CADDRA), dose of ADHD-medication, type of ADHD-medication, time in treatment

Results At 12 months follow-up: 232 patients (93%) completed evaluation 163 patients on-medication (70%) Most patients used Methylphenidate (by 80%) Improvements on the primary outcomes (ASRS and GAF) were statistically superior for those continuing on-medication – Median reduction of ADHD-symptoms (ASRS) on-medication at one year evaluation: 39% (versus 13% off-medication) Greatest improvements were observed in the first 6 weeks, but continued until 12 months completion for those adherent to medication

Results Higher cumulative dose was associated with greater improvements over time Comorbid psychiatric disorder and side-effects were associated with weakened recovery Out of those 69 patients who stopped medication (30%), 31 (45%) reported side-effects as the reason for discontinuation No serious adverse effects were observed during the study, but 9 patients had to stop medication due to elevated blood pressure (above defined levels 150/95 mmHg)

Weeks Primary Outcomes by Adherence to Medication

Primary Outcome by Adherence to Medication

Conclusion RCTs have shown efficacy of stimulants and atomoxetine in studies up to 6 months duration In this study we found effectiveness sustained in open-label observational study design in a clinical relevant setting for one year duration One year treatment of adult ADHD showed clinically significant reduction of symptoms and improved ratings of global functioning No serious side-effects occurred, and side-effects were for most patients tolerable

Thank you all….

Further Research Need for more and longer-duration longitudinal studies of medications of adult ADHD Other outcome measures are relevant; quality of life, different functional measures, cost- benefit analyses Other pharmacological agents than stimulants or atomexetine

Further Research Unresolved impact of psychiatric comorbidities Studies of benefit of early initiation of treatment or treatment programs are sparse Large scale epidemiological studies on treatment are few Limited knowledge of effectiveness of medication in age group above 50 years

Longitudinal study course Inclusion Start of medication Background variables: Outcome measures: 3 months6 months12 months Waiting-listBaseline 6 weeks Age and gender ADHD-symptoms (DIVA 2.0) Comorbid disorders (MINI) IQ (HASI; WAIS) Symptom severity in childhood (WURS) Other medication Educational and vocational attainments Adult ADHD symptoms (ASRSv1.1) Clinician rated global functioning (GAF) Clinician rated respons (CGI-I) Self rated symptoms [SCL-90-R (GSI)] Ratings of side-effects (CADDRA) Adverse events and drop-outs Somatic data (heart beat, BP, ECG, hight, weight)