Dopaminergic mechanism of antidepressant action in depressed patients

Journal of Affective Disorders 86 (2005) 37 – 45 www.elsevier.com/locate/jad

Research report

Dopaminergic mechanism of antidepressant action in depressed patients Paul Willnera,*, Anthony S. Haleb, Spilios Argyropoulosc b

a Department of Psychology, University of Wales Swansea, Swansea SA2 8PP, UK Kent Institute of Medicine and Health Sciences, University of Kent at Canterbury, Canterbury CT2 7NZ, UK c Psychopharmacology Unit, University of Bristol, Bristol BS8 1TD, UK

Received 5 September 2004; received in revised form 6 December 2004; accepted 8 December 2004

Abstract Clinical studies have not yet determined a common mechanism of action for antidepressant drugs, which have primary sites of action on a variety of different neurotransmitter systems. However, a large body of evidence from animal studies demonstrates that sensitisation of D2-like dopamine receptors in the mesolimbic dopamine system may represent a dfinal common pathwayT in antidepressant action. The present study aimed to determine whether, consistent with data from animal studies, the clinical antidepressant action of selective serotonin reuptake inhibitors (SSRIs) is reversed by acute administration of a receptor antagonist selective for D2-like receptors in the mesolimbic dopamine system. The participants were patients diagnosed with major depressive disorder (n=8) who had been treated successfully (Hamilton Depression Scaleb10) with selective serotonin uptake inhibitors (fluoxetine, citalopram or paroxetine); and age-matched, non-depressed, untreated volunteers (n=10). They attended a psychiatric research ward on an out-patient basis, and received double-blind acute administration of either placebo, or a low dose of the selective dopamine D2/D3 receptor antagonist sulpiride (200 mg), in a counterbalanced order. Mood and psychomotor effects were assessed using visual analogue scales and the Fawcett–Clark Pleasure Capacity Scale. Sulpiride slightly improved subjective well-being in the control group, but in the antidepressant-treated patients, sulpiride caused a substantial reinstatement of depressed mood. These data are consistent with the hypothesis that sensitisation of D2-like receptors may be central to the clinical action of SSRIs. D 2005 Elsevier B.V. All rights reserved. Keywords: Antidepressant; SSRI; Dopamine; Sulpiride; Depressed patients; Volunteers; Mood

* Corresponding author. Tel.: +1 792 295844; fax: +1 792 295679. E-mail address: [email protected] (P. Willner). 0165-0327/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2004.12.010

Antidepressant drugs have traditionally been assumed to exert their clinical effects via interactions with serotonergic and/or noradrenergic systems. In support of this assumption, it has been demonstrated that serotonin depletion blocks the

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action of serotonergic antidepressants and noradrenaline depletion blocks the action of noradrenergic antidepressants. However, serotonin depletion does not block the action of noradrenergic antidepressants, or vice versa (Miller et al., 1996; Salomon et al., 1993). Therefore, if there is a common pathway for antidepressant action, it must lie downstream of both the noradrenergic and serotonergic systems where antidepressants exert their primary action. A substantial body of preclinical literature now demonstrates that chronic antidepressant treatment increases the responsiveness of postsynaptic D2/D3 dopamine receptors in mesolimbic terminal regions (Maj, 1990; Willner, 1989, 2002). In animal models of depression, acute treatment with D2/D3 antagonists reverses the dtherapeuticT effects of chronic treatment with a wide variety of antidepressants (reviewed by Willner and Papp, 1997; Willner, 2002). In the present study, we have adopted the same methodology to investigate the role of D2/D3 receptors in the clinical action of antidepressant drugs. Specifically, we have asked whether the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs), in patients, would be reversed by acute treatment with a low, sub-threshold dose of the specific D2/D3 receptor antagonist sulpiride.

antipsychotic drugs. None had a history of drug abuse or positive urine drug screening at baseline, co-morbid psychiatric or medical conditions, or abnormalities on biochemical, endocrine or haematological screening. None were first episode and all had responded to antidepressant treatment in previous episodes. All had a normal ECG at baseline and after 2 weeks of antidepressant treatment. Three patients were smokers. Patients were told that they would be given on one occasion a single dose of an antipsychotic drug which was sometimes used in smaller doses as an antidepressant and that we would be assessing effects on psychological functioning. They were shown an information leaflet on sulpiride approved by the local Ethics Committee. The patients were treated with one of three SSRIs (fluoxetine, 20 mg, n=5; citalopram, 30 mg, n=2; paroxetine, 30 mg, n=1). Patients were invited to participate in the study as soon as a remission of symptoms became apparent (a drop in HDRS score below 10), following a minimum of three weeks of antidepressant treatment. This criterion had the effect of biasing the sample towards relatively early responders (three to four weeks of treatment). No patients were physically ill, actively suicidal or extremely agitated on the days of testing. Patients were discouraged from smoking during the assessments; all abstained, and none reported cravings.

1. Methods

1.1.2. Controls Controls were recruited through advertisement or word of mouth among hospital staff and friends. Their family doctors were informed of their participation and asked if there were any medical or psychiatric reasons that contraindicated their patient’s participation. Each volunteer was paid o100.00 upon completion of the study. All were non-smokers. Following medical and psychiatric screening (including ECG), they were told that they would receive an active tablet and a placebo and that the main purpose of the study was to look at the effects of the drug on mood. They were given the sulpiride datasheet. Controls had mean HDRS scores of 0.3 (range, 0– 2), measured immediately prior to placebo administration, and 0.9 (range, 0–3), measured immediately prior to sulpiride administration.

1.1. Participants Participants were 8 depressed patients [4 male, 4 female; mean (FSEM) age=43.5 (F4.1)], and 10 nondepressed controls [5 male, 5 female; mean (FSEM) age=42.3 (F2.6)]. They provided written informed consent. 1.1.1. Patients All patients were diagnosed as suffering from major depression according to DSM-IV criteria assessed by the SCID, with a minimum 17-item Hamilton Depression Rating Scale (HDRS) score of 20 at pre-treatment baseline. None were bipolar or had a known bipolar family history, had psychotic depression, or had previously received either ECT or

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1.2. Instruments

1.4. Drug

1.2.1. Visual analogue scales Mood was rated using 10 visual analogue scales (VAS) (Bond and Lader, 1974), which were 10 cm lines labelled at each end (e.g. sad/happy). Subjects were asked to bmark a cross on the line to show where your feelings at present fall between the two wordsQ. The dysphoric end was to the right for five of the scales and to the left for the other five scales.

Sulpiride and placebo were prepared and encapsulated by the hospital pharmacy, which also randomized the treatments. The 200 mg dose of sulpiride was closer to the antidepressant dose range (100–150 mg) than the antipsychotic dose range (400–600 mg), and was expected not to alter mood in control subjects (Mehta et al., 1999).

1.2.2. Fawcett–Clark pleasure capacity scale The Fawcett–Clark Pleasure Capacity Scale (FCPCS: Fawcett et al., 1983), contains 36 items describing pleasurable situations; for each item, participants were asked to rate on a 5-point scale how much pleasure they would experience from each situation, regardless of the likelihood of the situation actually occurring.

1.5.1. Visual analogue scales For the initial analysis, the mean of all 10 VAS was calculated at each time point. For more detailed analyses, each of the scales was attributed to one of three sets, labelled: depressed mood (sad, depressed), psychomotor retardation (mentally slow, drowsy, withdrawn, lethargic), and psychomotor agitation (tense, irritable, restless, bored). Time-course data were analysed by 3-way analysis of variance, with two within-subjects factors, drug (D: sulpiride vs. placebo) and time (T: 8 levels, hours 0– 7), and one between-subjects factor, group (G: control vs. depressed). Following the identification of a significant DGT interaction in the overall VAS data (see Results), 2-way DG analyses of each time point identified the 3 h time point as the time of maximal drug effect. Therefore, 2-way DG analyses of the 3 h data were also conducted for each of the three component sets of scales. Finally, in order to summarize the VAS data over time, an Area Under the Curve (AUC) measure was calculated, by subtracting baseline (time 0) values from each of the subsequent time points, and summing across hours 1–7. These data were also analysed by 2-way analysis of variance (drug, group).

1.3. Procedure All participants were tested twice, under medical supervision. On the two tests, they received either placebo or sulpiride (200 mg), in random order, with a one-week interval between tests. Patients spent the days on a research unit, where they stayed for 9 h on the days of the tests, with access to television, newspapers and books; they interacted regularly with medical, nursing and occupational therapy staff, who observed them for treatment-emergent side effects and performed hourly pulse, blood pressure and respiration monitoring. Control subjects were allocated a room in the research facilities with a desk and a video player. Participants were administered the HDRS at the start of each session. They then completed the VAS at hourly intervals, from 1 h before to 7 h after drug or placebo administration. The first completion of the scales was treated as a practice trial, and these data were not included in the analysis. The FCPCS was administered twice on each test day, immediately prior to drug/placebo administration, and at 2 h post drug, which was anticipated to be close to the time of maximum drug effect.

1.5. Statistical analysis

1.5.2. Fawcett–Clark pleasure capacity scale A mean item score was obtained for each administration of the FCPCS. Preliminary examination of these data identified one outlier: an unusually large decrease in FCPCS score following placebo administration, in one of the controls. Data from this participant were excluded from the analysis of FCPCS scores. The remaining data were then analysed by 3way analysis of variance (within-subjects: drug, time; between-subjects: group).

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2. Results 2.1. Antidepressant treatment During the course of antidepressant treatment, mean (FSEM) HDRS ratings in the patient group fell from 27.1 (F1.4) prior to treatment to 8.6 (F0.5: range, 6–10) at the time of testing. FCPCS scores increased significantly over the course of antidepressant treatment [meanFSEM: before treatment, 2.35F0.14; after treatment, 3.36F0.14; t(7)=6.23, pb0.001]. Post-treatment scores in the treated group were marginally lower than control scores [3.60F0.12]. 2.2. Effects of sulpiride on overall mood scores The statistical analysis of the VAS scores is summarized in Table 1. Analysis of the mean VAS rating, averaged across all 10 scales, revealed significant DG ( p=0.02) and DGT ( pb0.005) interactions, and a significant quadratic component to the DGT interaction ( pb0.001). Sulpiride increased overall depressive Table 1 Statistical analysis of VAS dataa, Interaction term

c

Degrees of freedom All VAS Depressed mood Sad Depressed Psychomotor retardation Mentally slowed Drowsy Withdrawn Lethargic Psychomotor agitation Tense Irritable Restless Bored

mood ratings, but only in the patient group; and this effect increased in the early part of the session, then decreased towards the end of the session (Fig. 1A, left panel). AUC (Fig. 1A, right panel) was decreased non-significantly by sulpiride in control subjects, but increased significantly in the depressed group, leading to a significant DG interaction ( pb0.02). The same pattern was present, to varying degrees, in each of the 10 individual scales. Two-way ANOVAs at each time point showed that the greatest DG interaction term was found 3 h after drug administration ( pb0.001). Fig. 2A shows the change in VAS scores at this time, while Fig. 2B shows the change in FCPCS score 2 h after drug administration. Similar to the VAS data, analysis of FCPCS scores revealed a significant DGT interaction ( pb0.001). As noted earlier one outlier was removed prior to analysis of the FCPCS data; if this outlier is included, the effect reported is even larger [F(1,16)=30.67]. On both measures, sulpiride caused a substantial worsening of mood in the patient group ( pb0.001), which was seen in all eight participants. Similar effects of sulpiride were seen in the three smokers and the five non-smokers.

b

DG

DGT

Quadratic

DG (3 h)

AUC

1, 16 6.70 (0.02) 8.50 (0.01)

7, 112 3.36 (0.003) 3.95 (0.008) 2.92 (0.008) 3.99 (0.001) 1.25 (N0.1) 2.27 (0.037) 1.02 (N0.1) 1.6 (N0.1) 0.87 (N0.1) 2.32 (0.03) 1.75 (N0.1) 1.89 (0.077) 1.37 (N0.1) 0.98 (N0.1)

1, 16 17.18 17.30 8.41 14.3 3.80 3.49 3.85 0.21 2.43 7.29 5.98 0.62 0.91 4.29

1, 16 16.76 (b0.001) 16.31 (b0.001)

1, 16 6.94 (0.018) 12.38 (0.003)

7.38 (0.015)

2.32 (N0.1)

5.62 (0.031)

5.08 (0.039)

6.18 (0.024)

1.40 (N0.1)

(b0.001) (b0.001) (0.01) (0.002) (0.069) (0.08) (0.067) (N0.1) (N0.1) (0.016) (0.026) (N0.1) (N0.1) (0.055)

a Values in the table are F-values for the specified interaction terms, with the associated p-values in parentheses. Analyses significant at pb0.01 are shown in bold. b Only the major measures are shown for the individual VAS. c DG=DrugGroup interaction, providing an initial test of the hypothesis that sulpiride would specifically increase mood scores in the depressed group; DGT=DrugGroupTime interaction, testing the hypothesis that this effect of sulpiride would be greater at certain time points than at others; Quadratic=quadratic component of the DGT interaction, testing the more specific hypothesis, that the effect of sulpiride would grow in the early part of the session and decline in the later part of the session, as the drug effect waned; DG (3 h)=DG interaction at the 3 h time-point, when maximal effects were observed; AUC=DG interaction for Area Under the Curve.

P. Willner et al. / Journal of Affective Disorders 86 (2005) 37–45

All VAS

12 Area under curve

5.0

VAS rating

4.0 3.0 Con-Plac

2.0

Con-Sul Dep-Plac

A

1.0

Dep-Sul

10 8

Plac Sul

4 2 0

0

1

2

3 4 Time (h)

5

6

7

CON

Depressed mood

6.0

14 12 Area under curve

5.0 VAS rating

All VAS

6

0.0

4.0 3.0 Con-Plac Con-Sul Dep-Plac Dep-Sul

2.0

B

1.0

0

1

2

3 4 Time (h)

5

6

Plac

6

Sul

4 2 0 -2

7

10 Area under curve

4.0 3.0 Con-Plac Con-Sul Dep-Plac Dep-Sul

2.0

C

1.0

Depressed mood

8

Psychomotor retardation

5.0

DEP

10

0.0

VAS rating

41

Psychomotor retardation

8

Plac Sul

6 4 2 0

0.0 0

1

2

3

4

5

6

7

CON

DEP

Time (h)

Psychomotor agitation

5.0

12 Area under curve

VAS rating

4.0 3.0 Con-Plac Con-Sul Dep-Plac Dep-Sul

2.0

D

1.0

Psychomotor agitation

10 8

Plac

6

Sul

4 2 0

0.0 0

1

2

3 4 Time (h)

5

6

7

-2

CON

DEP

Fig. 1. Effects of sulpiride on the mean mood ratings, averaged across (A) all 10 visual analogue scales (VAS); (B) scales reflecting depressed mood; (C) scales reflecting psychomotor retardation; or (D) scales reflecting psychomotor agitation. Left panels: Hourly mood ratings, for 7 h following administration of sulpiride (Sul) or Placebo (Plac) to volunteers (Con) or antidepressant-treated depressed patients (Dep). Right panels: Area under each of the curves shown in the left panels. Sulpiride significantly increased dysphoric mood ratings in patients but, if anything, tended to improve ratings in the controls; the effect was greatest on scales reflecting depressed mood (B).

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P. Willner et al. / Journal of Affective Disorders 86 (2005) 37–45

A

B

All VAS

***

2.0

FCPCS 0.5

1.5

Pre - Post difference

Pre - Post difference

*** Plac Sul

1.0

0.5

0.4 Plac

0.3

Sul

0.2 0.1 0

0.0

CON

DEP

CON

DEP

Fig. 2. Change in scores (Pre-Post) on (A: left panel) mean of all Visual Analogue Scales (VAS) 3 h post-drug and (B: right panel) the Fawcett– Clark Pleasure Capacity Scale (FCPCS) 2 h post-drug, following the administration of sulpiride (Sul) or Placebo (Plac) to volunteers (Con) or antidepressant-treated depressed patients (Dep). Sulpiride greatly decreased VAS ratings and pleasure scores in patients (seen as a large pre-post difference), but tended to improve scores in controls. *** pb0.001 relative to placebo.

In contrast to the significant decreases in mood following sulpiride administration to the patient group, sulpiride slightly improved mood in the control group (Fig. 2). While the improvements were not significant overall, on both measures there was a significant correlation between the initial mood rating and the change following sulpiride administration: that is, sulpiride caused greater mood improvements in individuals who were more depressed (VAS: r=0.67, pb0.05; FCPCS: r=0.71, pb0.025). 2.3. Treatment–emergent side effects No systematic changes in vital signs were observed during the study in either treatment condition. Two patients each showed transient bradycardia and tachycardia during the first 2 h of the procedure. Three patients complained of sedation and two of lethargy during the active drug condition, two each of lethargy and sedation with placebo. One patient complained of dizziness in the placebo condition. Other side effects were continuations of those experienced with SSRI treatment prior to the study. There were no reports or observations of akathisia or other extrapyramidal side effects (EPS). In order to examine in greater detail the possibility that sulpiride may have caused subtle EPS, the 10 VAS were separated into three groups, representing depressed mood, psychomotor retardation, and psychomotor agitation, respectively. On all three meas-

ures, sulpiride caused a significant worsening in the SSRI-treated patients but slightly improved psychological well-being in the control group. Compared with Fig. 1A, which shows the time course of sulpiride effects averaged across all VAS, Fig. 1B shows that the effect of sulpiride was substantially larger in the two VAS that reflect depressed mood, both of which showed highly significant ( pb0.01) changes (Table 1). By contrast, the effects of sulpiride on scales representing psychomotor retardation (Fig. 1C) and psychomotor agitation (Fig. 1D) were much smaller, with significant effects ( pb0.05) seen on only two of the eight contributing scales (Table 1). As the effects of sulpiride on psychomotor symptoms were far smaller than the effects on depressed mood, they cannot readily be attributed to psychomotor side-effects.

3. Discussion Consistent with an earlier study (Mehta et al., 1999), the administration of a low dose of sulpiride caused no worsening of mood in non-depressed, nonantidepressant-treated volunteers. Indeed, in the control group, sulpiride caused a slight enhancement of psychological well-being. This observation may be relevant to the efficacy of low-dose sulpiride as an antidepressant (Del Zompo et al., 1990; Ruther et al., 1999), and most likely reflects the inhibitory action of

P. Willner et al. / Journal of Affective Disorders 86 (2005) 37–45

sulpiride at presynaptic D2/D3 receptors (Serra et al., 1990; Drago et al., 2000; Papp and Wieronska, 2000). In sharp contrast, sulpiride caused a marked worsening of mood when administered acutely to patients treated chronically with SSRIs. This presumably reflects an inhibitory action at supersensitive postsynaptic D2/D3 receptors in mesolimbic terminal regions (Maj, 1990; Willner, 1989, 2002). The reemergence of depressive subjective changes, following sulpiride administration, was seen using both VAS measures and the Fawcett–Clark Pleasure Capacity Scale. Further exploration of the individual VAS showed that the effects of sulpiride were maximal on scales reflective of depressed mood (sad, depressed), but smaller on scales reflecting psychomotor changes (retardation or agitation), suggesting some degree of specificity for sulpiride to reverse the anti-anhedonic effect of antidepressant treatment. The observation that sulpiride reinstated depressive mood following successful antidepressant treatment at first sight appears contrary to clinical experience that depression can be treated using low dose benzamides (Del Zompo et al., 1990; Ruther et al., 1999; Smeraldi, 1998), or antidepressant/neuroleptic cocktails (Nelson, 1987; Willner, 2002). However, there is no real inconsistency, because the conditions of the present study are very different from the clinical situation, in which sulpiride would be administered chronically to a patient who was actively depressed. In the present study, sulpiride was administered acutely only after the patients had recovered, a situation that would almost never arise in the clinic. The selective effect of sulpiride in the antidepressant-treated patients is consistent with studies showing that antidepressants increase subcortical D2/D3 receptor binding following successful treatment of anhedonic rats (Papp et al., 1994) or depressed patients (Bowden et al., 1997; Larisch et al., 1997; D’haenen et al., 1999; Klimke et al., 1999: but not Ebert et al., 1996; Moresco et al., 2000), which was not seen in nondepressed volunteers (Tiihonen et al., 1996), or depressed patients who failed to respond to SSRIs (D’haenen et al., 1999; Klimke et al., 1999). It is possible that sulpiride-induced relapse to a dysphoric mood state could be related to akathisia, which has sometimes been reported following the combination of an SSRI and an antipsychotic (Lane,

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1998; Caley, 1998). However, this is unlikely, because no observable signs of akathisia were apparent in the patient group. Furthermore, no significant subjective effects of sulpiride were seen in the two individual VAS most closely related to akathisia, restlessness and irritability. For ethical reasons, this study did not include the control group that would definitively rule out akathisia: that is, non-depressed volunteers treated acutely with sulpiride after chronic SSRI treatment. However, the comparable group was included in two preclinical studies using the chronic mild stress model (Willner, 1997a), neither of which showed adverse effects of this drug combination in control animals, at doses that were pharmacologically active in reversing (fluoxetine) and reinstating (raclopride) stress-induced anhedonia (Muscat et al., 1992; D’Aquila et al., 1997). The study has some methodological shortcomings. First, we have tested only eight patients. However, the reversal of antidepressant effects by sulpiride was highly significant and seen in all eight participants, so the sample size was adequate for the purposes of this initial study. Nevertheless, the study should be replicated. Second, the patient group included some smokers. While this could in principle have been a complicating factor, the effects reported were of similar magnitude in the smokers and the nonsmokers. Third, patients received three different SSRIs. However, as the effects of sulpiride were seen in all eight participants, this could be viewed as a strength, since it demonstrated that the effect is not specific to a particular SSRI. Fourth, the study did not include a placebo wash-out period, and the design of the study favoured the inclusion of early responders, so it is possible that a portion of the clinical improvement under SSRI treatment reflects a placebo effect. This shortcoming could be addressed in a subsequent study, in which patients were tested after longer periods of treatment. However, placebo effects are unlikely to be a major factor, as the relevant animal studies did include placebo-treated groups, and the effects of D2/D3 receptor blockade were restricted to the antidepressant-treated groups (Muscat et al., 1992; D’Aquila et al., 1997). Finally, we did not examine the effect of sulpiride in depressed patients who had not been treated with antidepressants. Some studies (D’haenen and Bossuyt, 1994; Shah et al., 1997; Verbeeck et al., 2001) though not others

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(Bowden et al., 1997; Wong et al., 1985) have suggested that D2 receptors might be supersensitive in untreated depressed patients. Hence, a potential mood-lowering effect of sulpiride might have been present in our patients even before they received SSRI treatment. However, this is rather unlikely, as sulpiride and its congener, amisulpride, have been widely used in the treatment of depression (indeed, this was the reason for choosing sulpiride for this study, rather than raclopride), and to the best of our knowledge, adverse effects on mood early in treatment have not been reported. In summary, both the animal and the human data are consistent with the hypothesis that D2/D3 receptors in the nucleus accumbens may represent a dfinal common pathwayT in the reversal of hedonic impairments by antidepressant drugs. The antidepressant effects of drugs that act primarily as direct (pramipexole) or indirect (nomifensine, bupropion, amoxapine, low-dose amisulpride) dopamine agonists are also consistent with a dopaminergic mechanism of antidepressant action (Willner and Papp, 1997; Willner, 1997b). However, the failure of DA synthesis inhibitors to block the antidepressant effect of SSRIs (Miller et al., 1996; McTavish et al., 2004) highlights the importance of postsynaptic receptor modulation in the action of dconventionalT antidepressants. Our working hypothesis is that (i) antidepressants act primarily at serotonergic or noradrenergic synapses in regions such as amygdala, hippocampus or prefrontal cortex, but (ii) all of these regions project primarily to the nucleus accumbens, where their outputs to the motor system are gated by dopaminergic inputs from the ventral tegmental area, and (iii) it is this gating function that is modulated by antidepressant sensitisation of D2/D3 receptors (Willner, 2002). Further studies of this hypothesis are warranted: in particular, a test of the prediction that, in common with serotonergic antidepressants, the action of noradrenergic antidepressants would also be blocked by acute low dose neuroleptic administration to depressed patients.

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