Effects of Buprenorphine on Responses to Emotional Stimuli in Individuals with a Range of Mood Symptomatology

Effects of Buprenorphine on Responses to Emotional Stimuli in Individuals with a Range of Mood... Background: The opioid drug buprenorphine has been shown to modify responses to emotional stimuli and may have antidepressant properties. In preclinical studies, it shows antidepressant-like and anxiolytic-like effects, and a handful of clinical studies suggest it may reduce symptoms of depression in patients. We have shown that low doses of buprenorphine reduce responses to negative emotional stimuli in healthy adults. Here we extended these findings to individuals with symptoms of depression and anxiety. Methods: We examined the effects of buprenorphine on attention to emotional facial expressions and ratings of and psychophysiological responses to emotional images in adults with a range of mood symptomatology. Volunteers (n = 38) were recruited with low, mild, moderate, and severe scores on the Depression-Anxiety-Stress Scale. They attended 2 laboratory sessions during which they received either placebo or 0.2 mg sublingual buprenorphine in randomized order under double- blind conditions. During peak drug effect, participants completed a visual attention task assessing responses to emotional faces and a picture-rating task assessing responses to emotional images with and without social content. Results: Buprenorphine reduced attention to fearful facial expressions as it did in our previous study, and the emotion-specific effect was especially pronounced in individuals with high Depression-Anxiety-Stress Scale scores. The drug also increased ratings of positivity of images with social content, but this effect was less strong in individuals with higher Depression- Anxiety-Stress Scale scores. Conclusions: These results suggest low doses of buprenorphine may reduce some dimensions of responses to negative emotional stimuli in individuals high on depression or anxiety, while leaving other dimensions unaffected. Keywords: buprenorphine, opioids, depression, anxiety, psychophysiology Introduction Buprenorphine, a mu-opioid partial agonist and kappa antagon- (Falcon et al., 2014 , 2016). Early studies suggested that buprenor - ist, has received attention recently for its possible role as a mood phine might be effective as an antidepressant in patients with regulator. In preclinical studies with rodents, buprenorphine treatment-resistant depression disorders (e.g.,Emric h et  al., shows antidepressant-like and anxiolytic-like effects on the 1982; Bodkin et al., 1995 ). In patients treated for opioid depend - forced swim test and novelty-induced hypophagia paradigms ence, Kosten et al. (1990) noted that buprenorphine significantly Received: June 1, 2017; Revised: July 13, 2017; Accepted: August 31, 2017 © The Author(s) 2017. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 120 provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/120/4102059 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Bershad et al. | 121 Significance Statement This study investigates the effects of a potential opioid antidepressant medication, buprenorphine, on responses to emotional stimuli in adults with a range of mood symptomatology. It is the first study to assess the effects of this drug on emotion pr - o cessing in this study population in a controlled laboratory setting, and it lays the foundation for future investigations of novel opioid-based therapies for disorders of emotion processing. reduced symptoms in depressed opioid dependent patients. consciously be perceived, and such images can evoke responses Extending these findings beyond opioid users, Bodkin et al. (1995) in the zygomatic and corrugator muscles ( Dimberg et al., 2000). reported notable improvement in non-drug-abusing patients This suggests that these physiological indices may be more sen - with refractory depression after just a single week of treatment sitive measures of emotional responses than self-report indices. with buprenorphine. Several more recent reports support the Finally, another important component of emotional respond - efficacy of opioids in treating depression and anxiety ( Nyhuis ing is immediate visual attention to stimuli with positive or et al., 2008 ; Norelli et al., 2013 ; Karp et al., 2014 ; Schatzberg, 2015 ; negative content ( McCabe et al., 2000 ). Attention to emotionally Yovell et al., 2015 ; Kosten, 2016). For example, Yovell et al. (2015) valenced stimuli can be objectively assessed using EOG and a found that low doses of buprenorphine reduced suicide idea - visual probe task (Wardle et  al., 2012 ), measuring initial gazes tion in suicidal adults, and Norelli et al. (2013) reported 6 cases toward faces expressing negative and positive emotions vs neu - in which buprenorphine reduced nonsuicidal self-injury.Karp tral faces. Together, these psychophysiological metrics augment et al. (2014) conducted an open label study with buprenorphine self-report indices in human laboratory studies and provide a (mean dose 0.4 mg/d), in which adults with treatment-resistant more complete picture the effects of buprenorphine on reactiv - depression reported a sharp decline in depressive symptoms. ity to affective stimuli. Finally, Sullivan (2016) has noted that because depression is a risk factor for initiation and maintenance of opioid use, the Methods drug may be used in part to self-medicate depression. Thus, buprenorphine may have a role in treating mood disorders. Yet, Study Design the emotional processes by which it has a therapeutic effect are not known. This study used a 2-session, within-subjects, double-blind Several controlled laboratory studies have investigated the design in which young adults with a range of scores on a psy - effects of buprenorphine on emotion processing in healthy vol - chiatric rating scale received either buprenorphine (0.2  mg unteers. For example, buprenorphine reduces the ability to rec - sublingual) or placebo in randomized order during two 4-hour ognize fearful faces ( Ipser et al., 2013 ) and enhances memory for laboratory sessions. Outcome measures included ratings of postively valenced emotional stimuli ( Syal et al., 2015 ). Further, mood states and emotional images with social or nonsocial con - we have recently shown that buprenorphine reduces responses tent, psychophysiological responses to emotional images, and to both psychosocial stress Bershad et  ( al., 2014 ) and other types visual attention to emotional faces. of negative affective stimuli ( Bershad et  al., 2016 ). These tasks shed light on how drugs produce antidepressant effects: drugs Participants with known antidepressant efficacy such as serotonin reuptake inhibitors (SSRIs) modulate responses to emotional stimuli Healthy volunteers (n = 38) aged 18 to 40  years were recruited on these and related tasks ( Harmer et  al, 2003). Notably, these from the University of Chicago and surrounding area. We effects with SSRIs are evident even after a single dose, predat - recruited participants with low, mild, moderate, and high scores ing and predicting their therapeutic effectiveness after several on the Depression Anxiety Stress Scale (DASS-21; Lovibond and weeks of treatment (Harmer et  al., 2003). In the present study, Lovibond, 1995; see below). At a preliminary screening session, we extended our previous findings with buprenorphine by participants underwent a physical and psychiatric screening, examining its effects on emotion processing in individuals with which included an in-person psychiatric interview and detailed symptoms of depression. We recruited non-treatment-seeking drug use history questionnaire, electrocardiogram, and com - volunteers who reported low to high symptoms of depression pletion of the DASS-21. Exclusion criteria included Major Axis and anxiety and studied their responses to a single dose of I  psychiatric disorders, including Major Depression (DSM 2015; buprenorphine (0.2 mg) or placebo on emotion-processing tasks. APA 2013), serious medical condition, history of cardiac or liver We hypothesized that buprenorphine would dampen reactiv- disease, current or past substance abuse, individuals using any ity to negative emotional stimuli and that this effect would be contraindicated medications, and individuals with a previous most pronounced in individuals reporting the most severe mood negative reaction to buprenorphine. Women who were preg - symptoms. nant, planning to become pregnant, or lactating were excluded. In addition to obtaining subjective reports of “feeling states” Inclusion criteria were: a fluency in English, a high school edu - and performance on behavioral tasks, we also collected object - cation, and BMI between 19 and 30 kg/m . ive measures of emotional reactivity using psychophysiological indices of facial electromyography (EMG) and electrooculogr - a Study Drug phy (EOG) ( Blascovich et  al., 2011 ). Facial EMG is based on the fact that the zygomaticus major (zygomatic, “smile”) muscle is At each session, participants received 2 sublingual tablets, either activated by pleasant stimuli, while the corrugator supercilii (cor- a drug and a placebo tablet or 2 placebo tablets. In the drug con - rugator, “frown”) muscle is reciprocally deactivated by positive dition, they received 0.2 mg buprenorphine (Temgesic, Indivior) stimuli and activated by negative stimuli ( Larsen et  al., 2003 ). and a physically similar placebo (Splenda sucralose tablet), and EMG is sensitive even to images that are presented too quickly to in the placebo condition they received 2 placebo tablets. The Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/120/4102059 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 122 | International Journal of Neuropsychopharmacology, 2018 tablets were identical in size and shape, and the placebo ta - b 2012. Two different sets of these images matched for valence let helped to mask taste cues in the drug condition. The drugs and arousal were prepared, one for each session, to minimize were administered in counterbalanced order at 2 sessions under habituation across sessions. Social stimuli depicted 2 people double-blind conditions. Buprenorphine is a mu-opioid partial or parts of people interacting, whereas nonsocial stimuli con - agonist and kappa-opioid antagonist that is used to treat mod - tained no images of people or parts of people. Thus, each set erate to severe pain and opioid dependence. Notably, the dose consisted of 6 subsets: social/negative, social/neutral, social/ used in this study was less than one-twentieth that used in opi - positive, nonsocial/negative, nonsocial/neutral, and nonso - oid replacement therapy. This dose has been shown to improve cial/positive. Further, each subset contained 9 images, 3 each memory for social reward (Syal et al., 2015 ), reduce recognition of mild, moderate, and extreme intensity. Images were pre- of fear (Ipser et  al., 2013), and reduce attention bias to emo - sented using E-Prime 2.0 software (Psychology Software Tools) tive faces and responses to emotional images (Bershad et  al., in randomized order with no more than 2 pictures of consist - 2016) without producing appreciable subjective effects or nau - ent valence appearing consecutively. Each image presentation sea. In our previous study (Bershad et  al., 2014 ), a higher dose began with a 3-second fixation cross and a 6-second presenta- of buprenorphine (0.4  mg) produced significant nausea in the tion followed by a 3-second fixation mark. Subjects rated each majority of participants. Peak plasma concentrations of the drug image immediately after its presentation using an evaluative occur 90 to 360 minutes after ingestion ( Mendelson et al., 1997 ). space grid (Larsen et  al., 2009), which allowed for independ- ent evaluations of emotional valence in both positive and negative dimensions (“0”: not at all; “4” extreme). Emotional Session Procedures reactivity to images was determined through EMG of corrug - a Orientation tor and zygomatic musculature. EMG measures of facial mus - During a 1-hour orientation session, participants were pr -o cle activity (corrugator and zygomatic muscles) are indicative vided with information about the study and gave informed of affective responses to emotional stimuli and can provide a consent. The study was approved by the University of Chicago more objective measure of emotional reactivity than subject - Institutional Review Board. Participants were told the goal of ive reports alone ( Dimberg et al., 2000). Highly positive stimuli the study was to examine the effects of drugs on mood, per - increase activity in the zygomatic, or “smile” muscle, and relax ceptions, and behavior. To minimize expectancy effects, they the corrugator (“frown”) muscle. Negative stimuli activate the were informed that they could receive a stimulant drug such as corrugator muscle. EMG was measured with 4  mm Ag/AgCl amphetamine, a sedative drug such as valium, an opioid such as electrodes precisely placed on the cheek and left brow. An buprenorphine, or placebo. 8-mm Ag/AgCl ground sensor was placed on the subject’s for- e head. Signals were amplified, filtered through a 10- to 500-Hz Study Sessions band pass, digitized, refiltered, rectified, and then integrated Participants completed two 4-hour sessions from 1:00 pm to 5:00 over 20 milliseconds using EMG100C amplifiers, an MP150 Data pm. The sessions were separated by at least 2  days and were Acquisition System, and Acqknowledge software from Biopac conducted in a comfortably furnished room containing chairs, Systems (Goleta). a desk, computer, a television, video player, and reading materi - als. During the sessions, the participants were allowed to watch Attention Bias Task (ABT) movies, read, or relax when not completing study question - The ABT was adapted from Garner et al. (2006) . Participants were naires or tasks. Subjects were asked to abstain from drugs and shown pairs of faces, one on each side of the screen. Each pair alcohol for 48 hours before each session, and compliance was contained one neutral face and one emotional expression face verified at the start of each session with a urine drug (ToxCup, using the same actor. The emotional expressions were collected Branan Medical Corporation) and breathalyzer tests (Alco- from the standardized Karolinska set Goele ( ven et  al., 2008 ). sensorIII, Intoximeters). Women were also tested for pregnancy Each face pair presentation consisted of a 1-second pre-pic - before each session (AimStickPBD, hCG professional, Craig ture fixation, then a 2-second picture presentation. To distract Medical Distribution). After these tests, participants completed the participants from the purpose of the task, a probe (either a baseline measures for their mood and cardiovascular state (see square or a circle) was presented following the 2-second onset below for mood and cardiovascular measures). At 1:30 pm, par- of the face pair, and the participants were asked to indicate ticipants took 2 sublingual tablets, either 0.2  mg of buprenor - whether the shape presented was a square by pressing one key - phine and placebo or 2 placebo tablets. Participants then relaxed board key or if it was a circle by pressing a different key. After a for 1 hour, and subjective and cardiovascular measures were response, or 10 seconds elapsed, an intertrial interval of 750 to collected again at 2:00 pm and 2:30 pm. At 2:45 pm, psychophysio - 1250 milliseconds began, followed by another trial. EOGs were logical sensors were placed to collect electromyographic data, used to quantify which face was initially fixated on in each trial. and participants completed the emotional images task and EOGs were collected using a 4-mm silver/silver chloride elec - attentional bias task in randomized order. At 4:00 pm, the psy- trode attached 1.5 cm from the outer canthus of each eye. The chophysiological sensors were removed and subjective and car - application and data collection process was the same as the diovascular measures were re-assessed at 4:30 pm and 5:00 pm. EMG application and collection detailed above. Trained, blinded Participants then completed an end of session questionnaire scorers discarded trials in which the gaze was not centrally fixed and left the laboratory at 5:15 pm. prior to the trial, initial fixation was <100 milliseconds after pic - ture onset, or noise obscured eye movements. Behavioral Tasks Cardiovascular Measures Emotional Images Task Heart rate and blood pressure were monitored with portable Positive, negative, and neutral emotional images with and with - monitors (Omron 10 Plus, Omron Healthcare) 5 times dur - out social content were taken from the International Affective ing the session (-15, 30, 60, 180, and 240 minutes post drug Picture System (Lang et al., 1999 ), as described in Wardle et al., Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/120/4102059 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Bershad et al. | 123 administration). Mean arterial pressure was calculated using did not differ on any demographic or substance use character - the formula: (systolic BP+2 x diastolic BP)/3. istics (Table 2). Subjective Questionnaires Subjective and Physiological Effects of Buprenorphine DASS The DASS-21 (Lovibond and Lovibond, 1995) is a reliable 21-item Buprenorphine slightly increased ratings of “feel drug” Figur ( e 1: questionnaire that provides an assessment of negative affect 2 time x drug F[4,132] = 3.4, P < .05, ηρ = 0.09; peak at 180 minutes), along 3 dimensions: depression, anxiety, and stress, experienced 2 “like drug” (time x drug F[4,132] = 5.2, P < .001, ηρ   =  0.14; peak over the prior week. Each question is scored from 0 to 3, with at 180 minutes), and “want more” (time x drug F[4,132] = 3.0, higher scores indicating more symptoms. We recruited subjects 2 P < .05, ηρ   =  0.08; peak at 180 minutes). Buprenorphine did with a range of scores on this questionnaire. Scores on the DASS not significantly affect ratings of “feel high,” or “dislike drug.” are categorized based on responses on the subscales ( Table  1; Buprenorphine did not exert significant effects on heart rate or Lovibond and Lovibond, 1995). Thus, low or normal scores are 0 to blood pressure. DASS scores did not significantly predict sub - 9 on the depression subscale, 0 to 7 on the anxiety subscale, and 0 jective drug responses. to 14 on the stress scale; mild scores are 10 to 13 on depression or 8 to 9 on anxiety or 15 to 18 on the stress scale; moderate scores are 14 to 20 on depression or 10 to 14 on anxiety or 19 to 25 on the Table 2. Demographic and Lifetime Nonmedical Drug Use Based on stress scale; and severe scores are 21 to 27 on depression or 15 to DASS Scores (n = 38) 19 on anxiety or 26 to 33 on the stress scale. We used this group - Mean (SEM) or Percent (n) ing strategy to recruit subjects with a wide range of scores, but on most measures during data analysis we treated DASS scores Category Normal Mild Moderate Severe as a continuous variable. Because the scores on the 3 dimensions (n = 9) (n = 8) (n = 10) (n = 11) (depression, anxiety, and stress) were highly correlated, we used Gender the sum for the entire DASS for each subject. Male/female 3/6 3/5 4/6 5/6 Age 25.26 (3.87) 21.75 (5.55) 25.00 (6.67) 22.63 (3.20) Drug Effects Questionnaire (DEQ) Education 16.44 (2.60) 14.25 (0.71) 15.00 (1.41) 15.09 (1.04) The DEQ consists of 6 questions on a visual analog scale assess - BMI 24.73 (4.22) 23.03 (2.85) 24.73 (2.92) 23.63 (2.87) ing subjective drug effects. Subjects were asked to rate the Depression 1.44 (1.13) 5.75 (1.39) 7.30 (2.16) 12.10 (3.62) extent they felt a drug effect, whether they liked or disliked the Anxiety 0.67 (0.50) 3.13 (1.89) 3.10 (2.64) 5.27 (5.10) drug effect, if they felt high, and if given a choice, would they Stress 2.56 (2.70) 5.25 (3.33) 6.70 (3.77) 8.00 (4.76) want more of the drug. Race Caucasian 44.4% (4) 37.5% (3) 50.0% (5) 72.7% (8) African-American 22.2% (2) 12.5% (1) 30.0% (3) 27.3% (3) Statistical Analysis Asian 11.1% (1) 0.0% (0) 10.0% (1) 0.0% (0) Analyses were conducted using SPSS version 16.0 for Windows. Other 22.2% (2) 50.0% (4) 10.0% (1) 0.0% (0) Missing cases (due to equipment malfunction or other data col - Lifetime drug use lection problems) were deleted list wise, which led to smaller Marijuana 55.5% (5) 75.0% (6) 60.0% (6) 90.9% (10) Opiates 11.1% (1) 12.5% (1) 0.0% (0) 18.2% (2) sample sizes for some analyses. To verify that the 4 groups (nor - MDMA 22.2% (2) 12.5% (1) 20.0% (2) 18.2% (2) mal, mild, moderate, severe) were matched, we compared demo - Hallucinogens 22.2% (2) 62.5% (5) 30.0% (3) 45.5% (5) graphic information and baseline measures between the groups Stimulants 22.2% (2) 25.0% (2) 10.0% (1) 54.5% (6) using a 1-way analysis of variance (ANOVA) and chi-squared tests Sedatives 22.2% (2) 0.0% (0) 10.0% (1) 18.2% (2) where appropriate (Table  2). Subjective effects of the drug were assessed using a 2-way ANOVA, with dose and time as within- The groups did not differ on any measure except for DASS-21 scores. subject factors and DASS score as a covariate. The ABT and Emotional Images Task were analyzed with mixed ANOVAs, with dose and valence as within-subject factors and DASS group as a covariate. Significant main effects and interactions were followed with posthoc t tests. Values < P = .05 were considered significant. Results Participant Characteristics Participants were mostly Caucasian (53%) with a mean age of 24 years and an average of 15 years education. The DASS groups Table 1. DASS Scoring and Groups Depression Anxiety Stress Normal 0–9 0–7 0–14 Mild 10–13 8–9 15–18 Figure  1. Mean (± SEM) ratings of “feel drug” throughout the sessions during Moderate 14–20 10–14 19–25 placebo sessions (circles, dotted line) and after buprenorphine (0.2 mg; squares, Severe 21–27 15–19 26–33 dashed line). Shaded area indicates the time during which the tasks took place. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/120/4102059 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 124 | International Journal of Neuropsychopharmacology, 2018 that buprenorphine most dramatically reduced first gazes ABT toward fearful faces in these individuals ( Figure 3; type x drug Buprenorphine slightly decreased the number of first gazes 2 x DASS score F[3,96] = 4.1, P < .01, ηρ = 0.11; fear vs happy, P < .01). toward emotive faces overall (drug F[1,32] = 8.0, P < .01, ηρ = 0.20), but this effect was most pronounced for first gazes toward Emotional Images Task fearful expressions compared with other emotions (type x drug F[3,96] = 4.8, P < .05, ηρ = 0.09; fear vs happy P < .05). Strikingly, Data from 2 subjects were excluded because of equipment mal- the effects of buprenorphine on visual orienting toward emo - function during the task, and from one subject because they tional faces were strongest in individuals with high DASS scores did not complete the task as directed. The task produced its (Figure 2; drug x DASS score F[1,32] = 8.6, P < .01, ηρ = 0.21) such expected effects on affective ratings and corrugator reactivity as measured by facial EMG. That is, subjects rated positive images more positively and negative images more negatively than neu- tral images (valence F[2,34] = 33.5, P < .001; ηρ = 0.67; positive > neutral P < .001, negative < neutral P < .001). Corrugator activity increased with responses to negative images compared with neutral ones (valence F[2,34] = 3.8, P < .05; ηρ = 0.18; negative > neutral P < .01). As we previously showed, buprenorphine selectively enhanced positivity ratings of images with social content (Figure 4; Drug x social F[1,34] = 8.4, P < .01; ηρ = 0.20; social > nonsocial on buprenorphine: P = .06). This effect was slightly less pronounced in individuals with higher DASS scores (drug x social x DASS score F[1,34] = 10.3, P < .01; ηρ = 0.23). Neither buprenorphine nor DASS score affected corrugator or zygomatic responses to emotional images. Drug Identifications After receiving the dose of buprenorphine, 4 participants cor - Figure  2. Number of initial gazes toward fearful faces for individual subjects rectly guessed they had received an opioid drug. Of the remain - after buprenorphine minus placebo, as a function of total DASS score. Dashed ing participants, 23 guessed they had received a sedative, 5 line signifies no difference between buprenorphine and placebo sessions, solid guessed they had received a stimulant, and 6 guessed placebo. line indicates correlation ( r=-0.6, p<0.001). Figure 3. Mean (± SEM) number of initial gazes after placebo and buprenorphine (0.2 mg) toward faces depicting fear, anger, sadness, and happiness, separated by DASS scores (Low N=9; Mild N=8, Moderate N=10, Severe N=11). DASS score was treated as a continuous variable for statistical analyses. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/120/4102059 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Bershad et al. | 125 Another, somewhat surprising, result of this study was that individuals with high DASS scores do not respond as strongly to the enhancing effects of buprenorphine on positivity ratings of social images. We and others have reported that low doses of buprenorphine not only reduce responses to negative stim - uli but also enhance reactivity to positive stimuli ( Syal et  al., 2015; Bershad et  al., 2016). This is consistent with studies in nonhuman animals that suggest that opioids are involved in socially rewarding activities such as play behavior ( Panksepp et  al., 1985 ; Vanderschuren et  al., 1995a , 1995b; Trezza et  al., 2010). The fact that buprenorphine did not enhance positive responses more strongly in individuals with high DASS scores was unexpected, given that some other antidepressants acutely increase responses to positive stimuli ( Harmer et al., 2003 , 2009). It remains to be determined which behavioral responses are critical to predicting antidepressant effectiveness, dampening responses to negative stimuli, or enhancing responses to posi - tive stimuli (Pizzagalli, 2014 ). One question raised by this study is what is the optimal Figure  4. Mean (± SEM) difference scores (buprenorphine minus placebo) on selection of participants to study potential antidepressant positivity ratings of images with and without social content for all subjects effects. Our first study used healthy asymptomatic volunteers together. The DASS groups did not differ on this measure. (Bershad et  al., 2016 ), while this study used participants with a range of scores on the DASS, which included symptoms of During the placebo session, 20 participants correctly guessed both anxiety and depression. While anxiety and depression are placebo, 2 guessed an opioid drug, 10 guessed a sedative, and 6 classified as separate disorders, there is a great deal of overlap guessed they had received a stimulant. The drug identifications between the two Lo ( vibond and Lovibond, 1995), and the opi- were not related to DASS scores. oid system seems to be involved in both anxiety and depressed mood. For example, individuals high on either depression or anxiety exhibit heightened reactivity to negative facial expr -es Discussion sions (Warren et  al., 2015). Furthermore, the opioid system In this study, we aimed to assess the effects of buprenorphine seems to be involved in both anxiety and depression-related on behavioral and subjective responses to emotional stimuli in processes. A polymorphism in the opioid receptor ( OPRM1) that volunteers with a range of mood symptoms, from low to high. results in reduced mu-opioid signaling both increases the like - Extending our previous findings with nonsymptomatic volun - lihood of developing depression following social rejection and teers, we found that buprenorphine reduced initial orienting also alters anxiety-like responses to various stressors ( Chong toward fearful facial expressions and increased ratings of posi - et al., 2005 ; Slavich et al., 2014 ). Thus, our results and those from tivity of images with social content. Importantly, both these other groups suggest that the opioid system is involved in neg -a effects were more pronounced in individuals with high depres - tive affective responses broadly, beyond the boundaries of a spe - sion and anxiety scores. Additionally, we replicated our earlier cific DSM disorder. In the present study, we had the capability to finding that buprenorphine increased ratings of positivity of investigate separate contributions of symptoms of either anx - images with social content. On this measure, however, individu - iety or depression, using the DASS scales. However, the partici - als with higher DASS scores seemed to be less sensitive to the pants scores on all 3 scales were highly correlated ( r = 0.4–0.8), effect. It is notable that we detected these behavioral effects and so we used a total DASS score for the analyses. A future - dir of buprenorphine on emotional reactivity at a very low dose, a ection of this work will be to examine the effects of buprenor - dose that did not increase ratings of euphoria or “feel high.” phine in more severely symptomatic individuals, such as those The main result of this study is that buprenorphine reduces with a clinical diagnosis of a DSM-V mood disorder. attention to fearful faces most strongly in individuals with It is not yet clear how buprenorphine’s mechanism of action high scores on the DASS. This finding provides further support contributes to its effects on emotion processing. Two recent for the idea that the drug may have antidepressant properties. studies attempted to create a functional kappa antagonist by The profile of effects resembles the effects of single doses of combining buprenorphine with a mu opioid antagonist, assess- standard SSRI antidepressant drugs, which decrease recogni - ing its effects in patients with major depression who had not tion of fearful facial expressions in individuals with depression responded to previous antidepressant medications (Ehrich (Bhagwagar et al., 2004 ) and reduce amygdala responses to such et al., 2015 ; Fava et al., 2016 ). In both studies, patients exhibited faces (Murphy et  al., 2009). Although the therapeutic effects of improved outcome on 3 standard clinical measures of depres- SSRIs take weeks to develop, single doses of these drugs produce sion, suggesting pure kappa antagonism may be sufficient to behavioral effects on tasks such as those used here, and these reduce negative mood, even in the absence of mu effects. Other acute effects are predictive of the therapeutic effectiveness that studies, however, have suggested that it is a combination of develops weeks later (Warren et  al., 2015 ). To the extent that mu and kappa mechanisms that make buprenorphine effect - the effects of buprenorphine resembled the effects of a known ive (Lutz and Kieffer, 2013a, 2013b), and there is a long history antidepressant, our findings with buprenorphine suggest that of using mu-agonists in the treatment of depression before it may have similar therapeutic effects. Our findings are also in the development of SSRIs (Emrich et  al., 1982). Although both line with results from rodent models showing that the effects receptor systems seem to be involved in mediating emotional of buprenorphine on time to immobility in the forced swim test responses, the relative contributions of the MOR and KOR resemble those of standard SSRIs ( Falcon et al., 2014 ). actions in the antidepressant effect of buprenorphine remain to Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/120/4102059 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 126 | International Journal of Neuropsychopharmacology, 2018 be determined (Sher, 1998; Ehrich et al., 2015 ; Balon, 2016; Fava in subjects with a previous history of depression. Am J Psych - et al., 2016 ; Li et al., 2016 ). iatry 161:166–168. A few limitations warrant consideration. While the stimuli in Blascovich J, Vanman E, Mendes WB, Dickerson S (2011) Social controlled laboratory studies like the one described here are mod - psychophysiology for social and personality psychology. Sage eled after real-world social encounters, they are not as salient or Publications. immersive as a real-world experience might be. Images of emo - Bodkin JA, Zornberg GL, Lukas SE, Cole JO (1995) Buprenorphine tional faces allow us to isolate dimensions of behavior we might treatment of refractory depression. J Clinical Psychopharma - not otherwise be able to (e.g., visual attention), but they lack the col 15:49–57. intensity of actual social interaction. Furthermore, we tested only Chong RY, Oswald L, Yang X, Uhart M, Lin P-I, Wand GS (2005) a single dose of buprenorphine, and it may be the case that mul - The mu-opioid receptor polymorphism A118G predicts corti - tiple different doses exert different effects on socio-emotional sol responses to naloxone and stress. Neuropsychopharma - processing. While there are limitations to the study presented cology 31:204–211. here, it provides further evidence in support of the effectiveness Dimberg U, Thunberg M, Elmehed K (2000) Unconscious facial of buprenorphine in dampening responses to negative emotional reactions to emotional facial expressions. Psychol Sci 11:86– stimuli in individuals with mood symptomatology. 89. In summary, in this study we tested the effects of buprenor - Ehrich E, Turncliff R, Du Y, Leigh-Pemberton R, Fernandez E, phine on responses to 2 emotion-processing tasks in individu- Jones R, Fava M (2015) Evaluation of opioid modulation als with low to high anxiety and depression symptoms. We in major depressive disorder. Neuropsychopharmacology replicated our previous findings, showing that buprenorphine 40:1448–1455. reduces attention to fearful faces and enhances ratings of posi - Emrich H, Vogt P, Herz A, Kissling W (1982) Antidepressant effects tivity of images with social content. Further, we found that indi - of buprenorphine. Lancet 320:709. viduals with high DASS scores exhibited a more pronounced Falcon E, Maier K, Robinson SA, Hill-Smith TE, Lucki I (2014) buprenorphine-induced decrease in attention to fearful faces. Effects of buprenorphine on behavioral tests for antidepres - Individuals with greater mood symptomology also exhibited less sant and anxiolytic drugs in mice. Psychopharmacology:1–9. response to buprenorphine on ratings of social images, suggest - Falcon E, Browne CA, Leon RM, Fleites VC, Sweeney R, Kirby LG, ing that while the drug may act to reduce responses to negative Lucki I (2016) Antidepressant-like effects of buprenorphine emotional stimuli in clinical populations, it may not be as effect - are mediated by kappa opioid receptors. Neuropsychophar - ive at increasing positive emotional responses. Antidepressant macology 41: 2344–2352. effects could result from both decreases in negative affect - Fava M, Memisoglu A, Thase ME, Bodkin JA, Trivedi MH, de Somer ive responses, or increases in positive affective responses. It M, Du Y, Leigh-Pemberton R, DiPetrillo L, Silverman B (2016) remains to be determined which of these, and which measures Opioid modulation with buprenorphine/samidorphan as of emotion processing, are most related to clinical response. adjunctive treatment for inadequate response to antidepres - sants: a randomized double-blind placebo-controlled trial. Am J Psychiatry 173:499–508. Funding Garner M, Mogg K, Bradley BP (2006) Orienting and maintenance of gaze to facial expressions in social anxiety. J Abnorm Psy - This work was supported by a grant from the National Institute on Drug Abuse (DA02812), and A.K.B. was supported by a training chol 115:760. Goeleven E, De Raedt R, Leyman L, Verschuere B (2008) The Karo- grant from the National Institute of General Medical Sciences (2T32GM007281). linska directed emotional faces: a validation study. Cogn Emot 22:1094–1118. Harmer C, Bhagwagar Z, Perrett D, Vollm B, Cowen P, Goodwin Acknowledgments G (2003) Acute SSRI administration affects the processing of social cues in healthy volunteers. Neuropsychopharmacol - We thank Dr. Royce Lee for his assistance in screening subjects ogy 28:148–152. for this study. Harmer C, O’Sullivan U, Favaron E, Massey-Chase R, Ayres R, Reinecke A, Goodwin G, Cowen P (2009) Effect of acute anti - Statement of Interest depressant administration on negative affective bias in The study drug was supplied by Indivior as an unrestricted, depressed patients. Am J Psychiatry 166:1178–1184. unsolicited grant of nonfinancial support. RBP had no role in Ipser JC, Terburg D, Syal S, Phillips N, Solms M, Panksepp J, Mal - study design; collection or analysis and interpretation of the colm-Smith S, Thomas K, Stein DJ, van Honk J (2013) Reduced data; in the writing of the manuscript; or in the decision to sub - fear-recognition sensitivity following acute buprenorphine mit the manuscript for publication. administration in healthy volunteers. Psychoneuroendocri - nology 38:166–170. Karp JF, Butters MA, Begley AE, Miller MD, Lenze EJ, Blumberger References DM, Mulsant BH, Reynolds C 3rd (2014) Safety, tolerability, Balon R (2016) Buprenorphine for the treatment of depression? and clinical effect of low-dose buprenorphine for treatment- Acta Psychiatr Scand 134:85–86. resistant depression in midlife and older adults. J Clin. Psyc -h Bershad AK, Jaffe JH, Childs E, de Wit H (2014) Opioid partial iatry 75:e785–793. agonist buprenorphine dampens responses to psychosocial Kosten TR (2016) An opioid for depression? Am J Psychiatry stress in humans. Psychoneuroendocrinology 52:281–288. 173:446–447. Bershad AK, Seiden JA, de Wit H (2016) Effects of buprenorphine Kosten TR, Morgan C, Kosten TA (1990) Depressive symptoms on responses to social stimuli in healthy adults. Psychoneu - during buprenorphine treatment of opioid abusers. J Subst roendocrinology 63:43–49. Abuse Treat 7:51–54. Bhagwagar Z, Cowen PJ, Goodwin GM, Harmer CJ (2004) Normal - Lang PJ, Bradley MM, Cuthbert BN (1999) International affective ization of enhanced fear recognition by acute SSRI treatment picture system (IAPS): technical manual and affective ratings. In: Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/120/4102059 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Bershad et al. | 127 Gainesville, FL: The Center for Research in Psychophysiology, Pizzagalli DA (2014) Depression, stress, and anhedonia: toward University of Florida. a synthesis and integrated model. Annu Rev Clin Psychol Larsen JT, Norris CJ, Cacioppo JT (2003) Effects of positive and 10:393––23. negative affect on electromyographic activity over zygo - Schatzberg AF (2015) Opioids in psychiatric disorders: back to maticus major and corrugator supercilii. Psychophysiology the future? Am. J. Psychiatry 173:564–565. 40:776–785. Sher L (1998) The role of the endogenous opioid system in the Larsen JT, Norris CJ, McGraw AP, Hawkley LC, Cacioppo JT (2009) pathogenesis of anxiety disorders. Medical Hypotheses The evaluative space grid: a single-item measure of positivity 50:473–474. and negativity. Cogn. Emot. 23:453–480. Slavich GM, Tartter MA, Brennan PA, Hammen C (2014) Endogen - Li W, Sun H, Chen H, Yang X, Xiao L, Liu R, Shao L, Qiu Z (2016) ous opioid system influences depressive reactions to socially Major depressive disorder and kappa opioid receptor antago - painful targeted rejection life events. Psychoneuroendocri - nists. Transl Perioper Pain Med 1:4. nology 49:141–149. Lovibond PF, Lovibond SH (1995) The structure of negative emo - Sullivan, MD (2016) Why does depression promote long-term tional states: comparison of the Depression Anxiety Stress opioid use? Pain 157:2395–2396. Scales (DASS) with the Beck Depression and Anxiety Invento - Syal S, Ipser J, Terburg D, Solms M, Panksepp J, Malcolm-Smith ries. Behav Res Ther 33:335–343. S, Bos PA, Montoya ER, Stein DJ, van Honk J (2015) Improved Lutz P-E, Kieffer BL (2013a) The multiple facets of opioid recep - memory for reward cues following acute buprenorphine tor function: implications for addiction. Curr Opin Neurobiol administration in humans. Psychoneuroendocrinology 23:473–479. 53:10–15. Lutz P-E, Kieffer BL (2013b) Opioid receptors: distinct roles in Trezza V, Baarendse PJ, Vanderschuren LJ (2010) The pleasures mood disorders. Trends Neurosci 36:195–206. of play: pharmacological insights into social reward mecha - McCabe SB, Gotlib IH, Martin RA (2000) Cognitive vulnerability nisms. Trends Pharmacol Sci 31:463–469. for depression: deployment of attention as a function of his - Vanderschuren LJ, Stein EA, Wiegant VM, Van Ree JM (1995a) tory of depression and current mood state. Cognit Ther Res Social play alters regional brain opioid receptor binding in 24:427–444. juvenile rats. Brain Res 680:148–156. Mendelson J, Upton RA, Everhart ET, Jones RT (1997) Bioavailabil - Vanderschuren LJ, Niesink RJ, Spruijt BM, Van Ree JM (1995b) ity of sublingual buprenorphine. J Clin Pharmacol 37:31–37. μ-and κ-opioid receptor-meiated opioid effects on social play Murphy SE, Norbury R, O’Sullivan U, Cowen PJ, Harmer CJ (2009) in juvenile rats. Eur J Pharmacol 276:257–266. Effect of a single dose of citalopram on amygdala response to Wardle MC, Garner MJ, Munafò MR, de Wit H (2012) Amphet - emotional faces. Br J Psychiatry 194:535–540. amine as a social drug: effects of d-amphetamine on Norelli LJ, Smith HS, Sher L, Blackwood TA (2013) Buprenorphine social processing and behavior. Psychopharmacology in the treatment of non-suicidal self-injury: a case series and 223:199–210. discussion of the literature. Int J Adolesc Med Health 25:323– Warren MB, Pringle A, Harmer CJ (2015) A neurocognitive model 330. for understanding treatment action in depression. Phil Trans Nyhuis PW, Gastpar M, Scherbaum N (2008) Opiate treatment in R Soc B 370:20140213. depression refractory to antidepressants and electroconvul - Yovell Y, Bar G, Mashiah M, Baruch Y, Briskman I, Asherov J, Lotan sive therapy. J Clin Psychopharmacol 28:593–595. A, Rigbi A, Panksepp J (2015) Ultra-low-dose buprenorphine as Panksepp J, Jalowiec J, DeEskinazi F, Bishop P (1985) Opiates and a time-limited treatment for severe suicidal ideation: a rand - play dominance in juvenile rats. Behav Neurosci 99:441. omized controlled trial. Am J Psychiatry 173:491–498. 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Effects of Buprenorphine on Responses to Emotional Stimuli in Individuals with a Range of Mood Symptomatology

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Abstract

Background: The opioid drug buprenorphine has been shown to modify responses to emotional stimuli and may have antidepressant properties. In preclinical studies, it shows antidepressant-like and anxiolytic-like effects, and a handful of clinical studies suggest it may reduce symptoms of depression in patients. We have shown that low doses of buprenorphine reduce responses to negative emotional stimuli in healthy adults. Here we extended these findings to individuals with symptoms of depression and anxiety. Methods: We examined the effects of buprenorphine on attention to emotional facial expressions and ratings of and psychophysiological responses to emotional images in adults with a range of mood symptomatology. Volunteers (n = 38) were recruited with low, mild, moderate, and severe scores on the Depression-Anxiety-Stress Scale. They attended 2 laboratory sessions during which they received either placebo or 0.2 mg sublingual buprenorphine in randomized order under double- blind conditions. During peak drug effect, participants completed a visual attention task assessing responses to emotional faces and a picture-rating task assessing responses to emotional images with and without social content. Results: Buprenorphine reduced attention to fearful facial expressions as it did in our previous study, and the emotion-specific effect was especially pronounced in individuals with high Depression-Anxiety-Stress Scale scores. The drug also increased ratings of positivity of images with social content, but this effect was less strong in individuals with higher Depression- Anxiety-Stress Scale scores. Conclusions: These results suggest low doses of buprenorphine may reduce some dimensions of responses to negative emotional stimuli in individuals high on depression or anxiety, while leaving other dimensions unaffected. Keywords: buprenorphine, opioids, depression, anxiety, psychophysiology Introduction Buprenorphine, a mu-opioid partial agonist and kappa antagon- (Falcon et al., 2014 , 2016). Early studies suggested that buprenor - ist, has received attention recently for its possible role as a mood phine might be effective as an antidepressant in patients with regulator. In preclinical studies with rodents, buprenorphine treatment-resistant depression disorders (e.g.,Emric h et  al., shows antidepressant-like and anxiolytic-like effects on the 1982; Bodkin et al., 1995 ). In patients treated for opioid depend - forced swim test and novelty-induced hypophagia paradigms ence, Kosten et al. (1990) noted that buprenorphine significantly Received: June 1, 2017; Revised: July 13, 2017; Accepted: August 31, 2017 © The Author(s) 2017. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 120 provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/120/4102059 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Bershad et al. | 121 Significance Statement This study investigates the effects of a potential opioid antidepressant medication, buprenorphine, on responses to emotional stimuli in adults with a range of mood symptomatology. It is the first study to assess the effects of this drug on emotion pr - o cessing in this study population in a controlled laboratory setting, and it lays the foundation for future investigations of novel opioid-based therapies for disorders of emotion processing. reduced symptoms in depressed opioid dependent patients. consciously be perceived, and such images can evoke responses Extending these findings beyond opioid users, Bodkin et al. (1995) in the zygomatic and corrugator muscles ( Dimberg et al., 2000). reported notable improvement in non-drug-abusing patients This suggests that these physiological indices may be more sen - with refractory depression after just a single week of treatment sitive measures of emotional responses than self-report indices. with buprenorphine. Several more recent reports support the Finally, another important component of emotional respond - efficacy of opioids in treating depression and anxiety ( Nyhuis ing is immediate visual attention to stimuli with positive or et al., 2008 ; Norelli et al., 2013 ; Karp et al., 2014 ; Schatzberg, 2015 ; negative content ( McCabe et al., 2000 ). Attention to emotionally Yovell et al., 2015 ; Kosten, 2016). For example, Yovell et al. (2015) valenced stimuli can be objectively assessed using EOG and a found that low doses of buprenorphine reduced suicide idea - visual probe task (Wardle et  al., 2012 ), measuring initial gazes tion in suicidal adults, and Norelli et al. (2013) reported 6 cases toward faces expressing negative and positive emotions vs neu - in which buprenorphine reduced nonsuicidal self-injury.Karp tral faces. Together, these psychophysiological metrics augment et al. (2014) conducted an open label study with buprenorphine self-report indices in human laboratory studies and provide a (mean dose 0.4 mg/d), in which adults with treatment-resistant more complete picture the effects of buprenorphine on reactiv - depression reported a sharp decline in depressive symptoms. ity to affective stimuli. Finally, Sullivan (2016) has noted that because depression is a risk factor for initiation and maintenance of opioid use, the Methods drug may be used in part to self-medicate depression. Thus, buprenorphine may have a role in treating mood disorders. Yet, Study Design the emotional processes by which it has a therapeutic effect are not known. This study used a 2-session, within-subjects, double-blind Several controlled laboratory studies have investigated the design in which young adults with a range of scores on a psy - effects of buprenorphine on emotion processing in healthy vol - chiatric rating scale received either buprenorphine (0.2  mg unteers. For example, buprenorphine reduces the ability to rec - sublingual) or placebo in randomized order during two 4-hour ognize fearful faces ( Ipser et al., 2013 ) and enhances memory for laboratory sessions. Outcome measures included ratings of postively valenced emotional stimuli ( Syal et al., 2015 ). Further, mood states and emotional images with social or nonsocial con - we have recently shown that buprenorphine reduces responses tent, psychophysiological responses to emotional images, and to both psychosocial stress Bershad et  ( al., 2014 ) and other types visual attention to emotional faces. of negative affective stimuli ( Bershad et  al., 2016 ). These tasks shed light on how drugs produce antidepressant effects: drugs Participants with known antidepressant efficacy such as serotonin reuptake inhibitors (SSRIs) modulate responses to emotional stimuli Healthy volunteers (n = 38) aged 18 to 40  years were recruited on these and related tasks ( Harmer et  al, 2003). Notably, these from the University of Chicago and surrounding area. We effects with SSRIs are evident even after a single dose, predat - recruited participants with low, mild, moderate, and high scores ing and predicting their therapeutic effectiveness after several on the Depression Anxiety Stress Scale (DASS-21; Lovibond and weeks of treatment (Harmer et  al., 2003). In the present study, Lovibond, 1995; see below). At a preliminary screening session, we extended our previous findings with buprenorphine by participants underwent a physical and psychiatric screening, examining its effects on emotion processing in individuals with which included an in-person psychiatric interview and detailed symptoms of depression. We recruited non-treatment-seeking drug use history questionnaire, electrocardiogram, and com - volunteers who reported low to high symptoms of depression pletion of the DASS-21. Exclusion criteria included Major Axis and anxiety and studied their responses to a single dose of I  psychiatric disorders, including Major Depression (DSM 2015; buprenorphine (0.2 mg) or placebo on emotion-processing tasks. APA 2013), serious medical condition, history of cardiac or liver We hypothesized that buprenorphine would dampen reactiv- disease, current or past substance abuse, individuals using any ity to negative emotional stimuli and that this effect would be contraindicated medications, and individuals with a previous most pronounced in individuals reporting the most severe mood negative reaction to buprenorphine. Women who were preg - symptoms. nant, planning to become pregnant, or lactating were excluded. In addition to obtaining subjective reports of “feeling states” Inclusion criteria were: a fluency in English, a high school edu - and performance on behavioral tasks, we also collected object - cation, and BMI between 19 and 30 kg/m . ive measures of emotional reactivity using psychophysiological indices of facial electromyography (EMG) and electrooculogr - a Study Drug phy (EOG) ( Blascovich et  al., 2011 ). Facial EMG is based on the fact that the zygomaticus major (zygomatic, “smile”) muscle is At each session, participants received 2 sublingual tablets, either activated by pleasant stimuli, while the corrugator supercilii (cor- a drug and a placebo tablet or 2 placebo tablets. In the drug con - rugator, “frown”) muscle is reciprocally deactivated by positive dition, they received 0.2 mg buprenorphine (Temgesic, Indivior) stimuli and activated by negative stimuli ( Larsen et  al., 2003 ). and a physically similar placebo (Splenda sucralose tablet), and EMG is sensitive even to images that are presented too quickly to in the placebo condition they received 2 placebo tablets. The Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/120/4102059 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 122 | International Journal of Neuropsychopharmacology, 2018 tablets were identical in size and shape, and the placebo ta - b 2012. Two different sets of these images matched for valence let helped to mask taste cues in the drug condition. The drugs and arousal were prepared, one for each session, to minimize were administered in counterbalanced order at 2 sessions under habituation across sessions. Social stimuli depicted 2 people double-blind conditions. Buprenorphine is a mu-opioid partial or parts of people interacting, whereas nonsocial stimuli con - agonist and kappa-opioid antagonist that is used to treat mod - tained no images of people or parts of people. Thus, each set erate to severe pain and opioid dependence. Notably, the dose consisted of 6 subsets: social/negative, social/neutral, social/ used in this study was less than one-twentieth that used in opi - positive, nonsocial/negative, nonsocial/neutral, and nonso - oid replacement therapy. This dose has been shown to improve cial/positive. Further, each subset contained 9 images, 3 each memory for social reward (Syal et al., 2015 ), reduce recognition of mild, moderate, and extreme intensity. Images were pre- of fear (Ipser et  al., 2013), and reduce attention bias to emo - sented using E-Prime 2.0 software (Psychology Software Tools) tive faces and responses to emotional images (Bershad et  al., in randomized order with no more than 2 pictures of consist - 2016) without producing appreciable subjective effects or nau - ent valence appearing consecutively. Each image presentation sea. In our previous study (Bershad et  al., 2014 ), a higher dose began with a 3-second fixation cross and a 6-second presenta- of buprenorphine (0.4  mg) produced significant nausea in the tion followed by a 3-second fixation mark. Subjects rated each majority of participants. Peak plasma concentrations of the drug image immediately after its presentation using an evaluative occur 90 to 360 minutes after ingestion ( Mendelson et al., 1997 ). space grid (Larsen et  al., 2009), which allowed for independ- ent evaluations of emotional valence in both positive and negative dimensions (“0”: not at all; “4” extreme). Emotional Session Procedures reactivity to images was determined through EMG of corrug - a Orientation tor and zygomatic musculature. EMG measures of facial mus - During a 1-hour orientation session, participants were pr -o cle activity (corrugator and zygomatic muscles) are indicative vided with information about the study and gave informed of affective responses to emotional stimuli and can provide a consent. The study was approved by the University of Chicago more objective measure of emotional reactivity than subject - Institutional Review Board. Participants were told the goal of ive reports alone ( Dimberg et al., 2000). Highly positive stimuli the study was to examine the effects of drugs on mood, per - increase activity in the zygomatic, or “smile” muscle, and relax ceptions, and behavior. To minimize expectancy effects, they the corrugator (“frown”) muscle. Negative stimuli activate the were informed that they could receive a stimulant drug such as corrugator muscle. EMG was measured with 4  mm Ag/AgCl amphetamine, a sedative drug such as valium, an opioid such as electrodes precisely placed on the cheek and left brow. An buprenorphine, or placebo. 8-mm Ag/AgCl ground sensor was placed on the subject’s for- e head. Signals were amplified, filtered through a 10- to 500-Hz Study Sessions band pass, digitized, refiltered, rectified, and then integrated Participants completed two 4-hour sessions from 1:00 pm to 5:00 over 20 milliseconds using EMG100C amplifiers, an MP150 Data pm. The sessions were separated by at least 2  days and were Acquisition System, and Acqknowledge software from Biopac conducted in a comfortably furnished room containing chairs, Systems (Goleta). a desk, computer, a television, video player, and reading materi - als. During the sessions, the participants were allowed to watch Attention Bias Task (ABT) movies, read, or relax when not completing study question - The ABT was adapted from Garner et al. (2006) . Participants were naires or tasks. Subjects were asked to abstain from drugs and shown pairs of faces, one on each side of the screen. Each pair alcohol for 48 hours before each session, and compliance was contained one neutral face and one emotional expression face verified at the start of each session with a urine drug (ToxCup, using the same actor. The emotional expressions were collected Branan Medical Corporation) and breathalyzer tests (Alco- from the standardized Karolinska set Goele ( ven et  al., 2008 ). sensorIII, Intoximeters). Women were also tested for pregnancy Each face pair presentation consisted of a 1-second pre-pic - before each session (AimStickPBD, hCG professional, Craig ture fixation, then a 2-second picture presentation. To distract Medical Distribution). After these tests, participants completed the participants from the purpose of the task, a probe (either a baseline measures for their mood and cardiovascular state (see square or a circle) was presented following the 2-second onset below for mood and cardiovascular measures). At 1:30 pm, par- of the face pair, and the participants were asked to indicate ticipants took 2 sublingual tablets, either 0.2  mg of buprenor - whether the shape presented was a square by pressing one key - phine and placebo or 2 placebo tablets. Participants then relaxed board key or if it was a circle by pressing a different key. After a for 1 hour, and subjective and cardiovascular measures were response, or 10 seconds elapsed, an intertrial interval of 750 to collected again at 2:00 pm and 2:30 pm. At 2:45 pm, psychophysio - 1250 milliseconds began, followed by another trial. EOGs were logical sensors were placed to collect electromyographic data, used to quantify which face was initially fixated on in each trial. and participants completed the emotional images task and EOGs were collected using a 4-mm silver/silver chloride elec - attentional bias task in randomized order. At 4:00 pm, the psy- trode attached 1.5 cm from the outer canthus of each eye. The chophysiological sensors were removed and subjective and car - application and data collection process was the same as the diovascular measures were re-assessed at 4:30 pm and 5:00 pm. EMG application and collection detailed above. Trained, blinded Participants then completed an end of session questionnaire scorers discarded trials in which the gaze was not centrally fixed and left the laboratory at 5:15 pm. prior to the trial, initial fixation was <100 milliseconds after pic - ture onset, or noise obscured eye movements. Behavioral Tasks Cardiovascular Measures Emotional Images Task Heart rate and blood pressure were monitored with portable Positive, negative, and neutral emotional images with and with - monitors (Omron 10 Plus, Omron Healthcare) 5 times dur - out social content were taken from the International Affective ing the session (-15, 30, 60, 180, and 240 minutes post drug Picture System (Lang et al., 1999 ), as described in Wardle et al., Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/120/4102059 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Bershad et al. | 123 administration). Mean arterial pressure was calculated using did not differ on any demographic or substance use character - the formula: (systolic BP+2 x diastolic BP)/3. istics (Table 2). Subjective Questionnaires Subjective and Physiological Effects of Buprenorphine DASS The DASS-21 (Lovibond and Lovibond, 1995) is a reliable 21-item Buprenorphine slightly increased ratings of “feel drug” Figur ( e 1: questionnaire that provides an assessment of negative affect 2 time x drug F[4,132] = 3.4, P < .05, ηρ = 0.09; peak at 180 minutes), along 3 dimensions: depression, anxiety, and stress, experienced 2 “like drug” (time x drug F[4,132] = 5.2, P < .001, ηρ   =  0.14; peak over the prior week. Each question is scored from 0 to 3, with at 180 minutes), and “want more” (time x drug F[4,132] = 3.0, higher scores indicating more symptoms. We recruited subjects 2 P < .05, ηρ   =  0.08; peak at 180 minutes). Buprenorphine did with a range of scores on this questionnaire. Scores on the DASS not significantly affect ratings of “feel high,” or “dislike drug.” are categorized based on responses on the subscales ( Table  1; Buprenorphine did not exert significant effects on heart rate or Lovibond and Lovibond, 1995). Thus, low or normal scores are 0 to blood pressure. DASS scores did not significantly predict sub - 9 on the depression subscale, 0 to 7 on the anxiety subscale, and 0 jective drug responses. to 14 on the stress scale; mild scores are 10 to 13 on depression or 8 to 9 on anxiety or 15 to 18 on the stress scale; moderate scores are 14 to 20 on depression or 10 to 14 on anxiety or 19 to 25 on the Table 2. Demographic and Lifetime Nonmedical Drug Use Based on stress scale; and severe scores are 21 to 27 on depression or 15 to DASS Scores (n = 38) 19 on anxiety or 26 to 33 on the stress scale. We used this group - Mean (SEM) or Percent (n) ing strategy to recruit subjects with a wide range of scores, but on most measures during data analysis we treated DASS scores Category Normal Mild Moderate Severe as a continuous variable. Because the scores on the 3 dimensions (n = 9) (n = 8) (n = 10) (n = 11) (depression, anxiety, and stress) were highly correlated, we used Gender the sum for the entire DASS for each subject. Male/female 3/6 3/5 4/6 5/6 Age 25.26 (3.87) 21.75 (5.55) 25.00 (6.67) 22.63 (3.20) Drug Effects Questionnaire (DEQ) Education 16.44 (2.60) 14.25 (0.71) 15.00 (1.41) 15.09 (1.04) The DEQ consists of 6 questions on a visual analog scale assess - BMI 24.73 (4.22) 23.03 (2.85) 24.73 (2.92) 23.63 (2.87) ing subjective drug effects. Subjects were asked to rate the Depression 1.44 (1.13) 5.75 (1.39) 7.30 (2.16) 12.10 (3.62) extent they felt a drug effect, whether they liked or disliked the Anxiety 0.67 (0.50) 3.13 (1.89) 3.10 (2.64) 5.27 (5.10) drug effect, if they felt high, and if given a choice, would they Stress 2.56 (2.70) 5.25 (3.33) 6.70 (3.77) 8.00 (4.76) want more of the drug. Race Caucasian 44.4% (4) 37.5% (3) 50.0% (5) 72.7% (8) African-American 22.2% (2) 12.5% (1) 30.0% (3) 27.3% (3) Statistical Analysis Asian 11.1% (1) 0.0% (0) 10.0% (1) 0.0% (0) Analyses were conducted using SPSS version 16.0 for Windows. Other 22.2% (2) 50.0% (4) 10.0% (1) 0.0% (0) Missing cases (due to equipment malfunction or other data col - Lifetime drug use lection problems) were deleted list wise, which led to smaller Marijuana 55.5% (5) 75.0% (6) 60.0% (6) 90.9% (10) Opiates 11.1% (1) 12.5% (1) 0.0% (0) 18.2% (2) sample sizes for some analyses. To verify that the 4 groups (nor - MDMA 22.2% (2) 12.5% (1) 20.0% (2) 18.2% (2) mal, mild, moderate, severe) were matched, we compared demo - Hallucinogens 22.2% (2) 62.5% (5) 30.0% (3) 45.5% (5) graphic information and baseline measures between the groups Stimulants 22.2% (2) 25.0% (2) 10.0% (1) 54.5% (6) using a 1-way analysis of variance (ANOVA) and chi-squared tests Sedatives 22.2% (2) 0.0% (0) 10.0% (1) 18.2% (2) where appropriate (Table  2). Subjective effects of the drug were assessed using a 2-way ANOVA, with dose and time as within- The groups did not differ on any measure except for DASS-21 scores. subject factors and DASS score as a covariate. The ABT and Emotional Images Task were analyzed with mixed ANOVAs, with dose and valence as within-subject factors and DASS group as a covariate. Significant main effects and interactions were followed with posthoc t tests. Values < P = .05 were considered significant. Results Participant Characteristics Participants were mostly Caucasian (53%) with a mean age of 24 years and an average of 15 years education. The DASS groups Table 1. DASS Scoring and Groups Depression Anxiety Stress Normal 0–9 0–7 0–14 Mild 10–13 8–9 15–18 Figure  1. Mean (± SEM) ratings of “feel drug” throughout the sessions during Moderate 14–20 10–14 19–25 placebo sessions (circles, dotted line) and after buprenorphine (0.2 mg; squares, Severe 21–27 15–19 26–33 dashed line). Shaded area indicates the time during which the tasks took place. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/120/4102059 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 124 | International Journal of Neuropsychopharmacology, 2018 that buprenorphine most dramatically reduced first gazes ABT toward fearful faces in these individuals ( Figure 3; type x drug Buprenorphine slightly decreased the number of first gazes 2 x DASS score F[3,96] = 4.1, P < .01, ηρ = 0.11; fear vs happy, P < .01). toward emotive faces overall (drug F[1,32] = 8.0, P < .01, ηρ = 0.20), but this effect was most pronounced for first gazes toward Emotional Images Task fearful expressions compared with other emotions (type x drug F[3,96] = 4.8, P < .05, ηρ = 0.09; fear vs happy P < .05). Strikingly, Data from 2 subjects were excluded because of equipment mal- the effects of buprenorphine on visual orienting toward emo - function during the task, and from one subject because they tional faces were strongest in individuals with high DASS scores did not complete the task as directed. The task produced its (Figure 2; drug x DASS score F[1,32] = 8.6, P < .01, ηρ = 0.21) such expected effects on affective ratings and corrugator reactivity as measured by facial EMG. That is, subjects rated positive images more positively and negative images more negatively than neu- tral images (valence F[2,34] = 33.5, P < .001; ηρ = 0.67; positive > neutral P < .001, negative < neutral P < .001). Corrugator activity increased with responses to negative images compared with neutral ones (valence F[2,34] = 3.8, P < .05; ηρ = 0.18; negative > neutral P < .01). As we previously showed, buprenorphine selectively enhanced positivity ratings of images with social content (Figure 4; Drug x social F[1,34] = 8.4, P < .01; ηρ = 0.20; social > nonsocial on buprenorphine: P = .06). This effect was slightly less pronounced in individuals with higher DASS scores (drug x social x DASS score F[1,34] = 10.3, P < .01; ηρ = 0.23). Neither buprenorphine nor DASS score affected corrugator or zygomatic responses to emotional images. Drug Identifications After receiving the dose of buprenorphine, 4 participants cor - Figure  2. Number of initial gazes toward fearful faces for individual subjects rectly guessed they had received an opioid drug. Of the remain - after buprenorphine minus placebo, as a function of total DASS score. Dashed ing participants, 23 guessed they had received a sedative, 5 line signifies no difference between buprenorphine and placebo sessions, solid guessed they had received a stimulant, and 6 guessed placebo. line indicates correlation ( r=-0.6, p<0.001). Figure 3. Mean (± SEM) number of initial gazes after placebo and buprenorphine (0.2 mg) toward faces depicting fear, anger, sadness, and happiness, separated by DASS scores (Low N=9; Mild N=8, Moderate N=10, Severe N=11). DASS score was treated as a continuous variable for statistical analyses. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/120/4102059 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Bershad et al. | 125 Another, somewhat surprising, result of this study was that individuals with high DASS scores do not respond as strongly to the enhancing effects of buprenorphine on positivity ratings of social images. We and others have reported that low doses of buprenorphine not only reduce responses to negative stim - uli but also enhance reactivity to positive stimuli ( Syal et  al., 2015; Bershad et  al., 2016). This is consistent with studies in nonhuman animals that suggest that opioids are involved in socially rewarding activities such as play behavior ( Panksepp et  al., 1985 ; Vanderschuren et  al., 1995a , 1995b; Trezza et  al., 2010). The fact that buprenorphine did not enhance positive responses more strongly in individuals with high DASS scores was unexpected, given that some other antidepressants acutely increase responses to positive stimuli ( Harmer et al., 2003 , 2009). It remains to be determined which behavioral responses are critical to predicting antidepressant effectiveness, dampening responses to negative stimuli, or enhancing responses to posi - tive stimuli (Pizzagalli, 2014 ). One question raised by this study is what is the optimal Figure  4. Mean (± SEM) difference scores (buprenorphine minus placebo) on selection of participants to study potential antidepressant positivity ratings of images with and without social content for all subjects effects. Our first study used healthy asymptomatic volunteers together. The DASS groups did not differ on this measure. (Bershad et  al., 2016 ), while this study used participants with a range of scores on the DASS, which included symptoms of During the placebo session, 20 participants correctly guessed both anxiety and depression. While anxiety and depression are placebo, 2 guessed an opioid drug, 10 guessed a sedative, and 6 classified as separate disorders, there is a great deal of overlap guessed they had received a stimulant. The drug identifications between the two Lo ( vibond and Lovibond, 1995), and the opi- were not related to DASS scores. oid system seems to be involved in both anxiety and depressed mood. For example, individuals high on either depression or anxiety exhibit heightened reactivity to negative facial expr -es Discussion sions (Warren et  al., 2015). Furthermore, the opioid system In this study, we aimed to assess the effects of buprenorphine seems to be involved in both anxiety and depression-related on behavioral and subjective responses to emotional stimuli in processes. A polymorphism in the opioid receptor ( OPRM1) that volunteers with a range of mood symptoms, from low to high. results in reduced mu-opioid signaling both increases the like - Extending our previous findings with nonsymptomatic volun - lihood of developing depression following social rejection and teers, we found that buprenorphine reduced initial orienting also alters anxiety-like responses to various stressors ( Chong toward fearful facial expressions and increased ratings of posi - et al., 2005 ; Slavich et al., 2014 ). Thus, our results and those from tivity of images with social content. Importantly, both these other groups suggest that the opioid system is involved in neg -a effects were more pronounced in individuals with high depres - tive affective responses broadly, beyond the boundaries of a spe - sion and anxiety scores. Additionally, we replicated our earlier cific DSM disorder. In the present study, we had the capability to finding that buprenorphine increased ratings of positivity of investigate separate contributions of symptoms of either anx - images with social content. On this measure, however, individu - iety or depression, using the DASS scales. However, the partici - als with higher DASS scores seemed to be less sensitive to the pants scores on all 3 scales were highly correlated ( r = 0.4–0.8), effect. It is notable that we detected these behavioral effects and so we used a total DASS score for the analyses. A future - dir of buprenorphine on emotional reactivity at a very low dose, a ection of this work will be to examine the effects of buprenor - dose that did not increase ratings of euphoria or “feel high.” phine in more severely symptomatic individuals, such as those The main result of this study is that buprenorphine reduces with a clinical diagnosis of a DSM-V mood disorder. attention to fearful faces most strongly in individuals with It is not yet clear how buprenorphine’s mechanism of action high scores on the DASS. This finding provides further support contributes to its effects on emotion processing. Two recent for the idea that the drug may have antidepressant properties. studies attempted to create a functional kappa antagonist by The profile of effects resembles the effects of single doses of combining buprenorphine with a mu opioid antagonist, assess- standard SSRI antidepressant drugs, which decrease recogni - ing its effects in patients with major depression who had not tion of fearful facial expressions in individuals with depression responded to previous antidepressant medications (Ehrich (Bhagwagar et al., 2004 ) and reduce amygdala responses to such et al., 2015 ; Fava et al., 2016 ). In both studies, patients exhibited faces (Murphy et  al., 2009). Although the therapeutic effects of improved outcome on 3 standard clinical measures of depres- SSRIs take weeks to develop, single doses of these drugs produce sion, suggesting pure kappa antagonism may be sufficient to behavioral effects on tasks such as those used here, and these reduce negative mood, even in the absence of mu effects. Other acute effects are predictive of the therapeutic effectiveness that studies, however, have suggested that it is a combination of develops weeks later (Warren et  al., 2015 ). To the extent that mu and kappa mechanisms that make buprenorphine effect - the effects of buprenorphine resembled the effects of a known ive (Lutz and Kieffer, 2013a, 2013b), and there is a long history antidepressant, our findings with buprenorphine suggest that of using mu-agonists in the treatment of depression before it may have similar therapeutic effects. Our findings are also in the development of SSRIs (Emrich et  al., 1982). Although both line with results from rodent models showing that the effects receptor systems seem to be involved in mediating emotional of buprenorphine on time to immobility in the forced swim test responses, the relative contributions of the MOR and KOR resemble those of standard SSRIs ( Falcon et al., 2014 ). actions in the antidepressant effect of buprenorphine remain to Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/120/4102059 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup 126 | International Journal of Neuropsychopharmacology, 2018 be determined (Sher, 1998; Ehrich et al., 2015 ; Balon, 2016; Fava in subjects with a previous history of depression. Am J Psych - et al., 2016 ; Li et al., 2016 ). iatry 161:166–168. A few limitations warrant consideration. While the stimuli in Blascovich J, Vanman E, Mendes WB, Dickerson S (2011) Social controlled laboratory studies like the one described here are mod - psychophysiology for social and personality psychology. Sage eled after real-world social encounters, they are not as salient or Publications. immersive as a real-world experience might be. Images of emo - Bodkin JA, Zornberg GL, Lukas SE, Cole JO (1995) Buprenorphine tional faces allow us to isolate dimensions of behavior we might treatment of refractory depression. J Clinical Psychopharma - not otherwise be able to (e.g., visual attention), but they lack the col 15:49–57. intensity of actual social interaction. Furthermore, we tested only Chong RY, Oswald L, Yang X, Uhart M, Lin P-I, Wand GS (2005) a single dose of buprenorphine, and it may be the case that mul - The mu-opioid receptor polymorphism A118G predicts corti - tiple different doses exert different effects on socio-emotional sol responses to naloxone and stress. Neuropsychopharma - processing. While there are limitations to the study presented cology 31:204–211. here, it provides further evidence in support of the effectiveness Dimberg U, Thunberg M, Elmehed K (2000) Unconscious facial of buprenorphine in dampening responses to negative emotional reactions to emotional facial expressions. Psychol Sci 11:86– stimuli in individuals with mood symptomatology. 89. In summary, in this study we tested the effects of buprenor - Ehrich E, Turncliff R, Du Y, Leigh-Pemberton R, Fernandez E, phine on responses to 2 emotion-processing tasks in individu- Jones R, Fava M (2015) Evaluation of opioid modulation als with low to high anxiety and depression symptoms. We in major depressive disorder. Neuropsychopharmacology replicated our previous findings, showing that buprenorphine 40:1448–1455. reduces attention to fearful faces and enhances ratings of posi - Emrich H, Vogt P, Herz A, Kissling W (1982) Antidepressant effects tivity of images with social content. Further, we found that indi - of buprenorphine. Lancet 320:709. viduals with high DASS scores exhibited a more pronounced Falcon E, Maier K, Robinson SA, Hill-Smith TE, Lucki I (2014) buprenorphine-induced decrease in attention to fearful faces. Effects of buprenorphine on behavioral tests for antidepres - Individuals with greater mood symptomology also exhibited less sant and anxiolytic drugs in mice. Psychopharmacology:1–9. response to buprenorphine on ratings of social images, suggest - Falcon E, Browne CA, Leon RM, Fleites VC, Sweeney R, Kirby LG, ing that while the drug may act to reduce responses to negative Lucki I (2016) Antidepressant-like effects of buprenorphine emotional stimuli in clinical populations, it may not be as effect - are mediated by kappa opioid receptors. Neuropsychophar - ive at increasing positive emotional responses. Antidepressant macology 41: 2344–2352. effects could result from both decreases in negative affect - Fava M, Memisoglu A, Thase ME, Bodkin JA, Trivedi MH, de Somer ive responses, or increases in positive affective responses. It M, Du Y, Leigh-Pemberton R, DiPetrillo L, Silverman B (2016) remains to be determined which of these, and which measures Opioid modulation with buprenorphine/samidorphan as of emotion processing, are most related to clinical response. adjunctive treatment for inadequate response to antidepres - sants: a randomized double-blind placebo-controlled trial. Am J Psychiatry 173:499–508. Funding Garner M, Mogg K, Bradley BP (2006) Orienting and maintenance of gaze to facial expressions in social anxiety. J Abnorm Psy - This work was supported by a grant from the National Institute on Drug Abuse (DA02812), and A.K.B. was supported by a training chol 115:760. Goeleven E, De Raedt R, Leyman L, Verschuere B (2008) The Karo- grant from the National Institute of General Medical Sciences (2T32GM007281). linska directed emotional faces: a validation study. Cogn Emot 22:1094–1118. Harmer C, Bhagwagar Z, Perrett D, Vollm B, Cowen P, Goodwin Acknowledgments G (2003) Acute SSRI administration affects the processing of social cues in healthy volunteers. Neuropsychopharmacol - We thank Dr. Royce Lee for his assistance in screening subjects ogy 28:148–152. for this study. Harmer C, O’Sullivan U, Favaron E, Massey-Chase R, Ayres R, Reinecke A, Goodwin G, Cowen P (2009) Effect of acute anti - Statement of Interest depressant administration on negative affective bias in The study drug was supplied by Indivior as an unrestricted, depressed patients. Am J Psychiatry 166:1178–1184. unsolicited grant of nonfinancial support. RBP had no role in Ipser JC, Terburg D, Syal S, Phillips N, Solms M, Panksepp J, Mal - study design; collection or analysis and interpretation of the colm-Smith S, Thomas K, Stein DJ, van Honk J (2013) Reduced data; in the writing of the manuscript; or in the decision to sub - fear-recognition sensitivity following acute buprenorphine mit the manuscript for publication. administration in healthy volunteers. Psychoneuroendocri - nology 38:166–170. Karp JF, Butters MA, Begley AE, Miller MD, Lenze EJ, Blumberger References DM, Mulsant BH, Reynolds C 3rd (2014) Safety, tolerability, Balon R (2016) Buprenorphine for the treatment of depression? and clinical effect of low-dose buprenorphine for treatment- Acta Psychiatr Scand 134:85–86. resistant depression in midlife and older adults. J Clin. Psyc -h Bershad AK, Jaffe JH, Childs E, de Wit H (2014) Opioid partial iatry 75:e785–793. agonist buprenorphine dampens responses to psychosocial Kosten TR (2016) An opioid for depression? Am J Psychiatry stress in humans. Psychoneuroendocrinology 52:281–288. 173:446–447. Bershad AK, Seiden JA, de Wit H (2016) Effects of buprenorphine Kosten TR, Morgan C, Kosten TA (1990) Depressive symptoms on responses to social stimuli in healthy adults. Psychoneu - during buprenorphine treatment of opioid abusers. J Subst roendocrinology 63:43–49. Abuse Treat 7:51–54. Bhagwagar Z, Cowen PJ, Goodwin GM, Harmer CJ (2004) Normal - Lang PJ, Bradley MM, Cuthbert BN (1999) International affective ization of enhanced fear recognition by acute SSRI treatment picture system (IAPS): technical manual and affective ratings. In: Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/120/4102059 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Copyedited by: oup Bershad et al. | 127 Gainesville, FL: The Center for Research in Psychophysiology, Pizzagalli DA (2014) Depression, stress, and anhedonia: toward University of Florida. a synthesis and integrated model. Annu Rev Clin Psychol Larsen JT, Norris CJ, Cacioppo JT (2003) Effects of positive and 10:393––23. negative affect on electromyographic activity over zygo - Schatzberg AF (2015) Opioids in psychiatric disorders: back to maticus major and corrugator supercilii. Psychophysiology the future? Am. J. Psychiatry 173:564–565. 40:776–785. Sher L (1998) The role of the endogenous opioid system in the Larsen JT, Norris CJ, McGraw AP, Hawkley LC, Cacioppo JT (2009) pathogenesis of anxiety disorders. Medical Hypotheses The evaluative space grid: a single-item measure of positivity 50:473–474. and negativity. Cogn. Emot. 23:453–480. Slavich GM, Tartter MA, Brennan PA, Hammen C (2014) Endogen - Li W, Sun H, Chen H, Yang X, Xiao L, Liu R, Shao L, Qiu Z (2016) ous opioid system influences depressive reactions to socially Major depressive disorder and kappa opioid receptor antago - painful targeted rejection life events. Psychoneuroendocri - nists. Transl Perioper Pain Med 1:4. nology 49:141–149. Lovibond PF, Lovibond SH (1995) The structure of negative emo - Sullivan, MD (2016) Why does depression promote long-term tional states: comparison of the Depression Anxiety Stress opioid use? Pain 157:2395–2396. Scales (DASS) with the Beck Depression and Anxiety Invento - Syal S, Ipser J, Terburg D, Solms M, Panksepp J, Malcolm-Smith ries. Behav Res Ther 33:335–343. S, Bos PA, Montoya ER, Stein DJ, van Honk J (2015) Improved Lutz P-E, Kieffer BL (2013a) The multiple facets of opioid recep - memory for reward cues following acute buprenorphine tor function: implications for addiction. Curr Opin Neurobiol administration in humans. Psychoneuroendocrinology 23:473–479. 53:10–15. Lutz P-E, Kieffer BL (2013b) Opioid receptors: distinct roles in Trezza V, Baarendse PJ, Vanderschuren LJ (2010) The pleasures mood disorders. Trends Neurosci 36:195–206. of play: pharmacological insights into social reward mecha - McCabe SB, Gotlib IH, Martin RA (2000) Cognitive vulnerability nisms. Trends Pharmacol Sci 31:463–469. for depression: deployment of attention as a function of his - Vanderschuren LJ, Stein EA, Wiegant VM, Van Ree JM (1995a) tory of depression and current mood state. Cognit Ther Res Social play alters regional brain opioid receptor binding in 24:427–444. juvenile rats. Brain Res 680:148–156. Mendelson J, Upton RA, Everhart ET, Jones RT (1997) Bioavailabil - Vanderschuren LJ, Niesink RJ, Spruijt BM, Van Ree JM (1995b) ity of sublingual buprenorphine. J Clin Pharmacol 37:31–37. μ-and κ-opioid receptor-meiated opioid effects on social play Murphy SE, Norbury R, O’Sullivan U, Cowen PJ, Harmer CJ (2009) in juvenile rats. Eur J Pharmacol 276:257–266. Effect of a single dose of citalopram on amygdala response to Wardle MC, Garner MJ, Munafò MR, de Wit H (2012) Amphet - emotional faces. Br J Psychiatry 194:535–540. amine as a social drug: effects of d-amphetamine on Norelli LJ, Smith HS, Sher L, Blackwood TA (2013) Buprenorphine social processing and behavior. Psychopharmacology in the treatment of non-suicidal self-injury: a case series and 223:199–210. discussion of the literature. Int J Adolesc Med Health 25:323– Warren MB, Pringle A, Harmer CJ (2015) A neurocognitive model 330. for understanding treatment action in depression. Phil Trans Nyhuis PW, Gastpar M, Scherbaum N (2008) Opiate treatment in R Soc B 370:20140213. depression refractory to antidepressants and electroconvul - Yovell Y, Bar G, Mashiah M, Baruch Y, Briskman I, Asherov J, Lotan sive therapy. J Clin Psychopharmacol 28:593–595. A, Rigbi A, Panksepp J (2015) Ultra-low-dose buprenorphine as Panksepp J, Jalowiec J, DeEskinazi F, Bishop P (1985) Opiates and a time-limited treatment for severe suicidal ideation: a rand - play dominance in juvenile rats. Behav Neurosci 99:441. omized controlled trial. Am J Psychiatry 173:491–498. Downloaded from https://academic.oup.com/ijnp/article-abstract/21/2/120/4102059 by Ed 'DeepDyve' Gillespie user on 16 March 2018

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Published: Feb 1, 2018

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