Clinical trial NCT02473185: Effects of Expectation, Medication and Placebo on Objective and Self-rated Performance During the QbTest
Official title: Effects of Expectation, Medication and Placebo on Objective and Self-rated Performance During the Quantified Behavior Test in Patients With Untreated ADHD
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Attention Deficit Hyperactivity Disorder
Lead sponsor: Region Västmanland
Sponsor class: OTHER
First posted: 2015-06-16
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: Aim: The purpose of the study is to examine the effects of medication, placebo and expectation on objective and self-rated performance of ADHD core signs during the Quantified Behavior Test in patients with untreated ADHD.

Subjects: Participants are 40 consecutive patients remitted to a neuropsychiatric investigation at the Dependence Clinic Västmanland, Västerås, Sweden.

Method: The study is a double-blind, randomized, placebo-controlled, cross-over study. The study is taken place during four hours on two investigating days, separated by a 4 days wash-out period.

All patients participate on two occasions: In one session they receive the Methylphenidate (MPH) condition, and in the other session they receive the placebo condition. MPH and placebo conditions are counterbalanced across subjects such that half of the participants receive MPH first, and the other half of the participants receive placebo first. Neither the participant nor the research assistant is aware when the participant receive the MPH condition or the placebo condition.

On each investigating day the participant accomplish Questionnaires (Visual Analogical Scales) concerning; (a) expectation, (b) self-rated performance, (c) exhausting exercise, (d) perceived help from the pill and (e) self-rated symptoms. In addition the participant completed A Quick Test of Cognitive Speed (AQT) and two separate Quantified Behavior Test Plus (QbTest) without medication vs MPH/Placebo. QbTest aims to provide objective information regarding core-symptoms of ADHD; hyperactivity on the basis of motor-activity measured with the camera, and inattention and impulsivity on basis of the CPT-test.

The Quantized Behavior Test (QbTest) can be included as part of an neuropsychiatric investigation. QbTest measures the three core signs of ADHD, hyperactivity, inattention and impulsivity. QbTest is a computer-based test that combines a test of attention ability with a movement analysis based on an infrared measurement system. The test results are presented in a report and compared with norm data fromm a group of the same sex amd age who do not have ADHD.

Detailed description: Introduction During the last decade, neuropsychiatric impairments in adults have more often been observed. Requests for neuropsychiatric investigations, especially concerning Attention Deficit Hyperactivity Disorder (ADHD) has increased. The core ADHD symptoms in adults include a frequent and persistent pattern of inattention/distractibility and/or hyperactivity/impulsivity (Adler 2004; Adler \& Chua 2002; McGough \& Barkley 2004). In a Swedish study, 22 % of the outpatients in general psychiatric care, were diagnosed with ADHD (Nylander et al 2009).

Individuals with ADHD also have an increased risk for other psychiatric disorders, e.g. major depressive episodes, bipolar disorder, anxiety disorders and antisocial personality disorder (Rasmussen \& Levander 2009; Torgersen, Gjervan \& Rasmussen 2006).

Patients' expectation can influence the outcome of a treatment (Bingel et al 2011). Linde et al showed that patients with high expectations before the acupuncture treatment, achieved better treating result than the patients who had lower expectations of treatment (Linde, Fässler \& Meissner 2011). A person's expectation is an important part of the so-called placebo effect . The placebo effect is well known and clinically important phenomenon in the patient's treatment. Extensive research has been conducted to elucidate this (Meissner et al 2011; Collocca et al 2013; Enck et al 2013).

Pharmacotherapy, mainly with central stimulant medication, is considered to be the treatment of choice for ADHD. In addition, there are patients who request an ADHD diagnosis to obtain drug treatment (Harrison, Edwards \& Parker 2007). Some of these patients have often learned to deal with awkward and difficult life situations using drugs (Whalen \& Henker 1976; Pelham \& Lang 1993). This may increases the risk that the person receives a low confidence in their own ability to solve critical situations without drugs. Therefore, it is important to identify those patients in order to give them a treatment specialized to their need.

This study intends to investigate whether the patient's expectation of their own ability to solve problems increases when they take a drug.

Aim The purpose of the study is to examine the effects of medication, placebo and expectation on objective and self-rated performance of ADHD core signs during the Quantified Behavior Test in patients with untreated ADHD.

This leads to the following questions ;

1. Does the participant's self-rated expectation of future performance change in the presence of active drug or placebo?
2. Does the participant's self-rated performance change in the presence of active drug or placebo?
3. Does the participant's perception of exertion change in the presence of active drug or placebo?
4. Does the participant's performance on the core signs, Hyperactivity, Inattention and Impulsivity on the QbTest change in the presence of active drug or placebo ?
5. Does the participant's experience of the tablet's efficacy change in the presence of active drug or placebo?

Method: The study is a double-blind, randomized, placebo-controlled, cross-over study. The study is taken place during four hours on two investigating days, separated by a 4 days wash-out period.

Subjects Participants are 40 consecutive patients remitted to a neuropsychiatric investigation at the Dependence Clinic Västmanland, Västerås, Sweden.

Instruments The Quantized Behavior Test (QbTest) can be included as part of an neuropsychiatric investigation. QbTest measures the three core signs of ADHD, hyperactivity, inattention and impulsivity.

The QbTest combines a Continuous Performance Test (CPT) installed as a software program on a PC with measures of attention and impulsivity and an activity test with measures of motor-activity during 20 minutes. While performing the CPT-test on the computer, movements of the participant are recorded using an infrared camera following a reflective marker attached to a head-band. The CPT-test involves rapid presentations of figures with various shapes (square or circle) and colors (red or blue) and the participant are instructed to press a handheld button when a stimuli subsequently repeats itself (a target) and not to press the button when the stimulus varies relative to the previous one (a non-target). The stimuli are presented at a pace of one per two seconds, each one visible for 200 milliseconds, and the total number of stimuli is 600, presented with a 25% target probability (Knagenhjelm \& Ulberstad 2010).

The clinical documentation for QbTest is extensive. Lis et al demonstrated that patients with ADHD were significantly different in the variables of attention and activity from a control group of healthy individuals (Lis et al 2010). Edebol showed that QbTest has a sensitivity of 83 % and a specificity of 57% to detect ADHD in adults (Edebol et al 2011).

The discriminative validity was tested and the results show that QbTest differ not only between those with ADHD and healthy controls , but between clients with ADHD and other clinical groups (Söderström, Pettersson \& Nilsson 2014; Edebol, Helldin \& Norlander 2012). QbTest has also shown good results as an objective method for monitoring drug treatment with methylphenidate (Ginsberg, Hirvikoski \& Grann 2012; Edebol, Helldin \& Norlander 2013; Bijlenga \& Henker 2014).

The Quick Test measure processing speed and automaticity of naming shapes and colours, Cognitive shifts between visual dimensions and semantic fields and Activation of working memory for processing and monitoring. AQT's objective measures are based on clocked total-naming time. Highly reliable (r = .88 - 96) over time and consistent over repeated trials.

Procedure All patients participate on two occasions: In one session they receive the Methylphenidate (MPH) condition, and in the other session they receive the placebo condition. MPH and placebo conditions are counterbalanced across subjects such that half of the participants receive MPH first, and the other half of the participants receive placebo first. Neither the participant nor the research assistant is aware when the participant receive the MPH condition or the placebo condition.

On each investigating day the participant accomplish Questionnaires (Visual Analogical Scales) concerning; (a) expectation, (b) self-rated performance, (c) exhausting exercise, (d) perceived help from the pill and (e) self-rated symptoms. In addition the participant completed A Quick Test of Cognitive Speed (AQT) and two separate Quantified Behavior Test Plus (QbTest) without medication vs MPH/Placebo.

Analyses In this study, hyperactivity has been operationalized with the parameter called "distance", i.e., the length of the path in metres describing the movement of the headband reflector during the test period. Inattention is operationalized on the basis of omission errors. An omission error occurs when no response is registered when the stimulus was a Target, i.e. the button was not pressed when it should have been. Impulsivity is operationalized on the bases of commission errors. A commission error occurs when a response is registered when the stimulus was a Non-Target, i.e. the handheld button is pressed when it should not have been pressed.

Eligibility criteria: Inclusion Criteria:

* 18 years old or older.
* ADHD is diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5 criteria).
* Qb-score 1.3 or higher on at least one of the the weighted summary parameters QbActivity, QbInattention or QbImpulsivity on the QbTest.
* Patients are given their written informed consent to participate in the study.

Exclusion Criteria:

* Affected by alcohol or drugs during the last month.
* Untreated severe comorbid psychiatric or somatic illness.
* Bloodpressure 150/95 or higher.
* Irregular pulse, or pulse 100 or higher.
* No counter indications according to the Medicinet pill.
* Concurrent clinical diagnosis that significantly could affect test performance.
* Concurrent prescription of medicines for ADHD or medicines that significantly could affect test performance.

Primary outcomes:
measure: Change in Weighted summary parameter QbInattention score on the QbTest.
timeFrame: Baseline, 2 hours
Secondary outcomes:
measure: Change in Weighted summary parameter QbActivity score on the QbTest.
timeFrame: Baseline, 2 hours
measure: Change in Weighted summary parameter QbImpulsivity score on the QbTest.
timeFrame: Baseline, 2 hours
measure: Change in Self-rated expected performance.
timeFrame: Baseline, 2 hours
measure: Change in Self-rated mental effort
timeFrame: Baseline, 2 hours
measure: Change in Self-rated severity of the task
timeFrame: Baseline, 2 hours
measure: Change in Self-rated experienced performance
timeFrame: Baseline, 2 hours
measure: Change in Self-rated help from the pill
timeFrame: Baseline, 2 ours
Other outcomes:
Locations:
city: Västerås
country: Sweden
facility: Landstinget Västmanland
Study officials:
affiliation: Region Västmanland
name: Lennart Jansson, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Adler LA. Clinical presentations of adult patients with ADHD. J Clin Psychiatry. 2004;65 Suppl 3:8-11.
citation: Adler LA, Chua HC. Management of ADHD in adults. J Clin Psychiatry. 2002;63 Suppl 12:29-35.
citation: Bijlenga D, Jasperse M, Gehlhaar SK, Sandra Kooij JJ. Objective QbTest and subjective evaluation of stimulant treatment in adult attention deficit-hyperactivity disorder. Eur Psychiatry. 2015 Jan;30(1):179-85. doi: 10.1016/j.eurpsy.2014.06.003. Epub 2014 Aug 27.
citation: Bingel U, Wanigasekera V, Wiech K, Ni Mhuircheartaigh R, Lee MC, Ploner M, Tracey I. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med. 2011 Feb 16;3(70):70ra14. doi: 10.1126/scitranslmed.3001244.
citation: Colloca L, Klinger R, Flor H, Bingel U. Placebo analgesia: psychological and neurobiological mechanisms. Pain. 2013 Apr;154(4):511-514. doi: 10.1016/j.pain.2013.02.002. Epub 2013 Feb 13. No abstract available.
citation: Edebol H; Helldin L; Holmberg E; Gustafsson S-A; Norlander T. In search for objective measures of hyperactivity, impulsivity and inattention in adult attention deficit hyperactivity disorder using the Quantified Behavior Test Plus. Europe´s Journal of Psychology 2011, 7, 443-457.
citation: Edebol H, Helldin L, Norlander T. Objective Measures of Behavior Manifestations in Adult ADHD and Differentiation from Participants with Bipolar II Disorder, Borderline Personality Disorder, Participants with Disconfirmed ADHD as Well as Normative Participants. Clin Pract Epidemiol Ment Health. 2012;8:134-43. doi: 10.2174/1745017901208010134. Epub 2012 Nov 2.
citation: Edebol H, Helldin L, Norlander T. The weighed core symptom scale and prediction of ADHD in adults - objective measures of remission and response to treatment with methylphenidate. Clin Pract Epidemiol Ment Health. 2013 Oct 18;9:171-9. doi: 10.2174/1745017901309010171. eCollection 2013.
citation: Enck P, Bingel U, Schedlowski M, Rief W. The placebo response in medicine: minimize, maximize or personalize? Nat Rev Drug Discov. 2013 Mar;12(3):191-204. doi: 10.1038/nrd3923.
citation: Ginsberg Y, Hirvikoski T, Grann M, Lindefors N. Long-term functional outcome in adult prison inmates with ADHD receiving OROS-methylphenidate. Eur Arch Psychiatry Clin Neurosci. 2012 Dec;262(8):705-24. doi: 10.1007/s00406-012-0317-8. Epub 2012 Apr 21.
citation: Harrison AG, Edwards MJ, Parker KC. Identifying students faking ADHD: Preliminary findings and strategies for detection. Arch Clin Neuropsychol. 2007 Jun;22(5):577-88. doi: 10.1016/j.acn.2007.03.008. Epub 2007 May 15.
citation: Knagenhjelm P; Ulberstad F. Qb Test Technical Manual. Stockholm: Qbtech AB 2010.
citation: Linde K, Fassler M, Meissner K. Placebo interventions, placebo effects and clinical practice. Philos Trans R Soc Lond B Biol Sci. 2011 Jun 27;366(1572):1905-12. doi: 10.1098/rstb.2010.0383.
citation: Lis S, Baer N, Stein-en-Nosse C, Gallhofer B, Sammer G, Kirsch P. Objective measurement of motor activity during cognitive performance in adults with attention-deficit/hyperactivity disorder. Acta Psychiatr Scand. 2010 Oct;122(4):285-94. doi: 10.1111/j.1600-0447.2010.01549.x. Epub 2010 Feb 25.
citation: McGough JJ, Barkley RA. Diagnostic controversies in adult attention deficit hyperactivity disorder. Am J Psychiatry. 2004 Nov;161(11):1948-56. doi: 10.1176/appi.ajp.161.11.1948.
citation: Meissner K, Bingel U, Colloca L, Wager TD, Watson A, Flaten MA. The placebo effect: advances from different methodological approaches. J Neurosci. 2011 Nov 9;31(45):16117-24. doi: 10.1523/JNEUROSCI.4099-11.2011.
citation: Nylander L, Holmqvist M, Gustafson L, Gillberg C. ADHD in adult psychiatry. Minimum rates and clinical presentation in general psychiatry outpatients. Nord J Psychiatry. 2009;63(1):64-71. doi: 10.1080/08039480802416323.
citation: Pelham WE; Lang AR. Parental alcohol consumption and deviant child beha-vior: Laboratory studies of reciprocal effects. Clinical Psychology Review 1993, 13, 763-784.
citation: Rasmussen K, Levander S. Untreated ADHD in adults: are there sex differences in symptoms, comorbidity, and impairment? J Atten Disord. 2009 Jan;12(4):353-60. doi: 10.1177/1087054708314621. Epub 2008 Mar 26.
citation: Soderstrom S, Pettersson R, Nilsson KW. Quantitative and subjective behavioural aspects in the assessment of attention-deficit hyperactivity disorder (ADHD) in adults. Nord J Psychiatry. 2014 Jan;68(1):30-7. doi: 10.3109/08039488.2012.762940. Epub 2013 Mar 26.
citation: Torgersen T, Gjervan B, Rasmussen K. ADHD in adults: a study of clinical characteristics, impairment and comorbidity. Nord J Psychiatry. 2006;60(1):38-43. doi: 10.1080/08039480500520665.
citation: Whalen CK, Henker B. Psychostimulants and children: a review and analysis. Psychol Bull. 1976 Nov;83(6):1113-30. No abstract available.