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Probing Brain Reward System Function in Major Depressive Disorder
Altered Response to Dextroamphetamine
Lescia K. Tremblay, BSc;
Claudio A. Naranjo, MD;
Laura Cardenas, MD;
Nathan Herrmann, MD;
Usoa E. Busto, PharmD
Arch Gen Psychiatry. 2002;59:409-416.
ABSTRACT
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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 effects
3.4-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.
INTRODUCTION
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,3-7
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.16-18
The mesocorticolimbic dopamine system is among the most studied BRS pathway
in animal models19-21
and has recently been implicated in human BRS studies of nicotine, cocaine,
and dextroamphetamine reward.22-25
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.28-30 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.31-35
Studies have shown that the intensity of the behavioral effects of dextroamphetamine
(eg, euphoria) correlates with the extent of dopamine binding to D2
receptors,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,36-38
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 AND METHODS
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  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
( = .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.
RESULTS
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.
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Characteristics of 40 Patients With Major Depressive Disorder (MDD)
vs 36 Control Subjects*
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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 R2
for the model was 0.63, and the P value for the interaction
between drug and HAM-D score was .04 (Figure
1). 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.
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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.
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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.
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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.
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The Cronbach 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 increased
21/14 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 of
165.68 (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 1
was 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).
COMMENT
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, 58-61
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
Studies71-74
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.28-29,77-80
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
AUTHOR INFORMATION
Submitted for publication June 5, 2000; final revision received May
31, 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, March
15, 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{at}utoronto.ca).
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.
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