Effects of Expectation, Medication and Placebo on Objective and Self-rated Performance

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). The co-occurrence of ADHD and substance use disorder (SUD) is a prevalent phenomenon that has been demonstrated in numerous studies over the past decade (Arias et al 2008; Bernardi et al 2012; van Emmerik-van Oortmerssen et al 2012).

The prevalence of substance abuse in adults with ADHD has been estimated at 50 % and among addicts seeking treatment, one third of the patients are identified as probable ADHD, when screening instruments have been used (Sullivan \& Rodnik-Levin 2001; Ohlmeier et al 2008). The National Board of Health and Welfare in Sweden noted that the presence of people with ADHD and substance abuse varies between 20 % and 35 % depending on what kind of drugs that have been used (Socialstyrelsen 2002).

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).

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).

Patients with substance syndrome often have other expectations for the drug compared to patients with other diagnoses. 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 and substance Use Disorders.

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 computer 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.