Striatal Dopamine D2/3 Receptor Availability in Treatment Resistant Depression
et al. (2014) Striatal Dopamine D2/3 Receptor Availability in Treatment Resistant
Depression. PLoS ONE 9(11): e113612. doi:10.1371/journal.pone.0113612
Striatal Dopamine D2/3 Receptor Availability in Treatment Resistant Depression
Bart P. de Kwaasteniet 0
Chedwa Pinto 0
Eric H. G. Ruhe 0
Guido A. van Wingen 0
Jan Booij 0
Damiaan Denys 0
Huaibin Cai, National Institute of Health, United States of America
0 1 Department of Psychiatry, Academic Medical Center, Amsterdam, the Netherlands, 2 Brain Imaging Center, Academic Medical Center, Amsterdam, the Netherlands, 3 Department of Psychiatry, MC groep, Lelystad, the Netherlands, 4 Department of Nuclear Medicine, Academic Medical Center, Amsterdam, the Netherlands, 5 The Institute for Neuroscience, an institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands, 6 University of Groningen, University Medical Center Groningen, Mood and Anxiety Disorders, Department of Psychiatry , Groningen , the Netherlands
Several studies demonstrated improvement of depressive symptoms in treatment resistant depression (TRD) after administering dopamine agonists which suggest abnormal dopaminergic neurotransmission in TRD. However, the role of dopaminergic signaling through measurement of striatal dopamine D2/3 receptor (D2/3R) binding has not been investigated in TRD subjects. We used [123I]IBZM single photon emission computed tomography (SPECT) to investigate striatal D2/3R binding in TRD. We included 6 severe TRD patients, 11 severe TRD patients on antipsychotics (TRD AP group) and 15 matched healthy controls. Results showed no significant difference (p = 0.75) in striatal D2/3R availability was found between TRD patients and healthy controls. In the TRD AP group D2/3R availability was significantly decreased (reflecting occupancy of D2/3Rs by antipsychotics) relative to TRD patients and healthy controls (p,0.001) but there were no differences in clinical symptoms between TRD AP and TRD patients. This preliminary study therefore does not provide evidence for large differences in D2/3 availability in severe TRD patients and suggests this TRD subgroup is not characterized by altered dopaminergic transmission. Atypical antipsychotics appear to have no clinical benefit in severe TRD patients who remain depressed, despite their strong occupancy of D2/3Rs.
Funding: Dr. H.G. Ruhe is supported by a NWO/ZonMW VENI-Grant #016.126.059. The funders had no role in study design, data collection and analysis, decision
to publish, or preparation of the manuscript.
Competing Interests: One of the authors (Chedwa Pinto) is employed at a commercial MC groep. The authors declare that this does not alter their adherence to
PLOS ONE policies on sharing data and materials.
. These authors contributed equally to this work.
About one third of patients with major depressive disorder
(MDD) do not respond to two or more trials with different classes
of antidepressants and are considered treatment resistant [1,2].
Treatment resistant depression (TRD) is associated with an overall
worse prognosis and high medical costs . At present, little is
known about the pathophysiology of TRD, however several
studies in TRD subjects demonstrated improvement of depressive
symptoms after treatment with dopamine agonists . These
findings therefore suggest that abnormal dopaminergic
neurotransmission is implicated in the pathophysiology of TRD .
In addition, aberrant dopaminergic neurotransmission is also
associated with dysfunctional reward/motivational systems and
anhedonia; the absolute or relative inability to experience
pleasure. Anhedonia is one of the two key symptoms required
for the diagnosis of MDD . In TRD, anhedonia is often more
profound and long-lasting and associated with a deficiency of the
reward/motivational systems in the brain. Reward and motivation
are mediated by the mesolimbic system, which is one of the major
brain dopaminergic tracts . This mesolimbic tract arises from
the ventral tegmental area (VTA) and projects to the ventral
striatum (including the nucleus accumbens), hippocampus and
Relatively few neuroimaging studies examined the
dopaminergic system in MDD with either positron emission tomography
(PET) or single photon emission computed tomography (SPECT),
and reported inconsistent findings [9,10]. Studies investigating
dopamine D2/3 receptor (D2/3R) availability reported increased
striatal D2/3R availability in MDD patients compared to controls
[11,12], as well as increased striatal D2/3R availability in a
subgroup of MDD patients with psychomotor retardation [13,14].
Increased D2/3R availability may reflect either an up-regulation
of D2/3 receptors, increased affinity of the receptor for the
radioligand or a decreased synaptic dopamine concentration .
Therefore, the evidence of altered dopaminergic function in MDD
is equivocal, also, as other studies demonstrated no differences
between MDD and healthy controls [15,16]. An explanation for
these inconsistent findings may be that these studies included
MDD patients with heterogeneous clinical characteristics which
might underlie different clinical subgroups. Interestingly, it has
been suggested that TRD is characterized by a more profound
dysfunction of mood regulating networks relative to non-treatment
resistant depression [17,18], which suggests that TRD patients are
at the worst end of a continuous depression spectrum.
Furthermore, as TRD patients are often more severely anhedonic and
psychomotorically retarded, and most of the time did not respond
to serotonergic or noradrenergic drugs, abnormalities in TRD
patients may be related to reduced dopaminergic signaling. To
date, striatal D2/3R binding has not been investigated in TRD
Therefore, the aim of the present study was to investigate
striatal D2/3R binding in severe TRD patients to test the
hypothesis whether TRD patients are characterized by diminished
dopaminergic transmission, reflected by increased D2/3R
binding. We performed in vivo measurements of striatal D2/3 binding
in 6 TRD patients compared to 15 healthy controls. We
additionally investigated the effect of antipsychotics on striatal
D2/3R availability in 11 TRD patients and whether these drugs
were associated with improvement of symptomatology.
We included 6 TRD patients, 11 TRD patients on
antipsychotics (TRD AP group) and 15 healthy control subjects matched
for age and gender. TRD patients were recruited at the
department of Psychiatry of the Academic Medical Center
(AMC) in Amsterdam and St. Elisabeth Hospital in Tilburg.
The study was approved by the Medical Ethical Committee of the
AMC of the University of Amsterdam (METC AMC), and the
Medical Ethical Committee of the St. Elizabeth Hospital (METC
St. Elisabeth). All subjects provided written informed consent.
Inclusion criteria for TRD and TRD AP subjects were: (i) age
between 18 and 65 years; (ii) total Hamilton Depression Rating
Scale (HAM-D) $18; (iii) primary diagnosis of MDD according to
the Diagnostic and Statistical Manual of Mental Disorders
(DSMIV) criteria and assessed by The Structured Clinical Interview for
DSM-IV (SCID) . To capture the most severely TRD patients,
we included only patients with an illness duration of .2 years, who
did not respond to (i) at least two adequate treatments of two
different modern antidepressants (selective serotonin reuptake
inhibitors, serotoninnorepinephrine reuptake inhibitors, or
noradrenergic and specific serotonergic antidepressants), and (ii) a
tricyclic antidepressant, and (iii) an irreversible monoamine
oxidase (MAO) inhibitor, and (iv) at least 6 sessions of bilateral
electroconvulsive therapy (ECT). Exclusion criteria were: (i)
Parkinsons disease, dementia or epilepsy; (ii) bipolar disorder;
(iii) schizophrenia or a history of psychosis unrelated to MDD; (iv)
alcohol or substance abuse during last 6 months; and (v) antisocial
personality disorder. Healthy controls were screened by the
structured clinical interview for DSM-IV disorders in order to
confirm the absence of psychiatric or neurological illness .
None of the healthy participants reported a family history of
psychiatric illness. We used the HAM-D  and Montgomery
Asberg Depression Rating Scale (MADRS)  to quantify
depression severity. The Maudsley Staging Method (MSM) was
used to quantify the level of treatment resistance [22,23]. The
MSM score includes various clinical parameters; duration of the
current depressive episode, symptom severity, and level of
functioning as measured by the Global Assessment of Functioning
(GAF) score. For a complete list of these clinical variables we refer
to Fekadu et al .
Single Photon Emission Computed Tomography protocol
SPECT scanning was performed using a 12-detector single-slice
brain-dedicated scanner (Neurofocus, Inc., Medfield, MA, USA).
Subjects underwent a measurement of the striatal D2/3R binding
potential (BPND) using the selective D2/3R antagonist
[123I]iodobenzamide ([123I]IBZM). We applied a bolus/constant infusion
technique, which has been described in detail previously [24,25].
SPECT data were acquired for 60 minutes, starting 120 minutes
after infusion of the radioligand. At the day of scanning subjects
were not allowed to use alcohol, coffee and cigarettes since this has
been associated with altered striatal dopamine release [26,27].
Image reconstruction and analysis
SPECT data were reconstructed in 3-D mode and attenuation
correction of all images was performed as described earlier .
For quantification, a region of interest (ROI) analysis was
performed. Fixed ROIs were positioned for the striatum and, as
a reference, the occipital cortex . Mean striatal and mean
occipital binding were averaged from right and left ROIs. Then,
BPND was calculated as the ratio of specific to non-specific binding
((total activity in striatum - activity in occipital cortex)/activity in
the occipital cortex). All scans were analyzed by one investigator
(CP) who was blind to the clinical data. To measure the inter-rater
agreement, two authors (CP and BdK) independently analysed
BPND in ten subjects. The intraclass correlation coefficient (ICC)
was 0.94 for left- and 0.95 for right striatum which indicates an
excellent agreement between both raters.
Differences in age, HAM-D and MADRS scores were evaluated
with a one way analysis of variance (ANOVA), and gender
differences using a chi-square test. Comparison of striatal D2/3R
availability between TRD, TRD AP and healthy control subjects
was performed with an ANOVA as well. Using a Least Significant
Difference (LSD) ANOVA post-hoc test, differences in D2/3R
availability were investigated between TRD patients and healthy
controls, between TRD AP patients and healthy controls and
between TRD AP and TRD patients. Since D2/3R availability is
influenced by age  and gender , we additionally included
these variables as covariates in the group analyses using a one way
analysis of covariance (ANCOVA). A two tailed probability value
of 0.05 was selected as significance level.
TRD, TRD AP and control subjects were comparable for age
and gender (Table 1). HAM-D and MADRS scores did not differ
between TRD and TRD AP patients which indicates no difference
in severity of depression between both groups. Mean MSM scores
of TRD patients were 11.8 (61.0) and for TRD AP patients 11.8
(60.5) which indicates a high level of treatment resistance in both
groups. An overview of medication use of each TRD and TRD AP
patient is reported in Table 2.
There were no significant differences in mean striatal D2/3R
availability between TRD patients and healthy controls (p = 0.75)
suggesting that dopaminergic neurotransmission was not
significantly altered in TRD patients (Table 1, Figure 1 and 2). The
standardized effect size was 0.21. Furthermore, the mean D2/3R
availability of the TRD AP group was significantly lower
compared to both the TRD (p = 0.001) and healthy control group
(p,0.001). Since the antipsychotics used by the TRD AP patients
Age of onset (SEM)
Striatal D2/3R availability (BPND) (SEM)
TRD (n = 6)
TRD AP (n = 11)
HCs (n = 15)
Abbreviations: TRD; Treatment resistant depression, TRD AP; Treatment resistant depression patients using antipsychotics, HCs; Healthy Controls, SEM; standard error of
the mean MADRS; Montgomery Asberg Depression Rating Scale, HAM-D; Hamilton Depression Rating Scale, MSM; Maudsley Staging Method, BPND; Binding Potential
non-displaceable (reflects striatal D2/3R availability)
1One way ANOVA.
2Chi square test.
were all dopamine receptor antagonists, this demonstrates strong
occupancy of striatal D2/3Rs (Table 1, Figure 2; occupancy of
50%620%). Correction for age and gender did not significantly
affect these results.
This preliminary study is, to the best of our knowledge, the first
to investigate striatal D2/3R availability in TRD. We included a
unique group of severe TRD patients which were eligible for deep
brain stimulation, with an illness duration of more than 2 years
defined as non-response to at least four adequate treatments of
different antidepressants and at least 6 sessions of bilateral ECT.
We showed no significant differences in striatal D2/3R availability
in TRD patients relative to healthy controls which suggests that
dopaminergic neurotransmission is not significantly altered in
TRD. Furthermore, the TRD AP subjects showed significantly
decreased striatal D2/3R availability relative to both TRD and
healthy control subjects, which reflects a significant occupancy of
D2/3Rs (estimated to be approximately 50%) by these atypical
antipsychotics. Interestingly, despite these large differences in
receptor occupancy depressive symptoms were not improved in
the TRD AP subjects.
Previously, it was suggested that particularly TRD is associated
with dopaminergic dysfunction . Since TRD is characterized by
a more profound dysfunction of mood regulating networks
[17,18], we expected them to show more severe dopaminergic
dysfunction and as such an increased D2/3R availability
compared to controls. Nevertheless, we observed no significant
difference in striatal D2/3R availability in TRD patients
compared to controls. We propose several explanations for this
finding. First, other studies reported differences in D2/3R
availability in psychomotor retarded patients [13,14]. In our
sample we used item 8 (range 0 to 4) of the HAM-D scores to
measure psychomotor retardation which showed these TRD
patients suffered only moderately from psychomotor retardation.
Unfortunately, our study lacks more sensitive tests to measure
motor retardation such as a finger tapping task . We therefore
Lithiumcarbonate 600 mg Quetiapine 300 mg Lorazepam 3 mg
Tranylcypromine 10 mg Zopiclon 7.5 mg
TRD AP patients (n = 11)
Olanzapine 5 mg Zoplicon 15 mg
Quetiapine 500 mg Lorazepam 1 mg
Tranylcypromine 90 mg Quetiapine 100 mg Aripiprazol 30 mg
Olanzapine 12.5 mg Flurazepam 15 mg Lorazepam 6 mg
Quetiapine 600 mg Venlafaxine 75 mg
Dipiperon 80 mg Lorazepam 5.5 mg Zoplicon 7.5 mg
Quetiapine 700 mg Oxazepam 10 mg Zolpidem 20 mg
Tranylcypromine 20 mg Dipiperon 80 mg
Imipramine 25 mg Olanzapine 10 mg
TRD patients (n = 6)
Lithiumcarbonate 800 mg Zolpidem 20 mg
Figure 1. Transversal images of D2/3R availability. Transversal [123I]IBZM SPECT slices at the level of the striatum showing D2/3 receptor
availability in a TRD patient, a TRD patient on antipsychotics (TRD AP), and a healthy control subject.
cannot exclude the option that our patients were less
psychomotorically retarded than in previous studies [13,14]. Second, in the
present sample TRD patients were only included after a
nonresponse to MAO-inhibitors. As MAO-inhibitors increase
dopamine concentrations, it could be hypothesized that especially in a
subgroup of patients with a good response to MAO-inhibitors a
hypodopaminergic state might exist. This could explain why in the
current sample of non-responders to MAO-inhibitors no
differences in striatal D2/3R availability were found. However, this
hypothesis has not been investigated yet. Third, the present sample
might be too small to detect differences in striatal D2/3R
availability between TRD and control subjects. Importantly,
however, the standardized effect size was small (d = 0.21). This
implies that at least 343 patients should be included to
demonstrate a significant group difference (at a statistical power
of 0.8). Therefore the chance that future larger studies will find
increased D2/3R availability in this subgroup of TRD-patients
appears to be low. Furthermore, our present findings are
consistent with several MDD studies which also reported no
differences in striatal D2/3R availability relative to healthy
controls [15,16]. However these studies included different clinical
groups with mostly treatment sensitive patients and a shorter
duration of illness which therefore hampers direct comparisons.
As expected, the TRD AP subjects showed significantly
decreased striatal D2/3R availability relative to TRD subjects
(which reflects occupancy of D2/3Rs by the antipsychotics). The
present D2/3R occupancy (approximately 50%) in the TRD AP
group is comparable with that of atypical antipsychotics in
schizophrenia patients [31,32]. Since we showed no significant
differences in depressive symptoms between these groups at
Figure 2. Striatal D2/3R availability for TRD, TRD AP and healthy control subjects. Striatal D2/3 receptor (D2/3R) availability of TRD
patients, TRD patients with antipsychotics (TRD AP) and healthy control subjects. The black dots represents the striatal D2/3R availability of each
subject. The horizontal lines indicate the mean D2/3R availability of each group which is 0.84 for the TRD, 0.50 for the TRD AP and 0.81 for the healthy
adequate occupancy levels, this suggests that either monotherapy
or augmentation with atypical antipsychotics does not provide
clinical benefits in this specific TRD group, suggesting that these
antipsychotics could be tapered in these patients. Importantly, all
antipsychotic drugs used by the TRD AP patients have
appreciable 5-HT2A receptor occupancy which has been shown
to improve depressive symptoms . The 5-HT2A receptor
occupancy in these patients therefore cannot explain the lack of
clinical improvement in this group. An explanation for the
nonresponse might be that these atypical antipsychotics are all
dopamine receptor antagonists. Interestingly, several studies
showed that adjunctive dopamine agonists like pramipexole are
effective in TRD patients [6,34,35] which suggests that dopamine
agonist augmentation therapy might also be effective in the present
severe TRD patients. We speculate that direct stimulation of
dopamine D2/3 receptors may be helpful to increase motivational
processes in the brain .
Despite the frequent use of atypical antipsychotic drugs in
psychotic depression [37,38], low-dose augmentation of these
drugs in (non-psychotic) TRD patients has been proven to be
effective [39,40]. However, in these augmentation studies TRD
was mostly defined as a non-response to only two trials of
antidepressants. The present TRD patients additionally did not
respond to more classes of antidepressants such as tricyclic
antidepressants and MAO-inhibitors which may further explain
the non-response to atypical antipsychotics, which might have no
clinical benefit in more severe TRD patients. However, a
randomized controlled trial would be necessary to definitely
conclude whether antipsychotic augmentation in severe TRD is
We acknowledge several limitations of the present study. First,
several studies showed that the striatum contains not only D2/3
receptors but also dopamine D1 receptors which operate via
different intracellular pathways . The dopamine D1 receptor is
part of a D1-like subfamily which also comprises the dopamine D5
receptor . Striatal D1 receptors are part of the direct
nigrostriatal output pathway whereas D2 receptors are more
prevalent in the indirect pathway . Despite these functional
differences, an animal study demonstrated that concurrent
activation of D1 and D2 receptors in the shell of the nucleus
accumbens produces a cooperative effect on the regulation of
motivation, i.e. dopamine mediated reward processes . Since
depression has been associated with a dysfunctional reward/
motivational system [44,45], these findings suggest that altered
expression of D1 receptors might lead to disturbances in the
motivational system in MDD patients. However, as far as we know
no human study has investigated striatal D1 availability in MDD
nor in TRD. The Positron Emission Tomography (PET)
radioligand [11C] SCH23390 binds to dopamine D1-like receptors
, and to a lesser extent to D5 receptors. Since the expression of
the D5 receptors in the striatum is lower, [11C] SCH23390
binding will predominantly reflect D1 receptor availability. [11C]
SCH23390, but also other ligands like [11C]NNC 756  or
[11C]SKF 82957  could therefore be used to investigate striatal
dopamine D1 receptor availability in MDD and TRD patients.
Second, three out six TRD patients used psychotropic
medication which might have influenced striatal D2/3R
availability. One of these patients used a MAO-inhibitor which
increases the synaptic dopamine concentration in the striatum
. Therefore, use of this drug could have reduced striatal D2/
3R availability in this patient by increased competition with the
radioligand. However, exclusion of this patient did not change
results. In fact, large increases in dopamine concentrations are
needed to reduce the [123I]IBZM binding in vivo. Another TRD
patient used mirtazapine which is a noradrenergic and specific
serotonergic antidepressant (NaSSA). Although mirtazapine has
no affinity for dopamine receptors it does increase dopamine
release in the prefrontal and occipital cortex by activation of the
5HT1A receptor and blockade of the a2-adrenergic receptors
[50,51]. However, there is no evidence that mirtazapine increases
striatal dopamine release which suggests striatal D2/3R binding is
not altered by mirtazapine use. Third, with [123I]IBZM we are
able to measure striatal D2/3Rs in vivo. However, consequently
we cannot exclude differences in extra-striatal D2/3Rs in TRD,
which cannot be quantified. Finally, we did not select
TRDpatients based on symptomatology like psychomotor retardation
and/or anhedonia which might represent a subgroup with
decreased D2/3R availability.
In conclusion, the present study did not detect differences in
striatal D2/3R receptor availability in severely treatment resistant
MDD patients relative to healthy controls. This contradicts the
hypothesis that TRD is characterized by altered dopaminergic
transmission. Furthermore, the results showed that additional
treatment with antipsychotics decreased striatal D2/3R receptor
availability (due to occupancy of D2/3R by the antipsychotics) in
TRD. Importantly, because depressive symptoms were not
reduced in these TRD AP patients, this suggest that in patients
who have been administered different antidepressant drugs and
remain depressed, atypical antipsychotics do not have a clinical
We gratefully acknowledge Elsmarieke van de Giessen and Evelien Zoons
for providing healthy controls, and both patients and healthy controls for
participating in SPECT-scanning. Provided healthy controls: EvdG, EZ.
Conceived and designed the experiments: BDK CP JB ER. Performed the
experiments: BDK CP. Analyzed the data: BDK CP. Contributed
reagents/materials/analysis tools: BDK CP JB. Wrote the paper: BDK
CP JB ER GVW DD.
1. Greden JF ( 2001 ) The burden of disease for treatment-resistant depression . J Clin Psychiatry 62 Suppl 16 : 26 - 31 .
2. Rush AJ , Trivedi MH , Wisniewski SR , Nierenberg AA , Stewart JW , et al. ( 2006 ) Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report . Am J Psychiatry 163 : 1905 - 1917 .
3. Ustun TB , Kessler RC ( 2002 ) Global burden of depressive disorders: the issue of duration . Br J Psychiatry 181 : 181 - 183 .
4. Cusin C , Iovieno N , Iosifescu DV , Nierenberg AA , Fava M , et al. ( 2013 ) A randomized, double-blind, placebo-controlled trial of pramipexole augmentation in treatment-resistant major depressive disorder . J Clin Psychiatry 74 : e636 - e641 .
5. Inoue T , Kitaichi Y , Masui T , Nakagawa S , Boku S , et al. ( 2010 ) Pramipexole for stage 2 treatment-resistant major depression: an open study . Prog Neuropsychopharmacol Biol Psychiatry 34 : 1446 - 1449 .
6. Lattanzi L , Dell'Osso L , Cassano P , Pini S , Rucci P , et al. ( 2002 ) Pramipexole in treatment-resistant depression: a 16-week naturalistic study . Bipolar Disord 4 : 307 - 314 .
7. Dunlop BW , Nemeroff CB ( 2007 ) The role of dopamine in the pathophysiology of depression . Arch Gen Psychiatry 64 : 327 - 337 .
8. American Psychiatric Association ( 1994 ) Diagnostic and Statistical Manual of Mental Disorders , 4th ed: American Psychiatric Press.
9. Dunlop BW , Nemeroff CB ( 2007 ) The role of dopamine in the pathophysiology of depression . Arch Gen Psychiatry 64 : 327 - 337 .
10. Ruhe HG , Visser KD , Frokjaer VG , Haarman CM , Klein C , et al. ( 2014 ) Molecular imaging of depressive disorders PET and SPECT in Psychiatry, den Boer ,J.A.; ed: Springer Verlag, pp 93 - 172 .
11. D'haenen HA , Bossuyt A ( 1994 ) Dopamine D2 receptors in depression measured with single photon emission computed tomography . Biol Psychiatry 35 : 128 - 132 .
12. Shah PJ , Ogilvie AD , Goodwin GM , Ebmeier KP ( 1997 ) Clinical and psychometric correlates of dopamine D2 binding in depression . Psychol Med 27 : 1247 - 1256 .
13. Ebert D , Feistel H , Loew T , Pirner A ( 1996 ) Dopamine and depression-striatal dopamine D2 receptor SPECT before and after antidepressant therapy . Psychopharmacology (Berl) 126 : 91 - 94 .
14. Meyer JH , McNeely HE , Sagrati S , Boovariwala A , Martin K , et al. ( 2006 ) Elevated putamen D(2) receptor binding potential in major depression with motor retardation: an [11C]raclopride positron emission tomography study . Am J Psychiatry 163 : 1594 - 1602 .
15. Parsey RV , Oquendo MA , Zea-Ponce Y , Rodenhiser J , Kegeles LS , et al. ( 2001 ) Dopamine D ( 2 ) receptor availability and amphetamine-induced dopamine release in unipolar depression . Biol Psychiatry 50 : 313 - 322 .
16. Yang YK , Yeh TL , Yao WJ , Lee IH , Chen PS , et al. ( 2008 ) Greater availability of dopamine transporters in patients with major depression-a dual-isotope SPECT study . Psychiatry Res 162 : 230 - 235 .
17. Konarski JZ , Kennedy SH , McIntyre RS , Rafi-Tari S , Soczynska JK , et al. ( 2007 ) Relationship between regional brain metabolism, illness severity and age in depressed subjects . Psychiatry Res 155 : 203 - 210 .
18. Paillere Martinot ML , Martinot JL , Ringuenet D , Galinowski A , Gallarda T , et al. ( 2011 ) Baseline brain metabolism in resistant depression and response to transcranial magnetic stimulation . Neuropsychopharmacology 36 : 2710 - 2719 .
19. First MB ( 2012 ) Structured Clinical Interview for DSM-IV-TR Axis I Disorders , Research Version, Patient Edition : New York State Psychiatric Institute .
20. Hamilton M ( 1960 ) A rating scale for depression . J Neurol Neurosurg Psychiatry 23 : 56 - 62 .
21. Montgomery SA , Asberg M ( 1979 ) A new depression scale designed to be sensitive to change . Br J Psychiatry 134 : 382 - 389 .
22. Fekadu A , Wooderson S , Donaldson C , Markopoulou K , Masterson B , et al. ( 2009 ) A multidimensional tool to quantify treatment resistance in depression: the Maudsley staging method . J Clin Psychiatry 70 : 177 - 184 .
23. Ruhe HG , van RG , Spijker J , Peeters FP , Schene AH ( 2012 ) Staging methods for treatment resistant depression. A systematic review . J Affect Disord 137 : 35 - 45 .
24. Booij J , Korn P , Linszen DH , van Royen EA , et al. ( 1997 ) Assessment of endogenous dopamine release by methylphenidate challenge using iodine-123 iodobenzamide single-photon emission tomography . Eur J Nucl Med 24 : 674 - 677 .
25. Boot E , Booij J , Zinkstok JR , Linszen DH , Baas F , et al. ( 2010 ) Striatal D ( 2 ) receptor binding in 22q11 deletion syndrome: an [123I]IBZM SPECT study . J Psychopharmacol 24 : 1525 - 1531 .
26. Kaasinen V , Aalto S , Nagren K , Rinne JO ( 2004 ) Dopaminergic effects of caffeine in the human striatum and thalamus . Neuroreport 15 : 281 - 285 .
27. Nevo I , Hamon M ( 1995 ) Neurotransmitter and neuromodulatory mechanisms involved in alcohol abuse and alcoholism . Neurochem Int 26 : 305 - 336 .
28. Booij J , Tissingh G , Boer GJ , Speelman JD , Stoof JC , et al. ( 1997 ) [123I]FP-CIT SPECT shows a pronounced decline of striatal dopamine transporter labelling in early and advanced Parkinson's disease . J Neurol Neurosurg Psychiatry 62 : 133 - 140 .
29. Rinne JO , Hietala J , Ruotsalainen U , Sako E , Laihinen A , et al. ( 1993 ) Decrease in human striatal dopamine D2 receptor density with age: a PET study with [11C]raclopride . J Cereb Blood Flow Metab 13 : 310 - 314 .
30. Trainor BC ( 2011 ) Stress responses and the mesolimbic dopamine system: social contexts and sex differences . Horm Behav 60 : 457 - 469 .
31. Kapur S , Zipursky RB , Remington G ( 1999 ) Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia . Am J Psychiatry 156 : 286 - 293 .
32. Tauscher J , Hussain T , Agid O , Verhoeff NP , Wilson AA , et al. ( 2004 ) Equivalent occupancy of dopamine D1 and D2 receptors with clozapine: differentiation from other atypical antipsychotics . Am J Psychiatry 161 : 1620 - 1625 .
33. Celada P , Puig M , Amargos-Bosch M , Adell A , Artigas F ( 2004 ) The therapeutic role of 5-HT1A and 5-HT2A receptors in depression . J Psychiatry Neurosci 29 : 252 - 265 .
34. Hori H , Kunugi H ( 2012 ) The efficacy of pramipexole, a dopamine receptor agonist, as an adjunctive treatment in treatment-resistant depression: an openlabel trial . ScientificWorldJournal 2012 : 372474 .
35. Izumi T , Inoue T , Kitagawa N , Nishi N , Shimanaka S , et al. ( 2000 ) Open pergolide treatment of tricyclic and heterocyclic antidepressant-resistant depression . J Affect Disord 61 : 127 - 132 .
36. Leentjens AF , Koester J , Fruh B , Shephard DT , Barone P , et al. ( 2009 ) The effect of pramipexole on mood and motivational symptoms in Parkinson's disease: a meta-analysis of placebo-controlled studies . Clin Ther 31 : 89 - 98 .
37. Farahani A , Correll CU ( 2012 ) Are antipsychotics or antidepressants needed for psychotic depression? A systematic review and meta-analysis of trials comparing antidepressant or antipsychotic monotherapy with combination treatment . J Clin Psychiatry 73 : 486 - 496 .
38. Wijkstra J , Lijmer J , Burger H , Geddes J , Nolen WA ( 2013 ) Pharmacological treatment for psychotic depression . Cochrane Database Syst Rev 11 : CD004044 .
39. Corya SA , Williamson D , Sanger TM , Briggs SD , Case M , et al. ( 2006 ) A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression . Depress Anxiety 23 : 364 - 372 .
40. Nelson JC , Papakostas GI ( 2009 ) Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials . Am J Psychiatry 166 : 980 - 991 .
41. Vallone D , Picetti R , Borrelli E ( 2000 ) Structure and function of dopamine receptors . Neurosci Biobehav Rev 24 : 125 - 132 .
42. Gerfen CR , Engber TM , Mahan LC , Susel Z , Chase TN ( 1990 ) D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons . Science 250 : 1429 - 1432 .
43. Ikemoto S , Glazier BS , Murphy JM , McBride WJ ( 1997 ) Role of dopamine D1 and D2 receptors in the nucleus accumbens in mediating reward . J Neurosci 17 : 8580 - 8587 .
44. Pizzagalli DA , Holmes AJ , Dillon DG , Goetz EL , Birk JL , et al. ( 2009 ) Reduced caudate and nucleus accumbens response to rewards in unmedicated individuals with major depressive disorder . Am J Psychiatry 166 : 702 - 710 .
45. Smoski MJ , Felder J , Bizzell J , Green SR , Ernst M , et al. ( 2009 ) fMRI of alterations in reward selection, anticipation, and feedback in major depressive disorder . J Affect Disord 118 : 69 - 78 .
46. Plaven-Sigray P , Gustavsson P , Farde L , Borg J , Stenkrona P , et al. ( 2014 ) Dopamine D1 receptor availability is related to social behavior: A positron emission tomography study . Neuroimage 102P2 : 590 - 595 .
47. Abi-Dargham A , Simpson N , Kegeles L , Parsey R , Hwang DR , et al. ( 1999 ) PET studies of binding competition between endogenous dopamine and the D1 radiotracer [11C]NNC 756 . Synapse 32 : 93 - 109 .
48. Palner M , McCormick P , Parkes J , Knudsen GM , Wilson AA , et al. ( 2010 ) Systemic catechol-O-methyl transferase inhibition enables the D1 agonist radiotracer R-[11C]SKF 82957 . Nucl Med Biol 37 : 837 - 843 .
49. Yamada M , Yasuhara H ( 2004 ) Clinical pharmacology of MAO inhibitors: safety and future . Neurotoxicology 25 : 215 - 221 .
50. Devoto P , Flore G , Pira L , Longu G , Gessa GL ( 2004 ) Mirtazapine-induced corelease of dopamine and noradrenaline from noradrenergic neurons in the medial prefrontal and occipital cortex . Eur J Pharmacol 487 : 105 - 111 .
51. Nakayama K , Sakurai T , Katsu H ( 2004 ) Mirtazapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation . Brain Res Bull 63 : 237 - 241 .