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Original Article |

Probing Brain Reward System Function in Major Depressive Disorder:  Altered Response to Dextroamphetamine FREE

Lescia K. Tremblay, BSc; Claudio A. Naranjo, MD; Laura Cardenas, MD; Nathan Herrmann, MD; Usoa E. Busto, PharmD
[+] Author Affiliations

From the Psychopharmacology Research Program, Sunnybrook & Women's College Health Sciences Centre–Sunnybrook Campus (Ms Tremblay and Drs Naranjo, Herrmann, and Busto), the Centre for Addiction and Mental Health, Addiction Research Centre Site (Drs Cardenas and Busto), and the Departments of Pharmacology (Drs Cardenas, Herrmann, and Busto), Psychiatry (Drs Naranjo and Herrmann), Medicine (Drs Naranjo and Herrmann), and Pharmaceutical Sciences(Ms Tremblay and Dr Busto), University of Toronto, Toronto, Ontario.


Arch Gen Psychiatry. 2002;59(5):409-416. doi:10.1001/archpsyc.59.5.409.
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Background  The state of the brain reward system in major depressive disorder was assessed with dextroamphetamine, which probes the release of dopamine within the mesocorticolimbic system, a major component of the brain reward system, and produces measurable behavioral changes, including rewarding effects (eg, euphoria). We hypothesized that depressed individuals would exhibit an altered response to dextroamphetamine due to an underlying brain reward system dysfunction reflected by anhedonic symptoms.

Methods  In a double-blind, placebo-controlled, randomized, parallel study, the behavioral and physiological effects of a single 30-mg dose of oral dextroamphetamine sulfate were measured. Forty patients with a diagnosis of DSM-IV major depressive disorder who were not taking antidepressant medications (22 assigned to dextroamphetamine and 18 to placebo) were compared with 36 control subjects (18 assigned to dextroamphetamine and 18 to placebo) using validated self-report drug effect measurement tools (eg, the Addiction Research Center Inventory), heart rate, and blood pressure.

Results  Multiple regression analysis showed that severity of depression as measured by the Hamilton Rating Scale for Depression correlated highly with the rewarding effects of dextroamphetamine in the depressed group (model R2 = 0.63; interaction P = .04). A subsequent analysis categorizing the depressed group into patients with severe symptoms (Hamilton score >23) and those with moderate symptoms revealed a significant interaction between drug and depression (P = .02). Patients with severe symptoms reported rewarding effects3.4-fold greater than controls.

Conclusions  The results suggest the presence of a hypersensitive response is present in the brain reward system of depressed patients, which may reflect a hypofunctional state and may provide a novel pathophysiologic and therapeutic target for future studies.

Figures in this Article

THE PATHOPHYSIOLOGY of major depressive disorder (MDD) consists of functional changes in the neurotransmitter and neuroendocrine systems, such as the monoamines and the hypothalamic-pituitary-adrenal axis,1,2 as well as functional neuroanatomical changes in the cingulate, insula, amygdala, basal ganglia, caudate, and frontal, prefrontal, parietal, and temporal lobes,37 some of which are consistent with postmortem findings.8,9 Despite evidence of complex neurobiological mechanisms, the therapeutic targets of novel antidepressants remain based on the monoamine hypothesis of depression10,11 selectively restoring the function of specific monoaminergic systems,12 without evidence of improved efficacy compared with older classes (eg, tricyclics).13

Although MDD is defined as a disorder comprising disturbances in emotional and motivational processing along with various somatic and endocrine changes, it is more plausible to study the symptoms rather than the syndrome given the involvement of multiple interacting neurotransmitters and pathways.14,15 We chose to target a specific neurobiological mechanism, the brain reward system (BRS), which may underlie specific and core symptoms of MDD, such as the loss of pleasure or interest (anhedonia). The BRS consists of extensive neural pathways that mediate behavioral components of reward such as pleasure and motivation.1618 The mesocorticolimbic dopamine system is among the most studied BRS pathway in animal models1921 and has recently been implicated in human BRS studies of nicotine, cocaine, and dextroamphetamine reward.2225 Reinforcing drugs (eg, psychostimulants and opiates) possess significant abuse potential because of their ability to stimulate BRS pathways, such as mesocorticolimbic dopamine by the psychostimulants and endogenous opioids by drugs such as heroin, eliciting positive behavioral states (eg, elation, increased energy, and high).26 Thus, these drugs represent tools for probing BRS function, a paradigm that has been described previously.27

The purpose of this study is to test whether BRS function is altered in MDD by measuring the degree of dextroamphetamine-induced rewarding effects. Dextroamphetamine is predominantly a dopamine releaser and a dopamine reuptake inhibitor with secondary serotonergic- and noradrenergic-releasing effects.2830 At safe doses (5-60 mg), dextroamphetamine reliably stimulates BRS sites and produces measurable, characteristic, and well-studied pleasurable effects such as euphoria and increased drive.3135 Studies have shown that the intensity of the behavioral effects of dextroamphetamine(eg, euphoria) correlates with the extent of dopamine binding to D2receptors,24,25 specifically in the nucleus accumbens and ventral medial caudate, both major BRS components.25 Thus, dextroamphetamine is considered a BRS probe. Theoretical constructs have been suggested,3638 and animal models of anhedonia or depression have generated a substantial knowledge base,39,40 but the question of whether the function of the BRS is altered in patients with depression has never been resolved and warrants empirical study.

PARTICIPANTS

Patients with depression were of either sex; were aged 18 to 65 years; met DSM-IV41 criteria for MDD; and were not using antidepressant medications for at least 2 weeks(5 weeks for fluoxetine). Patients were referred by collaborating psychiatrists from 3 mood disorder clinics in Toronto or were recruited through city newspaper advertisements or telephone surveys. Patients recruited from advertisements or surveys were assessed using the Structured Clinical Interview for the DSM-IV42 by a trained researcher and were also assessed by a staff psychiatrist for diagnostic confirmation and physical health. Exclusion criteria specific to patients with MDD included current suicidal ideation posing an immediate threat to the person's life and comorbid DSM-IV Axis I mental illness, including other mood disorders (eg, bipolar disorder) and substance use disorders.

Controls (n = 36) were recruited by word of mouth and were assessed by a trained researcher. They were excluded if their Hamilton Rating Scale for Depression (HAM-D) (21 items)43 score was greater than 6 or if they had a personal history of mood disorders or other psychiatric illnesses.

Exclusion criteria included the following: a current or past history of cardiovascular disorder, a medical condition requiring investigation or treatment, recent (<1 year) or current DSM-IV–defined psychoactive substance use (eg, alcohol) disorders, except nicotine and caffeine, pregnancy/lactation, or current use of any medication known to interact with the study drug (eg, opioid analgesics).

To recruit the MDD group, 238 individuals were contacted through referrals and advertisements: 64 were eligible and 53 were ineligible mostly because they were already taking antidepressant medications or reported another DSM-IV Axis I mental illness (eg, bipolar disorder). The remaining potential participants were not screened owing to cancellation of appointments or inability to be contacted. Of the 64 patients who were eligible, 42 completed the study session and the remainder did not attend their appointments. Of the 42 completers, 2 were excluded because of protocol violations (1 for use of bupropion hydrochloride and methotrimeprazine and 1 for use of sedatives).

The protocol was approved by the research ethics board of Sunnybrook & Women's College Health Sciences Centre or the Centre for Addiction and Mental Health. Signed informed consent was obtained from all participants.

PROCEDURE

This was a between-subject, randomized, double-blind, placebo-controlled, parallel study. Comparisons were made between patients diagnosed as having MDD and control subjects and between individuals receiving placebo and dextroamphetamine, resulting in 4 initial study arms: MDD-dextroamphetamine, MDD-placebo, control-dextroamphetamine, and control-placebo.

Dextroamphetamine sulfate (Dexedrine, SmithKline Beecham Pharmaceuticals, Chicago, Ill) and placebo doses were prepared in identical 10-mg capsules filled with drug or dextrose powder. A research pharmacist dispensed the medication and kept the randomization code.

After standardized screening based on previously described participant criteria, volunteers were seen between 8 and 10 AM for a study session. A urine sample was collected to assess compliance (ie, toxicology screen). Symptom severity was assessed using scales described in the "Assessments" subsection. After a light standardized breakfast, participants completed a baseline cycle(before drug administration) of computerized behavioral measurements (eg, the Addiction Research Center Inventory [ARCI]44,45). Baseline physiological measurements (eg, heart rate) were also recorded. Patients then ingested 30 mg of dextroamphetamine or placebo. Behavioral and physiological measurements were repeated 30, 60, 120, 180, and 240 minutes after drug administration to capture the rise, peak, and downslope of the response. Blood samples were drawn at baseline and 120 minutes after drug administration (near the peak time of subjective effects) to evaluate levels of homovanillic acid (HVA)(a dopamine metabolite) and only at 120 minutes for plasma drug concentrations. Gas chromatography–mass spectrometry was used for HVA detection with a deuterated HVA as the internal standard, which has been described previously using cerebrospinal fluid instead of plasma.46 Dextroamphetamine concentrations were determined using gas chromatography–mass spectrometry.47

ASSESSMENTS

The Beck Depression Inventory,48 the Snaith-Hamilton Pleasure Scale (SHAPS),49 and a modified version of the Sunnybrook Psychomotor Agitation and Retardation Questionnaire,50 all self-report instruments, were administered before drug ingestion only (ie, at baseline) to evaluate depression, anhedonia, and psychomotor symptom severity, respectively. Severity of depressive episodes experienced by patients during the 2 to 3 weeks before the study session day was evaluated using the HAM-D.43

Heart rate and blood pressure—the physiological, objective drug effect measures—were recorded by a trained researcher using a stethoscope and a sphygmomanometer. Instruments used to measure behavioral (subjective) drug effects were computerized versions of the Addiction Research Center Inventory,44,45 (ARCI) the Profile of Mood States51,52 (POMS), and the Visual Analogue Scale(VAS).53 The ARCI, the main outcome measure of dextroamphetamine rewarding effects, is composed of questions designed to measure characteristic positive effects of drugs that are reinforcing (ie, that can promote drug self-administration) and negative effects (eg, increased anxiety and agitation). Specific sets of these questions (eg, "I feel now as I have felt after a very exciting experience; I feel so good I know people can tell it") belong to empirically derived scales validated to measure characteristic effects of drugs or drug classes (eg, Amphetamine, Stimulation-Euphoria, and Unpleasantness Dysphoria).54 The POMS and the VAS are additional, less specific self-report measures administered to assess acute mood changes.

DATA ANALYSIS

The peak dextroamphetamine behavioral effect was defined as the highest scale score among the 60-, 120-, and 180-minute recordings. The corresponding baseline score was subtracted from this value to measure the change. The main dependent outcome variable, termed ARCI Rewarding Effects Composite, consisted of a composite of change scores from scales that measure positive reinforcing effects: Abuse-Potential, Amphetamine, Benzedrine, Morphine-Benzedrine, and Stimulation Euphoria. Similar rewarding effects composites were calculated with the POMS using the Elation, Vigor, and Friendliness scales and with the VAS using the peak "I like the drug," "I feel an increase in energy," "I feel high," and "I feel the drug's good effects" scales. An ARCI Negative Effects Composite measure was also calculated by grouping the change scores from the Pentobarbital Chlorpromazine Alcohol Group, LSD, Sedation-Motor, Sedation-Mental, Unpleasantness-Physical, and Unpleasantness-Dysphoria scales to evaluate increases in negative (ie, unpleasant) drug effects. Because of the different score ranges within the various scales, baseline and peak scores were converted to a score on a 100% scale before being added into the composite score. The Cronbach α coefficient was obtained for each composite measure to evaluate internal consistency.

Data were analyzed by simple factorial analysis of covariance (ANCOVA) using a statistical software program (SPSS version 10.0.0; SPSS Inc, Chicago, Ill). The effects of the independent variables, mood (depressed vs control) and drug (dextroamphetamine vs placebo), as well as the interaction were tested(α = .05, 2-tailed). Age and sex were included as covariates for all ANCOVAs. In addition to modeling mood as a dichotomous variable, we also modeled depression as a continuous variable using the actual HAM-D score. That is, multiple regression analysis was applied in the MDD group to examine the effect of drug (dextroamphetamine vs placebo), HAM-D score, and the interaction, adjusting for age and sex. Demographic and baseline measurements (ie, before drug administration) were compared using independent samples t tests. Pearson correlation coefficient tests were used for bivariate correlations.

PARTICIPANTS

Data were collected from 40 patients with MDD (22 receiving dextroamphetamine and 18 receiving placebo) and 36 controls (18 receiving dextroamphetamine and 18 receiving placebo). Participant characteristics are summarized in Table 1. There were no differences in baseline characteristics or baseline drug effect scores between the placebo and dextroamphetamine arms in the MDD group or in the control group. Eight control subjects had past histories (ie, ≥1 years before the study session) of substance use disorders (3 for alcohol only, 2 for alcohol and marijuana, 1 for alcohol and marijuana and stimulant, 1 for benzodiazepine, and 1 for opiate) compared with 7 in the MDD group (4 for alcohol, 1 for benzodiazepine, and 2 for marijuana). The number of smokers was similar in both groups (16 of 36 controls and 18 of 40 patients with MDD). Nineteen patients with MDD reported a family history of a psychiatric disorder compared with 9 in the control group. The significant age and sex differences between MDD and control subjects given in Table 1 led us to control for these variables in our analyses. Age and sex did not alter dextroamphetamine-induced behavioral or physiological measurements. The age and sex effects in all models were not statistically significant and were also minute compared with the effects of depression or drug administration (placebo/dextroamphetamine). No correlation was found between age and any drug effect measurement (eg, ARCI Rewarding Effects Composite score) in all individuals or subgroups.

Table Graphic Jump LocationCharacteristics of 40 Patients With Major Depressive Disorder (MDD) vs 36 Control Subjects*
DIFFERENCES WITHIN THE MDD GROUP

Multiple linear regression analysis (described in the "Data Analysis" subsection) revealed that severity of depression, as measured by the HAM-D, correlated strongly with the degree of dextroamphetamine rewarding effects reported by patients with MDD. The R2for the model was 0.63, and the P value for the interaction between drug and HAM-D score was .04 (Figure1). Similar but less robust trends occurred between the HAM-D and the POMS (R2 = 0.44; interaction P = .08) and the VAS (R2 = 0.43; interaction P = .35) reward composites.

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Figure 1.

Degree of dextroamphetamine rewarding effects vs severity of major depressive disorder. The multiple regression model (described in the "Data Analysis" subsection) in 40 patients with major depressive disorder revealed that the interaction between the Hamilton Rating Scale for Depression score and dextroamphetamine was significant (P = .04), indicating that the slope of the dextroamphetamine line was significantly greater than the slope of the placebo line. ARCI indicates Addiction Research Center Inventory.

Graphic Jump Location

Pearson correlation tests revealed that the ARCI Rewarding Effects Composite scores of the MDD-dextroamphetamine group correlated positively with the HAM-D item score, which most closely measures anhedonic symptoms, that is, loss of interest in work and activities (item 7) (r =0.45; P = .03) and decreased libido (item 14) (r = 0.51; P = .02). Psychomotor Retardation scores correlated positively with HAM-D (r= 0.33; P = .04) and Beck (r= 0.57; P<.001) scores; SHAPS (anhedonia) scores correlated with Beck scores only (r = 0.38; P = .02).

DEXTROAMPHETAMINE EFFECTS: PATIENTS WITH MDD VS CONTROLS

The originally planned analysis described in the "Data Analysis" subsection, ANCOVA treating mood as a dichotomous variable (MDD vs control), did not reveal differences between the MDD and control groups on all outcome measures of dextroamphetamine behavioral effects, including the ARCI Rewarding Effects Composite score, which showed no interaction between mood and drug (F1,70 = 1.54; P = .22). The lack of significance in this ANCOVA was probably due to the large variation in Rewarding Effect Composite scores in the MDD group, variation explained by the degree of depression(Figure 1). Thus, patients with MDD could not be treated as a homogeneous group. We separated patients with MDD into 2 groups—severely depressed and moderately depressed—using the median and mean HAM-D score found in this study (HAM-D score, 23), resulting in 6 study arms: severe-dextroamphetamine (n = 11), severe-placebo (n = 8), moderate-dextroamphetamine (n = 11), moderate-placebo (n = 10), control-dextroamphetamine(n = 18), and control-placebo (n = 18).

In the ANCOVA model testing differences in ARCI Rewarding Effects Composite scores, adjusting for age and sex, the interaction between depression severity(severe vs moderate vs control) and drug (placebo vs dextroamphetamine) was significant (F2,68 = 4.29; P = .02), where patients with severe depression showed a dextroamphetamine effect 3.4-fold greater than controls (Figure 2). The same trend occurred with the POMS (F2,68 = 3.10; P = .052) and VAS (P = NS) Rewarding Effects Composite scores. Statistical differences in ARCI Negative Effects Composite scores were not found between groups. The time course of the dextroamphetamine or placebo effect in the 6 groups is displayed in Figure 3.

Place holder to copy figure label and caption
Figure 2.

Degree of rewarding effects experienced by participants as measured by the mean peak minus baseline Addiction Research Center Inventory (ARCI) Rewarding Effects Composite score vs severity of major depressive disorder. The P value represents the interaction between severity and drug. The age- and sex-adjusted mean (95% confidence interval) for the dextroamphetamine effect compared with placebo was 156.40(94.64-218.16) in the severe group, 46.22 (−11.84 to 104.28) in the moderate group, and 55.70 (11.33-100.07) in the control group. The mean Hamilton Rating Scale for Depression (HAM-D) scores for the groups are 1.33 for control-dextroamphetamine, 0.28 for control-placebo, 19.73 for moderate-dextroamphetamine, 18.60 for moderate-placebo, 28.46 for severe-dextroamphetamine, and 27.25 for severe-placebo. Error bars represent SD.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Time course of dextroamphetamine vs placebo effects. Time zero represents the baseline score (ie, before drug administration). Values included in the computation of the mean peak effect value were the highest scores within the peak effect time window for dextroamphetamine(60-180 minutes). ARCI indicates Addiction Research Center Inventory.

Graphic Jump Location

The Cronbach α was 0.96 for the ARCI Rewarding Effects Composite, 0.87 for the ARCI Negative Effects Composite, 0.87 for the POMS Rewarding Effects Composite, and 0.83 for the VAS Reward Composite, confirming the reliability of the scale pooling method.

Physiological response differences were unlike those of the behavioral response. No differences were found between the MDD and control groups for dextroamphetamine-induced increases in blood pressure, which on average increased21/14 mm Hg. The ANCOVA including drug (dextroamphetamine vs placebo), severity(control vs moderate vs severe), and their interaction, with age and sex as covariates, showed that there was a greater increase in heart rate for the moderate group: 19 beats/min compared with 8 beats/min for the control-dextroamphetamine group and 11 beats/min for the severe-dextroamphetamine group (F2,68 = 4.70; P = .01). There was no correlation between the degree of physiological and behavioral dextroamphetamine measurement scores.

The t test results comparing demographic and baseline characteristics in patients with moderate vs severe depression showed significantly higher HAM-D, Beck, and Psychomotor Retardation scores in the severe group (P<.05 for all characteristics). Age, sex, SHAPS (anhedonia scale) scores, Psychomotor Agitation scores, education, substance use history, and baseline scores in physiological and behavioral(eg, ARCI) measures were similar.

BASELINE DIFFERENCES BETWEEN PATIENTS WITH MDD AND CONTROLS

Baseline heart rate and blood pressure differences did not occur between the MDD and control groups. However, compared with controls, the mean baseline(ie, before drug administration) score in the ARCI Rewarding Effects Composite was 1.5-fold lower (t74 = 6.84; P<.001) in the MDD group. To rule out the possibility that the increased rewarding effects seen in patients with MDD were due solely to lower baseline scores, we also tested differences in the raw peaks of the groups. Results showed that the interaction between severity and drug remained significant (F2,68 = 3.51; P = .04), with an age- and sex-corrected, placebo-controlled dextroamphetamine effect of165.68 (95% confidence interval, 91.53-239.84) for the severe group, 49.17(95% confidence interval, 20.54-118.88) for the moderate group, and 53.92(95% confidence interval, 0.64-107.20) for the control group. Thus, without the effect of baseline, the dextroamphetamine peak effect was 3-fold greater in patients with severe depression compared with controls. A significant interaction also occurred using peak POMS composite scores (F2,68 = 3.56; P = .03). As with the baseline-corrected scores used in Figure 1 (ie, the ARCI Rewarding Effects Composite scores), similar results were found with the raw peak values (model R2 = 0.52; interaction P= .02). Moreover, baseline ARCI Rewarding Effects Composite scores of patients with MDD did not correlate with depression severity (ie, HAM-D score), showing that the relationship seen in Figure 1was also unaffected by initial baseline scores.

DEXTROAMPHETAMINE AND HVA LEVELS

Adverse effects related to dextroamphetamine administration were few, mild, and reversible (eg, restlessness and anxiety). The mean plasma dextroamphetamine level was 42 ± 16 ng/mL. Drug (placebo vs dextroamphetamine) or mood(control vs moderate vs severe) did not interact with HVA concentrations (mean, 69 ± 30 ng/mL at baseline and 51 ± 28 ng/mL at the 120-minute measurement).

The main findings of our study are as follows: (1) There was a strong positive relationship between degree of MDD severity and degree of dextroamphetamine rewarding effects. (2) Patients with MDD and severe symptoms (those with HAM-D scores >23) experienced a greater degree of rewarding effects compared with controls, whereas patients with moderate depression were not different from controls. The HAM-D score separating the MDD groups was determined mathematically(ie, median and mean), and although there is no standardized definition for severe depression, this cutoff value (HAM-D score, 23) is clinically relevant.55 Intragroup variations found in controls were within those observed in other studies.54,56,57 Patients with more severe symptoms reported a greater change relative to their baseline and a greater absolute peak dextroamphetamine effect compared with controls, findings not confounded by sex and age. Results confirm that the behavioral effects of dextroamphetamine are distinguishable from the cardiovascular effects and that HVA levels are not altered by dextroamphetamine administration.35,5861 The results in Figure 1 and Figure 2 also show that patients with severe depression given placebo reported higher ARCI scores than the control and moderate groups, findings that will be discussed elsewhere (L.K.T., C.A.N., L.C., N.H., and U.E.B., unpublished data, 2002).

These results demonstrate the importance of the severity of MDD in the study of potential brain mechanisms. Symptom severity previously has been shown to be an important factor for the interpretation of data in neuroimaging studies with psychiatric patients7,62,63 and subjective response to a psychostimulant.64 The findings in this study could explain previous large discrepancies in the literature regarding the direction of dextroamphetamine response in patients with depression. De Wit et al65 reported that individuals with various diagnoses of depression (minor depression, dysthymia, and MDD) and a total mean HAM-D score of 12 showed no differences in their response to oral administration of dextroamphetamine (10 mg) compared with controls, which is in concordance with our findings in the moderately depressed group. Past studies using dextroamphetamine as a predictor for tricyclic antidepressant response have shown that patients who are depressed report dextroamphetamine effects, but findings were inconsistent, making dextroamphetamine a poor prognostic tool. However, these studies used observer rating scales or did not assess rewarding effects, did not compare responses with controls, were often not placebo controlled, and were characterized without proper diagnostic criteria and/or recruited a patient group with different mood disorders, such as bipolar disorder together with MDD.66

These results provide support for the hypothesis that an altered response to the rewarding effects of dextroamphetamine occurs in MDD due to an underlying BRS dysfunction. The importance of dopamine for BRS function,19,20 the ability of dextroamphetamine to stimulate this system at the mesoaccumbens(primarily through presynaptic dopamine-releasing effects but also through inhibition of the dopamine reuptake system),24,31,32,67 and the evidence linking dextroamphetamine behavioral effects to dopamine binding onto D2 receptors in important BRS substrates25 together suggest that the proposed BRS dysfunction may involve dopaminergic mechanisms within the BRS. Furthermore, changes in dopamine activity have recently been associated with changes in regional blood flow in the cingulate and the frontal cortex,68 regions implicated in the pathophysiology of depression.5,6

An enhanced response to a BRS probe such as dextroamphetamine may reflect decreased output, in which compensatory mechanisms (eg, secondary up-regulation of dopamine receptors) can be activated by an exogenous source (eg, dextroamphetamine) and can generate a supersensitive response. The dopaminergic system can exhibit important plastic changes.69 A dopamine storage deficit is unlikely because experimental depletion of dopamine in unmedicated patients with MDD does not produce exacerbation of symptoms.70 Studies7174 using equivalent neuroimaging techniques and radioligands with comparable mean HAM-D scores have looked at dopamine D2 receptor densities in patients with MDD vs controls, yielding inconsistent results. However, the study by Ebert et al74 found increased binding (ie, reflecting up-regulation) in the patient group with psychomotor retardation, a symptom that was more severe in this study's severely depressed group compared with the moderately depressed group. The degree of psychomotor retardation correlates with the degree of anhedonia, and anhedonia correlates with the degree of self-reported depression severity,75 findings confirmed in this study. In addition to receptor changes, decreased presynaptic dopamine function has been found in patients with MDD and affective flattening and psychomotor retardation.76 It may be argued that because of the ability of dextroamphetamine to release neurotransmitters other than dopamine, the differences in response between severely depressed and control subjects may be attributed to noradrenergic, serotonergic, or cholinergic mechanisms. The evidence59 regarding the involvement of these neurotransmitters in dextroamphetamine-induced rewarding effects in humans does not support this possibility; however, one cannot discount the possibility that they may modulate the BRS dopamine pathways in MDD.28,29,7780

A limitation of this study is that one measure of anhedonia, the SHAPS, was not predictive of the level of dextroamphetamine effects, as was shown in Figure 1 with the HAM-D. One challenge is that anhedonia is present in most patients and is a core symptom of MDD. Thus, the SHAPS score may more likely measure a depressed mood state rather than being a subtyping factor in data analysis.81 Nevertheless, the item within the HAM-D that most closely measures anhedonia(ie, loss of interest in activities), and decreased libido, a symptom that may also be modulated by the BRS,82 showed a positive correlation with dextroamphetamine reward. A greater number of patients, particularly men, with MDD; an improved measure of anhedonia (eg, with less cultural bias and preselected pleasures); and additional measures of reward that cover aspects other than pleasure (eg, motivation task) would strengthen the relationship between altered BRS function in MDD and anhedonic symptoms. Testing BRS function in remitted nonmedicated patients with MDD would also shed light on the state vs trait question, that is, whether a BRS dysfunction represents an underlying brain mechanism for symptoms in MDD or is a trait that affects the course of the illness.

In conclusion, the BRS may be an important therapeutic target to relieve anhedonia, a core symptom in MDD, and psychomotor retardation. Furthermore, studies are implicating the mesocorticolimbic dopamine system in functions other than reward behavior, such as stress, emotion, and cognition, which are pertinent for the study of the pathophysiology of MDD.83,84

Submitted for publication June 5, 2000; final revision received May31, 2001; accepted June 26, 2001.

This work was supported in part by a grant from the Ontario Mental Health Foundation, Toronto, Ontario, and by the Ontario Graduate Scholarship for Science and Technology, the Centre for Addiction and Mental Health–Addiction Research Foundation Division, and the Ben Cohen Bursary Fund, University of Toronto (Dr Tremblay). Laura Cardenas, a PhD candidate, contributed data for nearly half the subjects analyzed, and was supported by the Ontario Graduate Scholarship and the University of Toronto.

This study was presented in part at the annual meeting of the American Society for Clinical Pharmacology and Therapeutics, Los Angeles, Calif, March15, 2000.

We thank Janaki Srinivasan, MD, and Daniel Pollock, MD, for their referral of patients and support; Anthony Levitt, MD, and Stephen Sokolov, MD, for their help with patient assessments; and Ruth Croxford, MSc, for her assistance with statistical analysis.

Corresponding author and reprints: Claudio A. Naranjo, MD, Psychopharmacology Research Program, University of Toronto, Sunnybrook & Women's College Health Sciences Centre, 2075 Bayview Ave, Room F-327, Toronto, Ontario, Canada M4N 3M5 (e-mail: claudio.naranjo@utoronto.ca).

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Olds  MEMilner  PM Positive reinforcement produced by electrical stimulation of the septal area and other regions of the rat brain. J Comp Physiol Psychol. 1954;47419- 427
Link to Article
Wise  RA Addictive drugs and brain stimulation reward. Annu Rev Neurosci. 1996;19319- 340
Link to Article
Leshner  AIKoob  GF Drugs of abuse and the brain. Proc Assoc Am Physicians. 1999;11199- 108
Link to Article
Schultz  W Dopamine neurons and their role in reward mechanisms. Curr Opin Neurobiol. 1997;7191- 197
Link to Article
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Volkow  NDWang  GJFowler  JSLogan  JGatley  SJWong  CHitzemann  RPappas  NR Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D2 receptors. J Pharmacol Exp Ther. 1999;291409- 415
Laruelle  MAbi-Dargham  AVan Dyck  CRosenblatt  WZea-Ponce  YZoghbi  SSBaldwin  RMCharney  DSHoffer  PBKung  HFInnis  RB SPECT imaging of striatal dopamine release after amphetamine challenge. J Nucl Med. 1995;361182- 1190
Drevets  WCGautier  CPrice  JCKupfer  KJKinahan  PEGrace  AAPrice  JLMathis  CA Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria. Biol Psychiatry. 2001;4981- 96
Link to Article
Koob  GFLe Moal  M Drug abuse: hedonic homeostatic dysregulation. Science. 1997;27852- 58
Link to Article
Naranjo  CATremblay  LKBusto  UE The role of the brain reward system in depression. Prog Neuropsychopharmacol Biol Psychiatry. 2001;25781- 823
Link to Article
Shi  WXPun  CLZhang  XXJones  MDBunney  BS Dual effects of d-amphetamine on dopamine neurons mediated by dopamine and nondopamine receptors. J Neurosci. 2000;203504- 3511
Hedou  GHomberg  JMartin  SWirth  KFeldon  JHeidbreder  CA Effect of amphetamine on extracellular acetylcholine and monoamine levels in subterritories of the rat medial prefrontal cortex. Eur J Pharmacol. 2000;390127- 136
Link to Article
Kuczenski  RSegal  DSCho  AKMelega  W Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine. J Neurosci. 1995;151308- 1317
Pifl  CDrobny  HReither  H Mechanism of the dopamine-releasing actions of amphetamine and cocaine: plasmalemmal dopamine transporter versus vesicular monoamine transporter. Mol Pharmacol. 1995;47368- 373
Seiden  LSSabol  KE Amphetamine: effects on catecholamine systems and behaviour. Annu Rev Pharmacol Toxicol. 1993;33639- 677
Link to Article
Koob  GF Hedonic valence, dopamine and motivation. Mol Psychiatry. 1996;1186- 189
Uhlenhuth  EHJohanson  CEKilgore  KKobasa  SC Drug preference and mood in humans: preference for d-amphetamine and subject characteristics. Psychopharmacology. 74191- 194
Link to Article
Dommisse  CSSchulz  SCNarasimhachari  NBlackard  WGHamer  RM The neuroendocrine and behavioral response to dextroamphetamine in normal individuals. Biol Psychiatry. 1984;191305- 1315
Klein  DF Endogenomorphic depression: a conceptual and terminological revision. Arch Gen Psychiatry. 1974;31447- 454
Link to Article
Heinz  A Anhedonia: a general nosology surmounting correlate of a dysfunctional dopaminergic reward system? Nervenarzt. 1999;70391- 398
Link to Article
Carroll  BJ Neurobiological dimensions of depression and mania. Angst  Jed. The Origins of Depression: Current Concepts and Approaches. New York, NY Springer-Verlag1983;163- 186
Di Chiara  GLoddo  PTanda  G Reciprocal changes in prefrontal and limbic dopamine responsiveness to aversive and rewarding stimuli after chronic mild stress: implications for the psychobiology of depression. Biol Psychiatry. 1999;461624- 1633
Link to Article
Willner  P Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology. 1997;134319- 329
Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;161- 198
First  MBSpitzer  RLGibbon  MWilliams  JBW Structured Clinical Interview for DSM-IV Axis I Disorders–Patient Edition (SCID-I/P, Version 2.0).  New York Biometrics Research Dept, New York State Psychiatric Institute1994;
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;2356- 62
Link to Article
Hill  HEHaertzen  CAWolbach  AB  JrMiner  EJ The Addiction Research Center Inventory: standardization of scales which evaluate subjective effects of morphine, amphetamine, pentobarbital, alcohol, LSD-25, pirahexl and chloropromazine. Psychopharmacologia. 1963;4167- 183
Link to Article
Cole  JOOrzack  MHBeake  BBird  MBar-Tal  Y Assessment of the abuse liability of buspirone in recreational sedative users. J Clin Psychiatry. 1982;4369- 75
Vogt  WJacob  KOhnesorge  A-BSchwertfeger  G Highly sensitive method for the quantitation of homovanillic acid in cerebrospinal fluid. J Chromatogr. 1980;199191- 197
Link to Article
Midha  KKMcgilveray  IJCooper  JK Assay for simultaneous determination of fenfluramine and norfenfluramine in human plasma and urine. Can J Pharm Sci. 1979;1418- 21
Kendall  PHollon  SBeck  AHammen  CLIngram  RE Issues and recommendations regarding use of the Beck Depression Inventory. Cognit Ther Res. 1987;11289- 300
Link to Article
Snaith  RHamilton  MMorley  SHumayan  AHargreaves  DTrigwell  P A scale for the assessment of hedonic tone: the Snaith-Hamilton Pleasure Scale. Br J Psychiatry. 1995;16799- 103
Link to Article
Glassman  SWestrich  NParker  KLevitt  A Psychomotor Function in Depression: Proceedings of the American Psychiatric Association Meeting, San Diego, CA.  Washington, DC American Psychiatric Association1997;
McNair  DMLorr  MDroppleman  LF Profile of Mood States (Manual).  San Diego, Calif Educational and Industrial Testing Service1971;
Johanson  CEUhlenhuth  EH Drug preference and mood in humans: d-amphetamine. Psychopharmacology (Berl). 1980;71275- 279
Link to Article
Folstein  MFLuria  R Reliability, validity and clinical application of the Visual Analogue Mood Scale. Psychol Med. 1973;3479- 486
Link to Article
Busto  UEKaplan  HLZawertailo  LASellers  EM Pharmacologic effects and abuse liability of bretazenil, diazepam, and alprazolam in humans. Clin Pharmacol Ther. 1994;55451- 463
Link to Article
Versiani  MAmin  MChouinard  G Double-blind, placebo-controlled study with reboxetine in inpatients with severe major depressive disorder. J Clin Psychopharmacol. 2000;2028- 34
Link to Article
Kathiramalainathan  KKaplan  HLRomach  MKBusto  UELi  N-YSawe  JTyndale  RFSellers  EM Inhibition of P450 2D6 modifies codeine abuse liability. J Clin Psychopharmacol. 2000;20435- 444
Link to Article
Ocampo  JABusto  UEKaplan  HLTyndale  RFOtton  SVNolte  HSymanzik  CSellers  EM Does extent of p-hydroxylation alter methamphetamine kinetics? Clin Pharmacol Ther. 1996;59208- 212
Link to Article
Fabian  JESilverstone  PH Diltiazem, a calcium chanel antagonist, partly attenuates the effects of dextroamphetamine in healthy volunteers. Int Clin Psychopharmacol. 1997;12113- 120
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Nurnberger  JI  JrSimmons-Alling  SKessler  LJimerson  SSchreiber  JHollander  ETamminga  CANadi  NSGoldstein  DSGershon  ES Separate mechanisms for behavioral, cardiovascular, and hormonal responses to dextroamphetamine in man. Psychopharmacology. 1984;84200- 204
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Pillay  SSRenshaw  PFBonello  CMLafer  BFava  MYurgelun-Todd  D A quantitative magnetic resonance imaging study of caudate and lenticular nucleus gray matter volume in primary unipolar major depression: relationship to treatment response and clinical severity. Psychiatry Res. 1998;8461- 74
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Laruelle  MAbi-Dargham  Avan Dyck  CGil  RD'Souza  DCKrystal  JSeibyl  JBaldwin  RInnis  R Dopamine and serotonin transporters in patients with schizophrenia: an imaging study with [123I]β-CIT. Biol Psychiatry. 2000;47371- 379
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Sofuoglu  MBrown  SDudish-Poulsen  SHatsukami  DK Individual differences in the subjective response to smoked cocaine in humans. Am J Drug Alcohol Abuse. 2000;26591- 602
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De Wit  HUhlenhuth  EHJohanson  CE The reinforcing properties of amphetamine in overweight subjects and subjects with depression. Clin Pharmacol Ther. 1987;42127- 136
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D'haenen  HABossuyt  A Dopamine D2 receptors in depression measured with single photon emission computed tomography. Biol Psychiatry. 1994;35128- 132
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Bardo  MT Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens. Crit Rev Neurobiol. 1998;1237- 67
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Di Matteo  VDe Blasi  ADi Giulio  CEsposito  E Role of 5-HT(2C) receptors in the control of dopamine function. Trends Pharmacol Sci. 2001;22229- 232
Link to Article
Linner  LEndersz  HOhman  DBengtsson  FSchalling  MSvensson  TH Reboxetine modulates the firing pattern of dopamine cells in the ventral tegmental area and selectively increases dopamine availability in the prefrontal cortex. J Pharmacol Exp Ther. 2001;297540- 546
West  WBVan Groll  BJAppel  JB Stimulus effects of d-amphetamine II: DA, NE, and 5-HT mechanisms. Pharmacol Biochem Behav. 1995;5169- 76
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Parker  GWilhelm  KMitchell  PRoy  KHadzi-Pavlovic  D Subtyping depression: testing algorithms and identification of a tiered model. J Nerv Ment Dis. 1999;187610- 617
Link to Article
Meston  CMFrohlich  MA The neurobiology of sexual function. Arch Gen Psychiatry. 2000;571012- 1030
Link to Article
Pani  LPorcella  AGessa  GL The role of stress in the pathophysiology of the dopaminergic system. Mol Psychiatry. 2000;514- 21
Link to Article
Backman  LGinovart  NDixon  RAWahlin  TBWahlin  AHalldin  CFarde  L Age-related cognitive deficits mediated by changes in the striatal dopamine system. Am J Psychiatry. 2000;157635- 637
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Degree of dextroamphetamine rewarding effects vs severity of major depressive disorder. The multiple regression model (described in the "Data Analysis" subsection) in 40 patients with major depressive disorder revealed that the interaction between the Hamilton Rating Scale for Depression score and dextroamphetamine was significant (P = .04), indicating that the slope of the dextroamphetamine line was significantly greater than the slope of the placebo line. ARCI indicates Addiction Research Center Inventory.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Degree of rewarding effects experienced by participants as measured by the mean peak minus baseline Addiction Research Center Inventory (ARCI) Rewarding Effects Composite score vs severity of major depressive disorder. The P value represents the interaction between severity and drug. The age- and sex-adjusted mean (95% confidence interval) for the dextroamphetamine effect compared with placebo was 156.40(94.64-218.16) in the severe group, 46.22 (−11.84 to 104.28) in the moderate group, and 55.70 (11.33-100.07) in the control group. The mean Hamilton Rating Scale for Depression (HAM-D) scores for the groups are 1.33 for control-dextroamphetamine, 0.28 for control-placebo, 19.73 for moderate-dextroamphetamine, 18.60 for moderate-placebo, 28.46 for severe-dextroamphetamine, and 27.25 for severe-placebo. Error bars represent SD.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Time course of dextroamphetamine vs placebo effects. Time zero represents the baseline score (ie, before drug administration). Values included in the computation of the mean peak effect value were the highest scores within the peak effect time window for dextroamphetamine(60-180 minutes). ARCI indicates Addiction Research Center Inventory.

Graphic Jump Location

Tables

Table Graphic Jump LocationCharacteristics of 40 Patients With Major Depressive Disorder (MDD) vs 36 Control Subjects*

References

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Koob  GFLe Moal  M Drug abuse: hedonic homeostatic dysregulation. Science. 1997;27852- 58
Link to Article
Naranjo  CATremblay  LKBusto  UE The role of the brain reward system in depression. Prog Neuropsychopharmacol Biol Psychiatry. 2001;25781- 823
Link to Article
Shi  WXPun  CLZhang  XXJones  MDBunney  BS Dual effects of d-amphetamine on dopamine neurons mediated by dopamine and nondopamine receptors. J Neurosci. 2000;203504- 3511
Hedou  GHomberg  JMartin  SWirth  KFeldon  JHeidbreder  CA Effect of amphetamine on extracellular acetylcholine and monoamine levels in subterritories of the rat medial prefrontal cortex. Eur J Pharmacol. 2000;390127- 136
Link to Article
Kuczenski  RSegal  DSCho  AKMelega  W Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine. J Neurosci. 1995;151308- 1317
Pifl  CDrobny  HReither  H Mechanism of the dopamine-releasing actions of amphetamine and cocaine: plasmalemmal dopamine transporter versus vesicular monoamine transporter. Mol Pharmacol. 1995;47368- 373
Seiden  LSSabol  KE Amphetamine: effects on catecholamine systems and behaviour. Annu Rev Pharmacol Toxicol. 1993;33639- 677
Link to Article
Koob  GF Hedonic valence, dopamine and motivation. Mol Psychiatry. 1996;1186- 189
Uhlenhuth  EHJohanson  CEKilgore  KKobasa  SC Drug preference and mood in humans: preference for d-amphetamine and subject characteristics. Psychopharmacology. 74191- 194
Link to Article
Dommisse  CSSchulz  SCNarasimhachari  NBlackard  WGHamer  RM The neuroendocrine and behavioral response to dextroamphetamine in normal individuals. Biol Psychiatry. 1984;191305- 1315
Klein  DF Endogenomorphic depression: a conceptual and terminological revision. Arch Gen Psychiatry. 1974;31447- 454
Link to Article
Heinz  A Anhedonia: a general nosology surmounting correlate of a dysfunctional dopaminergic reward system? Nervenarzt. 1999;70391- 398
Link to Article
Carroll  BJ Neurobiological dimensions of depression and mania. Angst  Jed. The Origins of Depression: Current Concepts and Approaches. New York, NY Springer-Verlag1983;163- 186
Di Chiara  GLoddo  PTanda  G Reciprocal changes in prefrontal and limbic dopamine responsiveness to aversive and rewarding stimuli after chronic mild stress: implications for the psychobiology of depression. Biol Psychiatry. 1999;461624- 1633
Link to Article
Willner  P Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology. 1997;134319- 329
Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;161- 198
First  MBSpitzer  RLGibbon  MWilliams  JBW Structured Clinical Interview for DSM-IV Axis I Disorders–Patient Edition (SCID-I/P, Version 2.0).  New York Biometrics Research Dept, New York State Psychiatric Institute1994;
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;2356- 62
Link to Article
Hill  HEHaertzen  CAWolbach  AB  JrMiner  EJ The Addiction Research Center Inventory: standardization of scales which evaluate subjective effects of morphine, amphetamine, pentobarbital, alcohol, LSD-25, pirahexl and chloropromazine. Psychopharmacologia. 1963;4167- 183
Link to Article
Cole  JOOrzack  MHBeake  BBird  MBar-Tal  Y Assessment of the abuse liability of buspirone in recreational sedative users. J Clin Psychiatry. 1982;4369- 75
Vogt  WJacob  KOhnesorge  A-BSchwertfeger  G Highly sensitive method for the quantitation of homovanillic acid in cerebrospinal fluid. J Chromatogr. 1980;199191- 197
Link to Article
Midha  KKMcgilveray  IJCooper  JK Assay for simultaneous determination of fenfluramine and norfenfluramine in human plasma and urine. Can J Pharm Sci. 1979;1418- 21
Kendall  PHollon  SBeck  AHammen  CLIngram  RE Issues and recommendations regarding use of the Beck Depression Inventory. Cognit Ther Res. 1987;11289- 300
Link to Article
Snaith  RHamilton  MMorley  SHumayan  AHargreaves  DTrigwell  P A scale for the assessment of hedonic tone: the Snaith-Hamilton Pleasure Scale. Br J Psychiatry. 1995;16799- 103
Link to Article
Glassman  SWestrich  NParker  KLevitt  A Psychomotor Function in Depression: Proceedings of the American Psychiatric Association Meeting, San Diego, CA.  Washington, DC American Psychiatric Association1997;
McNair  DMLorr  MDroppleman  LF Profile of Mood States (Manual).  San Diego, Calif Educational and Industrial Testing Service1971;
Johanson  CEUhlenhuth  EH Drug preference and mood in humans: d-amphetamine. Psychopharmacology (Berl). 1980;71275- 279
Link to Article
Folstein  MFLuria  R Reliability, validity and clinical application of the Visual Analogue Mood Scale. Psychol Med. 1973;3479- 486
Link to Article
Busto  UEKaplan  HLZawertailo  LASellers  EM Pharmacologic effects and abuse liability of bretazenil, diazepam, and alprazolam in humans. Clin Pharmacol Ther. 1994;55451- 463
Link to Article
Versiani  MAmin  MChouinard  G Double-blind, placebo-controlled study with reboxetine in inpatients with severe major depressive disorder. J Clin Psychopharmacol. 2000;2028- 34
Link to Article
Kathiramalainathan  KKaplan  HLRomach  MKBusto  UELi  N-YSawe  JTyndale  RFSellers  EM Inhibition of P450 2D6 modifies codeine abuse liability. J Clin Psychopharmacol. 2000;20435- 444
Link to Article
Ocampo  JABusto  UEKaplan  HLTyndale  RFOtton  SVNolte  HSymanzik  CSellers  EM Does extent of p-hydroxylation alter methamphetamine kinetics? Clin Pharmacol Ther. 1996;59208- 212
Link to Article
Fabian  JESilverstone  PH Diltiazem, a calcium chanel antagonist, partly attenuates the effects of dextroamphetamine in healthy volunteers. Int Clin Psychopharmacol. 1997;12113- 120
Link to Article
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