Clinical trial NCT03810703
Conditions: Bipolar II Disorder
Sponsor: University of Chicago
Start date: 2017-02-09; Completion date: 2018-08-09
Enrollment: 93 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Young adults who exhibit "bipolar phenotype" (BPP), defined as occasional episodes of mood elevation and heightened activity, are at risk for several psychiatric disorders, including problem use of drugs and alcohol. Mood elevation has been linked to higher alcohol consumption and alcohol use disorders. Individuals with BPP show elevated lifetime prevalence of alcohol use disorders (between 39%-61%), figures that exceed those reported in both major depression and schizophrenia. Recently, the investigators demonstrated in a controlled laboratory study that individuals with BPP (but not meeting criteria for full Bipolar I Disorder), report dampened responses to a single dose of alcohol, compared to placebo. In the current study, the investigators seek to extend these findings to determine if young adults reporting BPP, based on a questionnaire, will exhibit reduced responses to other rewarding stimuli, such as d-amphetamine and sweet tastes. The investigators hypothesize that the BPP individuals will exhibit dampened subjective responses to stimulant and sweet taste rewards compared to healthy controls.

Detailed description:
This study will extend the understanding of risk factors for drug or alcohol misuse, or other reward-related behaviors. The investigators previously showed that individuals who report occasional feelings of high energy and excitability experience less effect from a single dose of alcohol, compared to people who have not experienced these effects. Now the investigators wish to determine if this dampened response also occurs with other rewards, namely feelings of wellbeing after a dose of amphetamine, or liking of a sweet solution. Individuals who exhibit the BPP (i.e., periods of excitability) also are more likely to develop alcohol problems, substance misuse, and weight gain and obesity. Therefore, the investigators will test the working hypothesis that young adults who report having these experiences, based on a questionnaire measure (i.e., BPP individuals) will show dampened subjective responses to both single oral doses of amphetamine or sweet palatable tastes. The investigators will also obtain objective measures (e.g. Respiratory Sinus Arrhythmia and heart rate) to amphetamine and sweet taste, to establish whether the dampened subjective response extends to physiological indices as well. This study will extend the previous literature regarding the blunted effects of alcohol in BPP individuals and will suggest possible mechanisms that promote broader addictive behaviors in individuals with mood disturbance. Importantly, the investigators are proposing to test individuals at a relatively young age, 18-19 years. This is important to identify a risk factor, that is thought to pre-date use of drugs. In older participants, it would be difficult to separate the role of the pre-existing trait from the effect of habitual drug or alcohol use that escalates markedly after age 20.

Arms: arm 1: Participant will receive placebo oral capsule during this four hour session. arm 2: Participant will receive d-amphetamine 10 mg oral capsule during this four hour session. arm 3: Participant will receive d-amphetamine 20 mg oral capsule during this four hour session.
Interventions: intervention 1: Placebo oral capsule intervention 2: d-amphetamine 10 mg oral capsule intervention 3: d-amphetamine 20 mg oral capsule
Intervention descriptions: intervention 1: Placebo oral capsule intervention 2: d-amphetamine 10 mg oral capsule intervention 3: d-amphetamine 20 mg oral capsule

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Differential responses to drugs and sweet tastes 
 
9.11.2017 
 
IRB16-1293 
 
NCT03810703 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
Protocol Name: Differential responses to drugs and sweet tastes 
 
Principal Investigator: Harriet de Wit, Ph.D. 
Co-investigators: David Arndt, Ph.D. and Royce Lee, MD 
 
Study Location: The University of Chicago Medical Center 
 
Version Date: 09/11/2017   
 
Background and Aims:  Young people screened in late adolescence report surprisingly high 
rates of mood elevation or 'hypomanic' experience (Calabrese et al., 2003; Chandler et al., 
2008). These experiences are characterized by intermittent periods of heightened activity, 
sleeplessness and reward-focused thinking. These experiences are also associated with 
increased risk of mental health problems, especially depression and anxiety (Calabrese et al., 
2003). Even individuals who report these experiences but do not meet criteria for bipolar 
disorder show some of the same problems in cognitive and emotional function as individuals 
who do meet diagnostic criteria (Chandler et al., 2008; Rock et al., 2010). This strongly suggests 
that intermittent mood elevation per se in young people constitutes a trait marker for vulnerability 
to psychological disorders as a bipolar phenotype (BPP). 
 
Individuals with the “bipolar phenotype” (BPP), defined as episodes of mood elevation and 
heightened activity, are at risk for several psychiatric disorders, including problem use of drugs 
and alcohol.  Mood elevation has been linked to heightened alcohol consumption and alcohol 
use disorders. Individuals with BPP show elevated lifetime prevalence of alcohol use disorders 
(between 39%-61%), figures that exceed those reported in both major depression and 
schizophrenia (Regier et al., 1990; Kessler et al., 1997). Recently, we demonstrated in a 
controlled laboratory study that individuals with BPP report dampened responses to a single 
dose of alcohol, compared to placebo (Yip et al., 2012).  Notably, these individuals were tested 
at ages 18 and 19, before they had extensive exposure to alcohol and other recreational drugs, 
suggesting that their responses reflect an underlying neurobiological risk factor.  In addition, 
another recent study found that a genetic polymorphism associated with susceptibility to Bipolar 
Disorder was also associated with dampened neural responses to reward in healthy volunteers, 
using fMRI (Trost et al., 2016).  These findings raise the possibility that individuals with BPP will 
exhibit dampened responses to other rewarding stimuli, including dampened feelings of well-
being or euphoria from amphetamine, or less pleasurable experiences with a sweet taste. 
 
In the present study, we will extend our previous findings and determine whether individuals with 
this phenotype also experience less positive effects from two other rewards: feelings of well-
being from a single oral dose of d-amphetamine and preference for sweet solutions. This would 
suggest a mild dysfunction of the reward circuits in BPP individuals, possibly related to 
mesolimbic dopamine function. 
 
Study Aim: To compare the rewarding effects of d-amphetamine (10 and 20 mg) and 
sweet tastes in young adults with low and high bipolar phenotypes.  The rewarding effects 
of d-amphetamine in young adults will be measured using subjective self-report measures of 
euphoria and arousal. We will also obtain psychophysiological measures to provide an objective 
index of positive emotional responses.  Based on our previous findings suggesting individuals 
with BPP display dampened subjective responses to alcohol, we hypothesize that individuals 


with BBP, compared to matched controls without these symptoms, will be hypo-reactive to both 
amphetamine reward and sweet taste reward. 
 
Method 
Subject Recruitment and Screening: We will recruit 48 healthy men and women, aged 18 or 19. 
This age range matches the age of our previous study with alcohol, and minimizes the 
confounding influence of habitual alcohol consumption.  Potential participants will complete the 
standardized Mood Disorders Questionnaire (MDQ)(Hirschfeld et al., 2000; Hirschfeld et al., 
2003).  We will recruit an even distribution of participants with higher or lower MDQ scores, 
totaling 48 individuals.  Potential participants will be recruited either through our regular 
recruitment process (Protocol 13681B), or through targeted ads in which they are invited to 
complete the MDQ online.  We will add the MDQ to our primary recruitment and screening 
protocol, and participants will come into lab for the in-person screening interview, under Protocol 
#13681B, which includes an EKG, physical exam, and clinical psychiatric interview.  
 
Screening assessments: During the in-person screening interview, participants will be screened 
by a clinical psychologist and will complete several standardized questionnaires. They will 
undergo a semi-structured Clinical Interview for DSM-5 (SCID-5) (First, 1995) to exclude any 
major DSM-V psychiatric illness   including alcohol and substance abuse/dependence  with 
the exception of bipolar II or NOS for BPP participants.  Other exclusion criteria will include: (i) 
any current psychotropic medication; (ii) any current non-psychotropic medication that might 
interact with amphetamine; (iii) history of cardiac or liver disease; (iv) high blood pressure; (v) 
night-shift work; (vi) more than 3-4 alcohol drinks per day for males and 2-3 drinks per day for 
females.  
 
Group matching: As we enroll participants we will attempt to match the BPP and Healthy Control 
(HC) groups for sex, age, drug use history, and (non-verbal) cognitive ability (Raven et al., 
1998).  
 
Drugs: Oral d-amphetamine at 10mg and 20mg (Dexedrine; GlaxoSmithKline, Research 
Triangle Park, NC; 5mg tablets) will be placed in size 00 capsules with dextrose filler. Placebo 
capsules will contain dextrose only. 
 
Self-report subjective measures: Subjective responses to amphetamine will be assessed using 
standardized scales.  
 
The Drug Effects Questionnaire (DEQ) (Johanson and Uhlenhuth, 1980). Participants use 
100mm visual analog scales (VAS) to provide ratings for four questions: 'Do you feel any 
drug effect?' ('None at all' to 'A lot'); 'Do you like the effects you are feeling now?' ('Dislike' 
to 'Like very much'); 'Are you high?' ('Not at all' to 'Very'); and 'Would you like more of 
what you consumed, right now?' ('Not at all' to 'Very much').  
 
The Addiction Research Center Inventory (ARCI) (Haertzen, 1966). The ARCI is a 49-
item true-false questionnaire that is sensitive to psychoactive drugs. Its 5 scales are 
sedation (Pentobarbital-Chlorpromazine Group; PCAG), stimulant-like effects 
(Amphetamine; A, and Benzedrine Group; BG), somatic and dysphoric effects (Lysergic 
Acid; LSD), and euphoria (Morphine-Benzedrine Group; MBG).  
 
The Profile of Mood States (POMS) (McNair et al., 1971). The 72-item POMS will be used 
to assess momentary mood states across 8 subscales: Anxiety, Depression, Anger, 
Vigor, Fatigue, Confusion, Friendliness and Elation; participants indicating how they feel 


at that moment in relation to 72 adjectives on a 5-point scale from 'Not at all' (0) to 
'Extremely' (4).  
 
Psychophysiology: Psychophysiological measures will be obtained to provide an objective index 
of responses to amphetamine and differences between the groups.  Resting heart rate (HR) will 
be measured at 1000Hz before amphetamine and then for 2min at set intervals using a Biopac 
multi-channel device (MP150-BIOPAC Systems Inc., Goleta, CA). Recordings will be wireless 
via a (Biopac) BioNomadix RSP, (Biopac) ECG amplifier and (Biopac) BioNomadix respiration 
transducer while participants are seated with eyes closed. We will use disposable pre-jelled Ag–
AgCl snap disposable vinyl electrodes placed in a modified Lead II configuration. Data analysis 
will proceed with AcqKnowledge v4 software. ECG signal will be converted to R-wave intervals 
(as interbeat intervals (IBI) to the nearest millisecond) and IBI values will be converted to beats 
per minute. Respiratory sinus arrhythmia (RSA) will be derived as a noninvasive index of cardiac 
vagal tone, or parasympathetic activity using the peak-valley method (Grossman and Taylor, 
2007). Maximum HR expressed as milliseconds IBI during the expiration window will be 
subtracted from the minimum HR during the inspiration window of the respiration cycle to yield 
RSA (ms)(Grossman et al., 1990).   
 
Study environment: The study will be conducted in the Human Behavioral Pharmacology 
Laboratory at The University of Chicago in secure, comfortable testing rooms. Medical 
assistance is readily available in the unlikely event of adverse drug experiences. 
 
Consent Procedures: After screening, subjects will attend an orientation session in which they 
read and sign the consent form. Participants will be told that the study purpose is to investigate 
the effects of psychoactive drugs and food tastes on mood and behavior, and that they might 
receive a stimulant (such as amphetamine), a sedative (such as Valium) or an inactive placebo. 
Participants will agree not to use any drugs except for their normal amounts of caffeine for 24hr 
before and 6hr following each study visit. They will be informed that urine tests for stimulants, 
opioids and cannabis, breath samples for alcohol use, and pregnancy tests for women will be 
taken at the start of each visit and that positive tests may result in dismissal. Participants will be 
instructed to fast on the morning of the visit.   
 
Orientation: During an initial orientation session, the study procedures will be explained, subjects 
will provide informed consent, and then practice study tasks.  After practicing the study tasks, 
the participants will complete the following questionnaires: the Quick Inventory for Depressive 
Symptomatology  (QIDS) (Rush et al., 2003); and neuroticism using the Eysenck Personality 
Questionnaire’s Neuroticism subscale (EPQ-N)(Eysenck et al., 1985), and the cognitive ability 
assessment: Wechsler Abbreviated Scale of Intelligence-Second Edition (Wechsler & Hsiao-pin, 
2011; WASI-II).  For comparison to other studies, subjects will also complete the Lifetime 
Drinking History  Interview (Jacob et al., 2006) and the Timeline Follow-Back method (Sobell 
& Sobell, 1992; Hoeppner et al., 2010).  Finally, participants will complete the revised Three 
Factor Eating Questionnaire (TFEQ) (de Lauzon et al., 2004), an 18-item questionnaire on 
eating attitudes and behaviors, with subscales to measure cognitive restraint, uncontrolled 
eating and emotional eating. 
 
Design & procedure: Following orientation, participants will complete three 4-hour drug study 
visits and a final 1-hour visit.  The 4-hour sessions will be conducted between 9am and 1pm 
separated by at least 48 hours in a double-blind, placebo-controlled, cross-over, within-subjects 
design. During these visits, they will consume capsules containing 10 or 20 mg d-amphetamine 
or placebo, double-blind in counterbalanced order. Women not using oral contraceptives will 
only be tested during the follicular phase (White et al., 2002).  
  


Upon arrival at the laboratory, participants will provide BrAL and compliant urine tests for recent 
drug or alcohol use, and pregnancy (in females). Participants will then complete baseline 
questionnaires (DEQ, POMS, and the ARCI) and psychophysiological measurements. 
Participants will be given a snack (granola bar) to standardize food consumption, and then 
ingest a capsule containing placebo, 10mg or 20 mg d-amphetamine under double-blind 
conditions. The order will be randomized across subjects via Latin square design.  Participants 
will complete the DEQ, POMS, and the ARCI scales at 30, 60, 90, 120, 150, 180, 210 and 
240min time-points; HR will be taken at the same time. At 1pm, participants will complete a final 
set of questionnaires to collect their final state and subjective responses before being 
discharged to go home.  
 
The Sweet Taste Test: On the final 1-hour study visit, participants will complete the sweet taste 
test and then the study will be explained. After BrAL and drug compliance tests, participants will 
complete the validated sweet taste test (Weafer et al., 2014). In this test, participants rate the 
sweetness intensity and liking of Kool-aid solutions of various sucrose concentrations. 
Participants will rate five concentrations equivalent to the molar sucrose concentrations typically 
used in sweet taste liking procedures (i.e. 0.05, 0.10, 0.21, 0.42 and 0.83M). The test will consist 
of five blocks, in which each of the five solutions will be presented in random order (i.e. a total of 
25 taste trials). On each presentation, participants will receive a 2ml serving of solution in a 
small opaque cup, instructed to swish the solution for 5s and then spit it out. They rate the 
sweetness of the taste (from 'Not sweet at all' to 'Extremely sweet') and their liking of the taste 
(from 'Disliked very much' to 'Liked very much') on two 100-mm visual analog scales. Between 
trials, subjects will rinse and spit a small amount of water. Sweetness and liking ratings will be 
calculated by averaging ratings for each solution across the five presentations. 
 
Data analysis and interpretation:  First we will ensure that the BPP and HC groups are matched 
for demographic variables, and covariates will be identified if needed. Primary outcome 
measures will be the stimulant (A scale) and euphoria (MBG) subscales of the ARCI (Haertzen, 
1966) and the Friendliness and Elation subscales of the POMs (McNair et al., 1971). These 
measures will be tested using GLMs with predictors of group (BPPs vs HCs), gender, treatment 
(placebo, 10mg and 20mg amphetamine) and time (0, 30, 60, 90, 120 and 150 and 180min). 
Sweet 'liking' responses will be tested using a GLM with the predictors of group, gender and 
concentration (i.e. 0.05, 0.10, 0.21, 0.42 and 0.83M). Participants will be classified as sweet-
likers if their liking ratings were greatest for the highest concentration solution (0.83 M); all other 
participants will be classified as sweet-dislikers (Weafer et al., 2014). 2-tests will test the 
supplementary prediction that there are more sweet-likers in the BPP group than in the HC 
groups. 
 
Sample size: Estimations of sample/group size have been derived from our previous 
demonstration of blunted subjective response to alcohol in BPP compared to HC males (Yip et 
al., 2012). In that study, the effect sizes (f2) for the two DEQ sub-scales of 'Feel high' and 'Feel 
effects' was 0.73 and 0.60, respectively. Taking the midpoint of these 2 values as our anticipated 
effect size (0.67), N=48 subjects would provide over 81% power (with α = .05) to detect 
treatment differences between BPP individuals and HC individuals. 
 
 
 
References 
 
Calabrese JR, Hirschfeld RM, Reed M, Davies MA, Frye MA, Keck PE, Lewis L, McElroy SL, McNulty 
JP, Wagner KD (2003) Impact of bipolar disorder on a U.S. community sample. J Clin 
Psychiatry 64:425-432. 


 
Chandler RA, Wang PW, Ketter TA, Goodwin GM (2008) A new US-UK diagnostic project: mood 
elevation and depression in first-year undergraduates at Oxford and Stanford universities. Acta 
Psychiatr Scand 118:81-85. 
 
de Lauzon, B., Romon, M., Deschamps, V., Lafay, L., Borys, J. M., Karlsson, J., Ducimetière, P., & 
Charles, M. A. (2004). The Three-Factor Eating Questionnaire-R18 is able to distinguish 
among different eating patterns in a general population. The Journal of nutrition, 134(9), 2372-
2380. 
 
Eysenck, S. B., Eysenck, H. J., & Barrett, P. (1985). A revised version of the psychoticism scale. 
Personality and individual differences, 6(1), 21-29. 
 
First, M. B. (1995). Structured clinical interview for the DSM (SCID). John Wiley  
& Sons, Inc. 
 
Grossman P, Taylor EW (2007) Toward understanding respiratory sinus arrhythmia: relations to 
cardiac vagal tone, evolution and biobehavioral functions. Biol Psychol 74:263-285. 
 
Grossman P, van Beek J, Wientjes C (1990) A comparison of three quantification methods for 
estimation of respiratory sinus arrhythmia. Psychophysiology 27:702-714. 
 
Haertzen CA (1966) Development of scales based on patterns of drug effects, using the addiction 
Research Center Inventory (ARCI). Psychol Rep 18:163-194. 
 
Hoeppner, B. B., Stout, R. L., Jackson, K. M., & Barnett, N. P. (2010). How good is fine-grained 
Timeline Follow-back data? Comparing 30-day TLFB and repeated 7-day TLFB alcohol 
consumption reports on the person and daily level. Addictive behaviors, 35(12), 1138-1143. 
 
Hirschfeld RM, Holzer C, Calabrese JR, Weissman M, Reed M, Davies M, Frye MA, Keck P, McElroy 
S, Lewis L, Tierce J, Wagner KD, Hazard E (2003) Validity of the mood disorder questionnaire: 
a general population study. Am J Psychiatry 160:178-180. 
 
Hirschfeld RM, Williams JB, Spitzer RL, Calabrese JR, Flynn L, Keck PE, Jr., Lewis L, McElroy SL, 
Post RM, Rapport DJ, Russell JM, Sachs GS, Zajecka J (2000) Development and validation of 
a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am J 
Psychiatry 157:1873-1875. 
 
Jacob, T., Seilhamer, R. A., Bargeil, K., & Howell, D. N. (2006). Reliability of lifetime drinking history 
among alcohol dependent men. Psychology of addictive behaviors, 20(3), 333. 
 
Johanson CE, Uhlenhuth EH (1980) Drug preference and mood in humans: d-amphetamine. 
Psychopharmacology (Berl) 71:275-279. 
 
Kessler RC, Crum RM, Warner LA, Nelson CB, Schulenberg J, Anthony JC (1997) Lifetime Co-
occurrence of DSM-III-R Alcohol Abuse and Dependence With Other Psychiatric Disorders in 
the National Comorbidity Survey. Arch Gen Psychiatry 54:313-321. 
 
McNair D, Lorr M, Dropperman L (1971) Manual for profile of mood states. San Diego: Educational 
and industrial testing services. 
 
Raven J, Court J, Raven J (1998) Raven's progressive matrices. Oxford: Oxford Psychologists Press. 


 
Regier D, Farmer M, Rae D, Locke B, Keith S, Judd L, Goodwin F (1990) Comorbidity of mental 
disorders with alcohol and other drug abuse. JAMA 264:2511-2518. 
 
Rock PL, Goodwin GM, Harmer CJ (2010) The common adolescent bipolar phenotype shows positive 
biases in emotional processing. Bipolar disorders 12:606-615. 
 
Rush, A. J., Trivedi, M. H., Ibrahim, H. M., Carmody, T. J., Arnow, B., Klein, D. N., Markowitz, J. C., 
Ninan, P. T., Kornstein, S., Manber, R., Thase, M. E., Kocsis, J. H., & Keller, M. B. (2003). The 
16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and 
self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. 
Biological psychiatry, 54(5), 573-583. 
 
Sobell, L. C., & Sobell, M. B. (1992). Timeline follow-back. In Measuring alcohol consumption (pp. 41-
72). Humana Press. 
 
Trost, S., Diekhof, E. K., Mohr, H., Vieker, H., Krämer, B., Wolf, C., Keil, M., Dechant, P., Binder, 
E.B., & Gruber, O. (2016). Investigating the Impact of a Genome-Wide Supported Bipolar Risk 
Variant of MAD1L1 on the Human Reward System.Neuropsychopharmacology. 
 
Weafer J, Burkhardt A, de Wit H (2014) Sweet taste liking is associated with impulsive behaviors in 
humans. Front Behav Neurosci 8:228. 
 
Wechsler, D., & Hsiao-pin, C. (2011). WASI-II: Wechsler abbreviated scale of intelligence. Pearson. 
 
White TL, Justice AJ, de Wit H (2002) Differential subjective effects of D-amphetamine by gender, 
hormone levels and menstrual cycle phase. Pharmacol Biochem Behav 73:729-741. 
 
Yip SW, Doherty J, Wakeley J, Saunders K, Tzagarakis C, de Wit H, Goodwin GM, Rogers RD 
(2012) Reduced subjective response to acute ethanol administration among young men with a 
broad bipolar phenotype. Neuropsychopharmacology 37:1808-1815.