Acta Neuropsychiatrica 2008: 20: 199–206All rights reservedDOI: 10.1111/j.1601-5215.2008.00284.x

# 2008 The AuthorsJournal compilation # 2008 Blackwell Munksgaard

ACTA NEUROPSYCHIATRICA

The response to sulpiride in major depressionbefore and after cognitive behaviouraltherapy: D2 receptor function

Bell C, Bhika S, Porter R, Frampton C, Carter J, McIntosh V, Jordan J,Joyce P. The response to sulpiride in major depression before and aftercognitive behavioural therapy: D2 receptor function.

Background: Previous studies have suggested that antidepressanttreatment of depression may potentiate dopamine transmission throughincreased sensitivity of postsynaptic D2 receptors.Method: D2 receptor function was assessed in 24 patients with majordepression before and 16 patients after 16 weeks of treatment withcognitive behavioural therapy (CBT) using a challenge with a selectiveD2 antagonist, sulpiride. Four hundred milligrams of sulpiride wasadministered orally on two test days and response was measured by thechange in prolactin levels and changes in self-rating scale measures ofmood, anxiety and pleasure.Results: The prolactin response to sulpiride (as measured by themaximum prolactin level) was significantly increased after CBT(z ¼ 22.792, p ¼ 0.005). Sulpiride resulted in an improvement on moodratings on both test days, but after CBT, this effect was significantlydiminished as measured by the Profile of Mood States score (t ¼ 22.27,p ¼ 0.038).Conclusions: After 16 weeks of CBT, we detected an enhanced prolactinresponse to sulpiride, suggesting an increased sensitivity of D2 receptorfunctioning.

Caroline Bell, Shamina Bhika,Richard Porter, Chris Frampton,Janet Carter, Virginia McIntosh,Jenny Jordan, Peter JoyceDepartment of Psychological Medicine,University of Otago, Christchurch, New Zealand

Keywords: cognitive behavioural therapy; depression;dopamine; sulpiride

Dr Caroline Bell, Department of PsychologicalMedicine, University of Otago, PO Box 4345,Christchurch, New Zealand.Tel: 164 3 372 0400;Fax: 164 3 372 0407;E-mail: caroline.bell@chmeds.ac.nz

Introduction

Several lines of evidence implicate the dopaminer-gic system both in the pathophysiology of dep-ression and in the mechanism of action ofantidepressant drugs (1) [reviewed in Dunlop andNemeroff (2)].Clinically, there is a high prevalence of depres-

sion in disorders associated with abnormaldopamine (DA) function such as Parkinson’sdisease and Huntington’s chorea with depressivesymptoms often predating the motor manifesta-tions of the conditions (3,4). There have also beenreports of typical antipsychotics with predomi-nant DA-blocking effects contributing to theemergence of depressive symptoms in patientswith schizophrenia (5). Dunlop and Nemeroff (2)in their review also suggest that there may be a�dopaminergic dysfunction’ subtype of depressionthat responds poorly to antidepressants, which act

primarily on serotonin (5HT) and noradrenaline(NA) neurons.Although most commonly used antidepressants

[selective serotonin reuptake inhibitors (SSRIs)and tricyclics] have little effect on the DA system,some do. These include nomifensine (a DA andNA reuptake inhibitor), amineptine (a DA trans-porter antagonist), sertraline (SSRI that blocksDA at high doses), bupropion (a DA and NAtransporter antagonist) and monoamine oxidaseinhibitors (which prevent breakdown of DA, NAand 5HT). There have been case reports anda preliminary small study (although not replicated)of the successful use of DA-enhancing treatmentsin patients with resistant depression (6). There hasalso been interest in the involvement of DA in thebrain reward system with studies suggesting alteredreward processing in patients with major de-pression, which may underlie the experience of

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anhedonia, one of the core symptoms of thedisorder (7,8).In animal models of depression such as learned

helplessness, behavioural despair and chronic mildstress, emergence of �depressed-like’ behaviour isassociated with a subsensitive dopaminergic sys-tem. Studies of these animal models have reporteda decrease in dopamine 2 (D2) receptor binding inthe nucleus accumbens (9) and reduced rewardingand locomotor stimulant effects of DA agonists atDA receptors (D2/D3) (10). DA antagonists havebeen reported to exacerbate this �depressed-like’behaviour, while DA agonists and antidepressantshave been reported to improve it (11,12). Mostpreclinical studies (but not all) (16) suggest thatchronic antidepressant treatments enhance DAneurotransmission by increasing the sensitivity orresponsiveness of postsynaptic D2/D3 receptors inmesolimbic terminal regions (1,13–15). Studieshave also reported a reversal of the reduced D2/D3 binding in models of chronic mild stress byantidepressants (9) and that acute treatment withlow-dose DA antagonists reverses the behaviouraleffects of chronic antidepressant treatment (14,17–19).Although the preclinical evidence discussed

above is suggestive of a role for DA in depression,the literature investigating DA function in depres-sed human subjects has been more conflicting.Most studies of measures of cerebrospinal fluid(CSF) levels of the DA metabolite homovanillicacid (HVA) have reported lower concentrations indepressed patients compared with controls, partic-ularly in patients with psychomotor retardation(20–22). A recent study of the direct measurementof brain monoamine metabolites from the internaljugular vein of patients with treatment refractorydepression similarly reported low HVA concen-trations, which correlated with illness severity (23).Findings from neuroendocrine studies have, how-ever, been very mixed with some suggesting anincreased sensitivity of D2 receptors in depressedpatients compared with healthy controls (24,25),while others report no difference (26,27). Neuro-imaging studies have similarly been inconclusive.Two single photon emission computed tomogra-phy (SPECT) studies reported increased D2binding in the striatum of depressed patientscompared with healthy controls (28,29), whileothers have failed to replicate these findings (30–32). A recent positron emission tomography studyhas also shown elevated D2 receptor bindingpotential in the striatum of depressed patients,which was particularly pronounced in patients withmotor retardation (33). There have also beenreports of an enhanced responsiveness to the

reward effects of dextroamphetamine in depressedpatients compared with controls, which the authorssuggest may be a reflection of a compensatoryupregulation of DA receptors (7,8). Although theliterature is not conclusive, there is a suggestionthat there may be a reduction in DA function indepression, which may be reflected in a compensa-tory upregulation and increased responsiveness ofD2 receptor binding in some brain areas. Asdiscussed in the recent review, however, �thequestion of what, if any, role DA circuit dysfunc-tion plays in the pathophysiology of depressionremains an open one’ (2).

The role of DA in the treatment response isunfortunately also to date unclear. Neuroendocrinestudies investigating the effects of treatment ondopaminergic function in depressed patients havereported increased sensitivity of D2 receptors aftersuccessful treatment with total sleep deprivation(34) but not in a study of antidepressant treatment(26). SPECT studies have similarly reportedincreased binding of D2 receptors in the striatumand the anterior cingulate cortex in depressedpatients after treatment with selective SSRIs anda positive correlation between this increase in D2binding and treatment response (31,35). Support-ing the animal literature, in a recent study of eightdepressed patients successfully treated with anSSRI, administration of a low-dose D2 antagonistled to a reinstatement of depressed mood (36).Although, as before there are some contradictoryfindings, taken together, the literature suggests thateffective treatment may potentiate DA transmis-sion through increased sensitivity of postsynapticD2 receptors. In fact, it has been suggested that thismay represent a �final common pathway’ of actionof antidepressant treatments (36). To date, nostudy has investigated the effect of psychologicaltreatments on DA function.

The aim of this study was to address thisquestion by assessing D2 receptor sensitivity indepressed patients before and after treatment withcognitive behavioural therapy (CBT) using a chal-lenge with a selective D2 antagonist, sulpiride.Sulpiride is a selective D2 antagonist and has beenrepeatedly reported to result in an increase inprolactin (PRL), which is thought to be as a resultof its D2 antagonist effects in the tuberoinfundib-ular pathway (37). This study investigated theeffects of sulpiride (as measured by the PRLresponse and changes to ratings of mood and theability to experience pleasure) before and aftertreatment with CBT. We hypothesised that treat-ment response to CBT would be accompanied byenhanced D2 receptor function, which would bereflected by changes to these measures.

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Methods

Subjects

Twenty-four patients with major depressive disor-der participated in this study. These patients wererecruited as part of an out-patient psychotherapytreatment study of depression at the ClinicalResearch Unit (CRU), Department of Psycholo-gical Medicine, Christchurch School of Medicine,Christchurch, New Zealand. All subjects providedinformed written consent for the study, which hadbeen approved by the Upper South B RegionalEthics Committee, Christchurch, New Zealand.Patients were diagnosed with major depression

according to DSM-IV criteria assessed by theStructured Clinical Interview for DSM-IV (38)administered by experienced clinicians (J. C., V. M.and J. J.) who then became the treating therapists.Patients had no ongoing alcohol or substanceabuse and no significant medical conditions. Allhad been psychotropic medication free for at least4 weeks prior to testing.At baseline, patients’ mood symptoms were

assessed using the Hamilton Depression RatingScale (HDRS) (39) and the Montgomery andAsberg Depression Rating Scale (MADRS) (40).After baseline testing (test day 1), patients were

treated with CBT by a registered clinical psycholo-gist for 16 weeks. Sessions were for 50–60 min oncea week. HDRS and MADRS were assessed by oneindependent clinician (i.e. not the treating therapist)at weeks 0–16. After 16 weeks of treatment, patientswere invited to repeat the test day.

Test days

The study involved two test days – one beforetreatment and one after at least 16 weeks of CBT.The test days took place in the CRU, Departmentof Psychological Medicine, Christchurch School ofMedicine, Christchurch, New Zealand.On each test day, patients came to the unit at

13.00 hours where they were given a standardisedlunch consisting of a sandwich, fruit and decaf-feinated tea or coffee. An antecubital catheter wasinserted and kept patent using heparinised saline.Patients then rested in a semi-supine position in thetest room where they remained for the duration ofthe study. They were allowed to watch neutralcontent videos, TV or read but were not allowed tosleep. They drank only water during the studyperiod. At 13.30 hours, a blood sample was takenfor prolactin, and subjects completed the ratingscales (see below).At 14.00 hours, they were given 400 mg of the

selective dopamine 2 receptor (D2) antagonist,

sulpiride orally. Subjects had been given writteninformation about potential temporary side effectsof sulpiride when they had consented to participatein the study (such as drowsiness, unhappy mood,tremor, rigidity, muscle spasms and an inability tosit still).Blood samples were then taken every 30 min for

the next 3 h for prolactin. Rating scales werecompleted again 60 min after sulpiride was given.At 17.00 hours, patients were allowed to go home.They were provided with access to medical cover,if required, over the following 24 h.The decision was made not to include a placebo

condition (which would have required a total offour test days – two before treatment, at leasta week apart, and two after treatment) in view ofthe fact that this would have unacceptably delayedthe commencement of treatment of the patients’depression.

Measures on test days. Plasma hormone and druglevels. The primary neuroendocrine measure wasthe plasma prolactin levels in response to thesulpiride challenge. Prolactin concentrations weremeasured using the Beckman Coulter Access analy-ser and prolactin assay, which is a one-step, two-siteimmunoenzymatic assay with chemiluminescentdetection. The between-assay coefficient of variationwas 3.5% at 150 mIU/l and 6% at 620 mIU/l.

Measures of mood and anxiety. Changes in moodsymptoms were assessed using the Profile of MoodStates (POMS) (41), in which patients rated ona scale of 0–4 of how strongly they felt certainemotions, grouped into five subscales (tension/anxiety, depression/dejection, anger/hostility, fatigue/inertia and confusion/bewilderment). The scores inthese five subscales were added to give a score for�total mood disturbance’. Anxiety symptoms wererated using the Spielberger Trait Anxiety Inventory(STAI) and Spielberger State Anxiety Inventory(SSAI) (42).

Measures of the experience of pleasure or anhedonia.In view of the hypothesis that anhedonia isassociated with a dysfunction of the DA rewardsystem (43), a measure of the ability to experiencepleasure was used, the Snaith-Hamilton PleasureScale (SHPS) (44). Patients rated 14 statementsdescribing their ability to experience pleasure incommon potential pleasurable situations (e.g. �Iwould be able to enjoy my favourite meal’) withone of the four responses: strongly disagree, disagree,agree and strongly agree. Responses were assignednumeric values and added to give a total score forhedonic tone.

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Measures of extrapyramidal side effects. Extra-pyramidal side effects as a result of the sulpiridewere rated using the St Hans Rating Scale (SHRS)for extrapyramidal syndromes (45).

Statistical analyses

Patient response to treatment with CBT wasmeasured by the percentage change in HDRS(the primary response measure) and MADRSscores after treatment compared with baseline.The prolactin response to sulpiride was sum-

marised as both the maximum prolactin increaseand the area under the curve (AUC) calculatedusing the trapezoid rule [as has been the conven-tion in neuroendocrine studies (37,46)]. Bothmeasures were calculated relative to the baselinelevel.The prolactin response was not normally dis-

tributed, which meant that nonparametric testswere used. The difference in the prolactin responseto sulpiride before and after treatment with CBTwas analysed using the Wilcoxon signed ranks test,and the association between prolactin response tosulpiride and response to treatment was analysedusing Spearman’s correlation coefficients.The effect of sulpiride was measured by com-

paring self-rating scores on the POMS, SHPS,STAI and SHRS scales before and after receivingsulpiride. This was done for both test days, i.e.before and after treatment with CBT. The changein the effect of sulpiride on rating scale scoresbefore and after treatment with CBT was com-pared using paired t-tests. Changes in moodresponse to sulpiride and response to treatmentwere tested using Spearman’s correlation coeffi-cients. A value of p , 0.05 was taken to indicatestatistical significance.

Results

Demographics

Twenty-four patients were recruited into the study(11 male, 13 female; age range 20–52, mean 37years). At baseline, the mean HDRS score withinthe group was 16 (SD ¼ 3.9, range 9–24); the meanMADRS score was 23 (SD ¼ 4.1, range 16–28).Ten patients were diagnosed with melancholicfeatures as defined by the DSM-IV, and nonehad psychotic depression. Of the 13 women, 4reported irregular periods. Three women weretaking oral contraceptives, and two had irregularmenstrual cycles.Of the 24 patients recruited to the study, 8 did

not have the repeat test. Of these, three patients

commenced taking antidepressants and thereforewere withdrawn from the study. Two patientswithdrew from the treatment; in one patient, therepeat test was not done because of timing ofmenstrual cycle, and two patients were not able tobe cannulated. There was no significant differencebetween the pre-treatment mean HDRS andMADRS scores in this group of 8 patients andthe 16 patients who completed both test days.There was also no significant difference betweenthe pre-treatment response to sulpiride challengeon measures of the PRL response (maximum PRLchange) and AUC, and self-rating scales.

Treatment response to CBT

After 16 weeks of treatment with CBT, 16 subjectsagreed to attend test day 2 and repeat testing. Inthis group, the mean post-treatment HDRS scorewas 4.0 (SD ¼ 3.7, range 0–14), and the meanMADRS score was 6.6 (SD ¼ 6.7, range 0–23). Ofthe 16 subjects, 15 showed .50% reduction inHDRS score, which is a standard measure used todescribe response. Across the group, there wasa mean 77% reduction in HDRS score (SD ¼ 21.8,range 12.5–100%) and a mean 73% reduction inMADRS score (SD ¼ 26.3, range 8–100%). Aftertreatment, all but one patient had an HDRS scorebelow 10. All 16 subjects were included in theanalysis.

Prolactin response to sulpiride

There was no significant difference between thebaseline PRL levels before and after CBT. On bothtest days, sulpiride resulted in an increase inprolactin level that peaked around 60 min aftertaking the drug with a gradual return towardsnormal (Fig. 1).

The prolactin response to sulpiride (as measuredby the maximum prolactin level) was significantlyincreased after treatment with CBT (z ¼ 22.792,p ¼ 0.005) (Fig. 2). This did not correlate withclinical response to treatment, as measured by thepercentage change in HDRS score (rs ¼ 20.050,p ¼ 0.854) or MADRS score (rs ¼ 0.021, p ¼ 0.940).

The difference in prolactin response to sulpiridebefore and after treatment (as measured by theAUC) did not reach statistical significance (z ¼21.706, p ¼ 0.088). There was, however, a non-significant trend for the mean AUC to be increasedafter CBT, i.e. in a similar direction to themaximum PRL response. A correlation wasdetected between the difference in prolactinresponse to sulpiride before and after treatment(as measured by the AUCs) and clinical response

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to treatment [as measured by the percentagechange in HDRS score (rs ¼ 20.551, p ¼ 0.027)but not by MADRS score (rs ¼ 20.265, p ¼0.341)]. In view of the fact that measuring responseby the percentage change in HDRS favours subjectwith an initially low HDRS (which this studyincluded), we also analysed these results using thefinal HDRS as the outcome measure and includedthe initial HDRS as a covariate. The correlationbetween the PRL response (as measured by theAUC) and HDRS score remained significant (p ¼0.007), whereas the correlation with the MADRSscore remained non-significant (p ¼ 0.12).

Effects of sulpiride on self-rating scale measures

Table 1 summarises the baseline statistics andeffect of sulpiride before and after treatment.Sulpiride resulted in an improvement of mood

on both test days, as seen by a significant reductionin the score for total mood disturbance (sum ofPOMS subscales) after ingestion of sulpiride beforetreatment (t ¼25.19, p, 0.01) and after treatment(t ¼ 22.15, p ¼ 0.05). Significant effects (p , 0.05)of sulpiride were seen in the depression/dejection,

tension/anxiety and anger/hostility subscales onboth test days, with patients reporting less of thesenegative mood symptoms after taking the drug.After treatment, these effects were significantly

diminished as seen by less of a reduction in scoresfor total mood disturbance (t ¼ 22.27, p ¼ 0.038),depression/dejection (t ¼ 23.090, p ¼ 0.007),anger/hostility (t ¼ 22.230, p ¼ 0.041) andconfusion/bewilderment (t ¼ 22.29, p ¼ 0.037).These differences did not correlate with percentageresponse measured by the HDRS or MADRS.In view of the finding that post-CBT the pre-

sulpiride challenge POMS scores were lower thanbefore CBT, we also analysed the results usingthe post-challenge scores as the outcome measureand the pre-sulpiride scores as a covariate. Whenthis was done, the changes to the POMS scoresfor total mood disturbance remained significant(p ¼ 0.011).Sulpiride had no effect on measures of pleasure

(SHPS) or anxiety (SSAI) before or after treatment.No measurable extrapyramidal side effects were

reported by the SHRS. No other adverse effectswere reported.

Discussion

This study investigated DA function in patientswith depression before and after CBT. Fifteen ofthe 16 patients who agreed to testing on both days(i.e. before and after treatment with CBT) weredescribed as responders in terms of .50% inHDRS scores. After 16 weeks of CBT in this groupof depressed patients, we detected an enhancedPRL response to sulpiride, as measured by themaximum increase in prolactin level. This PRLresponse was similar to that reported by otherstudies (24,34,37). Given that PRL secretion from

0

500

1000

1500

2000

2500

0 30 60 90 120 150 180

Min

Prol

actin

leve

l (µg

/ml)

Before CBT

After CBT

Fig. 1. Prolactin response to sulpiride before and after CBT.

0500

10001500200025003000

Before CBT After CBTMax

imum

PR

L in

crea

se(m

IU/l)

I=Standard error.

Fig. 2. Maximum increase in prolactin response to sulpiridebefore and after treatment with CBT.

Table 1. Effect of sulpiride before and after CBT

Before treatment,mean (SD)

After treatment,mean (SD)

Prolactin response (mIU/l)Maximum PRL increase 1606.1 (1254.7)† 2171.0 (1721.4)†AUC PRL 4165.3 (3010.1)† 4620.3 (3147.4)†

Change in POMS scoreDepression/dejection 28.438 (7.155)* 22.688 (4.527)*Tension/anxiety 23.188 (4.969)* 21.875 (3.442)*Anger/hostility 24.563 (4.926)* 21.812 (2.833)*Vigour/activity 21.125 (5.201)* 1.000 (7.788)*Fatigue/inertia 0.125 (4.856)* 21.000 (4.647)*Confusion/bewilderment 22.625 (3.557)* 20.063 (2.695)*

Total mood disturbance 219.813 (18.716)* 26.435 (11.966)*

Significant effects are given in bold (p , 0.05).*Paired t-test.†Wilcoxon signed ranks test.

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the pituitary is usually under tonic dopaminergicinhibition, this finding of increased prolactinsecretion in response to a D2 antagonist aftertreatment may reflect increased sensitisation of D2receptors in the tuberoinfundibular system. Thisfinding is consistent with our hypothesis and otheranimal and human studies reporting enhancedDA neurotransmission/increased sensitivity of D2receptors after antidepressant treatment (1,13–15,31,35,36). We did not detect a correlationbetween the prolactin response to sulpiride asmeasured by the maximum increase in prolactinlevel and clinical response to treatment. However,the majority of patients who remained in the studyfor the duration of the treatment responded wellgiving rise to a very limited range of clinicalresponses, making it unlikely that a correlationwould be seen.The effect of an increase in prolactin response to

sulpiride before and after treatment was notreplicated using the AUC as a measure of prolactinresponse (although there was a non-significanttrend in the same direction as the maximum PRLresponse). There was, however, a correlationbetween prolactin response to sulpiride (as mea-sured by the AUC) and clinical response totreatment as measured by the percentage changein HDRS score, which possibly lends furthersupport to the idea that the psychological effectsseen with CBT may be accompanied by changes inD2 receptor function. However, as mentionedabove, there was a very limited range of clinicalresponses; hence, this finding has limited reliabilityand may be incidental.Our results for the psychological effects of

sulpiride after CBT do not, however, fit with ouroriginal hypothesis. We found that sulpiride hada mood-improving effect as measured by thePOMS scale both before and after treatmentalthough this effect was diminished after treatment.These findings do, however, need to be interpretedwith caution because there was no placebocondition.Effects on mood after challenges with D2

antagonists in humans have not been well studied.A study of the effect of sulpiride in healthyvolunteers reported that sulpiride had no adverseeffects on mood (47). A recent study of eightpatients with depression who had responded toSSRI medication compared with 10 healthy con-trols is probably the most comparable studyalthough there are important differences betweenthis study and ours in both the methodology andthe subjects studied (36). The patients in theWillner study had a greater severity of depressionbefore treatment (mean HDRS, 27.1) than patients

in our study (mean HDRS, 16). The Willner studywas cross-sectional and only included subjects whohad responded to antidepressant treatment. It useda lower dose of sulpiride (200 mg compared withthe 400 mg used in our study) with response tosulpiride being measured over a 7-h period(compared with the 3-h duration of our study).The results from the Willner study reporteda significant worsening of mood (as measured byvisual analogue scales and the Fawcet-ClarkePleasure Scale) after sulpiride (200 mg) in theantidepressant responder group but a slightimprovement of mood in the control group. Theauthors suggested that this reflected an enhancedeffect of sulpiride at supersensitive postsynapticD2/D3 receptors in the antidepressant respondergroup. Our study did not replicate these findingsand in fact found an improvement in mood aftersulpiride. This may be because the patients studiedwere different, i.e. those in our study were at themore mildly depressed end of the depressioncontinuum and may not have had the sameneurobiological alterations seen in studies withmore severely depressed patient groups treatedwith antidepressant drugs. This may well have beenimportant because the literature does suggest thatmore pronounced dopaminergic abnormalitiesmay be found in patients with more severedepression (23) or those with motor retardation(33).

Our findings suggest that sulpiride resulted in animprovement of mood on both test days, i.e. bothbefore and after CBT. These positive effects ofsulpiride on mood are in keeping with studies thathave investigated the use of low-dose (50–400 mg/day) sulpiride (48–50). The hypothesised mecha-nism for this effect is the preferential and selectiveeffect of low-dose sulpiride on presynaptic D2autoreceptors that results in increased synaptic DAin mesocorticolimbic pathways (51). The findingsfrom Willner study discussed above do not fit withthis hypothesis.

The results from our study suggest that aftertreatment, these beneficial effects of sulpiride onmood were significantly diminished as seen by lessof a reduction in scores for total mood disturbance.There are several ways of interpreting this. Froma pharmacological perspective and in light of thehypothesis that the effects of low-dose sulpiride arepreferentially at D2 autoreceptors in mesocortico-limbic pathways, a diminished effect could beinterpreted as reflecting reduced responsiveness ofthese autoreceptors after treatment with CBT.Another explanation may be that the patients’mood had been improved by treatment; thus, therewas less potential for mood improvement after

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sulpiride. Alternatively and more speculatively (inview of the lack of placebo challenge), this findingmay be attributed to a specific effect of CBT-stabilising patients’ affect by addressing dysfunc-tional cognitions (52), therefore making them moreresilient to both pharmacological and exteriorchallenges affecting mood. A further explanationmay be that CBT does not require/involve anychanges to DA function for its effects.There were limitations to this study. The most

significant issue is that of the degree of depressionof the participants. The criteria for entry into thestudy were based on patients meeting DSM-IVcriteria for a major depressive episode and not ona minimum HDRS or MADRS score. As a result,and possibly because we were recruiting fora psychotherapy study, the patients studied hadmilder degrees of depression than would have beenincluded in an antidepressant trial. This compli-cates the interpretation and generalisability of theresults. The lack of a control group means wecannot infer that patients had abnormal D2receptor function in their untreated depressedstate. There was also no placebo condition forthe sulpiride. As described in the Methods section,this decision was based on not wanting to delaypatients’ commencing treatment. The number ofpatients (although twice the size of the Willnerstudy) does remain relatively small, and the drop-out rate was high, which resulted in reduced powerof the study. The test days allowed the consump-tion of a standardised lunch on both days that mayhave affected the absorption of sulpiride andtherefore the responses. The use of indirectmeasures of DA circuits such as those used in thisstudy do have limitations as discussed, particularlyin light of the development and advances inneuroimaging (although these studies are them-selves associated with limitations of cost andavailability).In conclusion, this is the first study to investigate

responses to a specific D2 antagonist in drug-freedepressed patients before and after treatment withCBT. Although very preliminary (because of thelimitations discussed above), the results suggest anenhancement of tuberoinfundibular D2 receptorfunction as seen by the increase in prolactinresponse to sulpiride after successful treatmentwith CBT.The role of DA in depression and the treatment

response remains an interesting and unresolvedarea. Similarly, the effects of psychological treat-ment on neurobiological function is an under-researched area that warrants further investigation.Future studies should pursue both avenues, andwith particular reference to CBT and DA address

some of the limitations mentioned above bystudying patients with a greater range of depres-sion severity and response in comparison withhealthy controls.

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