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. Author manuscript; available in PMC: 2015 Mar 30.
Published in final edited form as: Psychiatry Res. 2014 Jan 14;221(3):231–239. doi: 10.1016/j.pscychresns.2014.01.003

Antidepressant response to aripiprazole augmentation associated with enhanced FDOPA utilization in striatum: a preliminary PET study

Charles R Conway a,b,*, John T Chibnall b, Paul Cumming c, Mark A Mintun d, Marie Anne I Gebara a, Dana C Perantie a, Joseph L Price e, Martha E Cornell a, Jonathan E McConathy f, Sunil Gangwani a, Yvette I Sheline g
PMCID: PMC3982608  NIHMSID: NIHMS562109  PMID: 24468015

Abstract

Several double blind, prospective trials have demonstrated an antidepressant augmentation efficacy of aripiprazole in depressed patients unresponsive to standard antidepressant therapy. Although aripiprazole is now widely used for this indication, and much is known about its receptor-binding properties, the mechanism of its antidepressant augmentation remains ill-defined. In vivo animal studies and in vitro human studies using cloned dopamine dopamine D2 receptors suggest aripiprazole is a partial dopamine agonist; in this preliminary neuroimaging trial, we hypothesized that aripiprazole’s antidepressant augmentation efficacy arises from dopamine partial agonist activity. To test this, we assessed the effects of aripiprazole augmentation on the cerebral utilization of 6-[18F]-fluoro-3,4-dihydroxy-L-phenylalanine (FDOPA) using positron emission tomography (PET). Fourteen depressed patients, who had failed 8 weeks of antidepressant therapy with selective serotonin reuptake inhibitors, underwent FDOPA PET scans before and after aripiprazole augmentation; eleven responded to augmentation. Whole brain, voxel-wise comparisons of pre- and post-aripiprazole scans revealed increased FDOPA trapping in the right medial caudate of augmentation responders. An exploratory analysis of depressive symptoms revealed that responders experienced large improvements only in putatively dopaminergic symptoms of lassitude and inability to feel. These preliminary findings suggest that augmentation of antidepressant response by aripiprazole may be associated with potentiation of dopaminergic activity.

Keywords: Aripiprazole, treatment-resistant depression, Positron emission tomography, Dopamine, Caudate

1. Introduction

Three large multi-center trials have reported that the dopamine partial agonist aripiprazole (aripiprazole; Abilify®) is effective in augmenting the response of patients with major depressive disorder (MDD) to oral antidepressant therapy (Berman et al., 2007; Marcus et al., 2008; Berman et al., 2009). All three studies, using identical designs, demonstrated that that a large subset (ranging from 32–47%) of patients who failed to respond to 8 weeks of monotherapy, selectively responded to aripiprazole augmentation (as compared with blinded placebo). Data from the first two pivotal trials (Berman et al., 2007; Marcus et al., 2008) led to approval by the United States Food and Drug Administration of aripiprazole for use as an antidepressant augmentation agent in major depressive disorder.

How aripiprazole brings about this antidepressant potentiation is not known, although it clearly binds with high affinity to dopamine D2 and D3 (D2/3) receptor subtypes (Pae et al., 2008). In vivo animal studies suggest that aripiprazole has both dopamine D2, presynaptic agonist (Kikuchi et al., 1995; Semba et al., 1995; Momiysama et al., 1996) and antagonist activities (Kikuchi et al., 1995; Inoue et al., 1996), depending on the assay conditions. The complex pharmacology of aripiprazole may result from variable competition from endogenous dopamine at the same receptors (Burris et al., 2002). The results of studies in vitro in which endogenous dopamine is removed, more consistently indicate aripiprazole to be inherently a D2 partial agonist (Inoue et al., 1996, 1997; Lawler et al., 1999).

Whether aripiprazole functions as a partial agonist in humans is still not known with certainty; however, studies using cloned human D2 receptors strongly suggest it has partial activity at D2 receptors. Because multiple factors potentially interfere with assessment of receptor ligand activity (intrinsic receptor activity, receptor density, and signal transduction coupling efficiency [Kenakin, 1997]), Burris et al. (2002), conducted a series of studies in vitro using cloned human D2 receptors, designed to control for these factors. Here, binding properties of aripiprazole were consistent with that of a partial agonist. In particular, aripiprazole bound with slightly greater (2x) affinity to the G protein-coupled state of D2 receptors (a property of D2 receptor agonists [Lahti et al., 1992]), whereas full agonists have considerably higher affinity (30x). Further, aripiprazole also demonstrated affinity to the uncoupled state of the receptor, consistent with an antagonist. Furthermore, treatment of cells with an irreversible antagonist of D2 receptors (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline or EEDQ) revealed partial agonist properties, as evidenced by the relationship between perturbations in receptor reserve and signal transduction, i.e. cAMP accumulation).

Additional evidence that supports the partial agonist action of aripiprazole includes studies which reveal only a partial inhibition of prolactin release in transformed lactotrophs (Aihara et al., 2004), and low intrinsic efficacy at human D2 receptors expressed in Chinese Hamster Ovary (CHO) cells (Tadori et al., 2005). Further, human [11C]-raclopride PET studies have revealed occupancy exceeding 70% at dopamine D2/3 receptors following a single dose of aripiprazole (Takahata, 2012), and exceeding 95% with repeated dosing, while not provoking extrapyramidal side effects (Yokoi et al., 2002), and without the unfavorable subjective experience evoked by antagonist antipsychotic medications (Mizrahi et al. 2009).

In addition to its actions at dopamine D2/3 receptors, aripiprazole is also a D4 partial agonist, as well as a high-affinity partial agonist at serotonin 5HT1A, 5HT2C/5HT7, and 5HT2A/5HT6 receptors (Jordan et al., 2002; Pae et al., 2008); any or all of these receptors might conceivably contribute to the therapeutic effects of aripiprazole.

Multiple lines of evidence support the notion that brain dopamine plays a critical role in MDD (Dunlop and Nemeroff, 2007), primarily through the mesolimbic and mesocortical pathways. The mesocortical pathway, which arises in the midbrain ventral tegmental area and innervates the frontal and temporal cortical region, is implicated in working memory, concentration, and executive function, all of which are frequently disrupted in MDD (Nestler and Carlezon, 2006). Arising in parallel to the mesocortical pathway is the mesolimbic pathway, which sends projections to the ventral striatum (nucleus accumbens), hippocampus, amygdala, cingulate, and prefrontal cortices (among other structures) and is primarily implicated in the maintenance of motivation, hedonic capacity, and reward assessment (Nestler and Carlezon, 2006).

This trial investigated the mechanism of action of aripiprazole augmentation to ineffective treatment of major depressive disorder (MDD) with a selective serotonin reuptake inhibitor (SSRI). Our hypothesis was that efficacious augmentation therapy with aripiprazole occurs in association with potentiation of dopaminergic brain systems. To test this hypothesis, we used positron emission tomography (PET) with the DOPA decarboxylase substrate 6-[18F]-fluoro-3,4-dihydroxy-L-phenylalanine (FDOPA), which has been used extensively for imaging of the presynaptic dopaminergic system in brain. Specific signal in FDOPA-PET studies is derived via the formation of 6-[18F]fluorodopamine in situ and its retention within synaptic vesicles, mainly of dopamine fibers (Kumakura and Cumming, 2009).

Depressed subjects in the present molecular imaging study first underwent an eight week trial of the SSRI escitalopram, along with subject-blind aripiprazole placebo. Those subjects who did not respond to escitalopram plus placebo were recruited to undergo FDOPA-PET scans at escitalopram baseline (just prior to aripiprazole augmentation) and again after six weeks of subject-blind aripiprazole augmentation of escitalopram. Voxel-wise comparisons of FDOPA uptake ratios were then made to search for significant increases in tracer trapping among aripiprazole augmentation responders. Additionally, an exploratory analysis examined whether depressive symptoms that have been a priori identified as dopaminergic (lassitude and inability to feel) demonstrated a greater degree of improvement within the aripiprazole antidepressant augmentation responders (compared with nonresponsers).

2. Methods

2.1. Subjects

All subjects provided written, informed consent approved by the institutional review board at Washington University School of Medicine. Subjects were recruited from radio advertisements. Study inclusion criteria were as follows: 1) history of MDD (met criteria for MDD per the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revised (American Psychiatric Association, 2000), which was further verified via structured clinical interview with the Mini International Neuropsychiatric Interview (Sheehan et al., 1998); 2) history of non-response to one adequate dose-duration trial of antidepressant therapy; 3) age 18–55 years; and 4) score ≥18 on the Hamilton Depression Rating Scale (24-item HDRS; Hamilton, 1967) at baseline. The upper age restriction was included to avoid the potential confound of enhanced washout of FDOPA-derived specific signal in older individuals (Kumakura et al., 2010). Subsequent entry into the aripiprazole augmentation phase of the study required non-response to eight weeks of escitalopram therapy (< 50% change in Montgomery-Åsberg Depression Rating Scale [MADRS] score; Montgomery and Åsberg, 1979) from Baseline to Week 8.

Exclusion criteria included the following: 1) history of smoking, due to known effects of smoking on striatal dopamine release (Busto et al., 2009); 2) by DSM-IV TR criteria (DSM-IV_TR, 2000), significant history of active anxiety disorder, since anxiety disorders may significantly affect dopaminergic activity (Schneier et al., 2000); 3) pregnancy/lactation; 4) ability to become pregnant and not using effective contraception; 5) as defined by DSM-IV: organic mental disorders, substance abuse/dependence, schizophrenia, other psychotic disorders, bipolar disorder, and eating disorders; 6) acute suicide risk as judged by the study psychiatrists (i.e., presence of serious suicide intention or plan); 7) use of any other form of depression treatment.

2.2. Pharmacotherapy and assessment schedule

Subjects were informed that the purpose of the study was to assess the effects of aripiprazole antidepressant augmentation of their standard antidepressant treatment over 16 weeks, and that blinded inititiation of aripiprazole augmentation could occur at any point during the trial. In fact, all subjects received placebo aripiprazole up to Week 10. Assessments and treatment phases are outlined in Fig. 1.

Fig. 1.

Fig. 1

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Outline of study procedures.

Abbreviations: AIMS = Assessment of Involuntary Movements Scale; ARP = aripiprazole; BAS = Barnes Akathisia Scale; F-DOPA PET = 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine positron emission tomography; HDRS = Hamilton Depression Rating Scale-24 item; MADRS = Montgomery-Åsberg Depression Rating Scale; MRI = magnetic resonance imaging; PET = positron emission tomography; SAS = Simpson Angus Scale; SSRI = selective serotonin reuptake inhibitor (escitalopram).

2.2.1. Escitalopram monotherapy phase (8 weeks)

Subjects took open-label escitalopram and single-blinded placebo aripiprazole (“placebo 1” in Fig. 1). Escitalopram was selected as the primary treatment because of its generally high effectiveness and lack of significant direct interactions with dopamine transporters or receptors (Owens et al., 2001). Subjects were started on 10 mg per day of oral escitalopram which, if tolerated, was titrated up to 20 mg within the first week and maintained at this dose for the study duration. Subjects whose Week 8 MADRS scores declined from baseline by ≥50% were considered “responders” and exited the study.

2.2.2. Placebo aripiprazole-only phase (2 weeks)

Escitalopram nonresponders entered a further 2-week phase of escitalopram with placebo aripiprazole (“placebo 2” in Fig. 1), so as to further evaluate for potential placebo response.

2.2.3. Augmentation with aripiprazole (6 weeks)

Subjects entering the single-blind aripiprazole augmentation phase maintained their escitalopram dose and received an initial daily dose of 2 mg of oral aripiprazole. If tolerated, the dose was titrated up to 5 mg at the end of Week 11 and to 10 mg at the end of Week 12 (maximum study dose). In the event of emergence of akathisia or involuntary movements, the dose was decreased to the previous level.

2.2.4. Mood, extrapyramidal movement, and motor activity assessments

The MADRS was the primary measure to assess change in depression, which was administered at entry and at Weeks 4, 8, 10, 11, 12, 13, and 16. Extrapyramidal symptoms were assessed before and after the escitalopram monotherapy trial (study entry and Week 10) and throughout the aripiprazole augmentation phase (Weeks 10, 11, 12, 13, and 16) using the Barnes Akathisia Scale (BAS; Barnes, 1989), the Abnormal Involuntary Movement Scale (AIMS; Guy et al., 1976), and the Simpson and Angus Scale for Extrapyramidal Side Effects (SAS; Simpson and Angus, 1970). Motor activity was assessed on this same schedule using the Finger Tapping Test for dominant and nondominant hands (Echternacht, 1981).

2.3. Structural MRI scans and F-DOPA scans

At Week 10, subjects entering the aripiprazole augmentation phase (before receiving aripiprazole) underwent an FDOPA PET scan and a structural MRI scan for spatial assignment of PET findings. Following six weeks of aripiprazole augmentation, a second FDOPA PET scan was obtained. PET and MRI scans were performed at the Washington University Center for Clinical Imaging Research (WUCCIR). Using a Siemens Trio 3.0 T MRI scanner, a 3-D fast gradient echo MR acquisition magnetization prepared rapid gradient echo (MPRAGE) was obtained. FDOPA-PET scans were performed using a Siemens Biograph 40 PET-CT scanner with CT-based attenuation correction. Given the exploratory nature of this study, we recorded PET data in the interval 60–90 minutes post injection, which is deemed to provide a sensitive index of FDOPA utilization, with minimal risk of (uncorrectable) head motion during the recording interval. The FDOPA-PET protocol was designed with brief recordings during the interval of peak striatal uptake (Dhawan et al., 2002; Jokinen et al., 2009); while this sacrificed dynamic aspects of tracer uptake, it was done in the interest of a simple and robust procedure with the potential for translation to clinical routine.

Subjects were given carbidopa (2 mg/kg oral) at 60 min before FDOPA injection, so as to minimize tracer decarboxylation in peripheral tissues. FDOPA (3.5–5 mCi) was administered as a slow intravenous bolus, and the subjects rested in a quiet room during the initial uptake phase. Beginning at 60 min post injection, a series of six frames of five minutes each was recorded and reconstructed with decay and attenuation correction as a 128×128 matrix by filtered back projection, all pass with 2.3 zoom.

2.4. FDOPA PET processing

The algorithm used to preprocess reconstructed time-binned PET data has been previously described in detail (Eisenstein et al., 2012). To summarize briefly: 1) for each FDOPA PET scan, three successive pairs of 5-min time frames were averaged (frames 1 and 2, 3 and 4, 5 and 6); 2) within-session head motion correction was achieved by mutual co-registration of these three averaged pairs; 3) PET images were intensity-normalized to obtain a whole-brain mean value of 5000 in arbitrary units; 4) intensity-normalized PET data were registered across sessions and the cross-session sum was registered to the individual’s structural MRI; 5) MRI was registered (12-parameter affine transform) to a template representing Talairach atlas space (Talairach and Tournoux, 1988) using a spatial normalization method (Lancaster et al., 1995); 6) the sequence of transforms linking the PET data to the atlas was concatenated and the PET data were resampled to atlas space as 2-mm cubic voxels; 7) data were smoothed (10-mm FWHM) before statistical analysis.

Following this PET data processing, a new ratio image of relative FDOPA uptake was created for each scan using the program Statistical Parametric Mapping (SPM8, Welcome Trust Center for Neuroimaging; Hoshi et al., 1993; Dhawan et al., 2002). Here, a voxel-wise ratio image of FDOPA uptake was calculated relative to a bilateral portion of the occipital lobe, a reference region known to have minimal specific signal due to its sparse catecholamine innervation. Hence, the final ratio images represented FDOPA uptake at 60–90 minutes relative to the reference region.

2.5. Data analysis and statistics

Using the SPM software, pre-aripiprazole and post-aripiprazole FDOPA PET ratio maps were compared using a within-subjects (paired) t-test for all subjects combined (N = 14), and for the responders only (n = 11). The whole brain was searched using a cluster forming threshold of p < 0.001. The small number of aripiprazole nonresponders (n = 3) prohibited a meaningful comparison of aripiprazole responders versus nonresponders or a within-subjects analysis of aripiprazole nonresponders.

2.6. Exploratory post hoc analyses

2.6.1. Regional (medial caudate) FDOPA uptake subanalyses

Because the central hypothesis of the study was that aripiprazole augmentation entails engagement of the mesolimbic/ mesocortical dopamine system, an exploratory analysis of the largest region of relative FDOPA change (right medial caudate; 88 voxels) was undertaken. A three dimensional “object map” was created based on this SPM-identified medial caudate region. Regional mean FDOPA-derived activity was measured in this caudate region at baseline and follow-up PET in all 14 subjects.

This post hoc exploratory analysis involving the right medial caudate was performed for several reasons. First, we wished to determine if the increased FDOPA uptake observed in the right medial caudate region of responders was observed exclusively in responders; second, we wished to determine if all aripiprazole antidepressant responders underwent increased FDOPA uptake in this region; and, finally, to determine if there was a correlation between increase in FDOPA uptake and degree of antidepressant response (change in 10–16 week MADRS score).

Furthermore, because of the strong right-sided laterality of the exploratory findings, FDOPA uptake was also measured in the corresponding medial caudate region on the left side. Here, a mirror image template of the left medial caudate was created, using an affine transformation fixed by registering the group-averaged structural MRI to a transverse flipped version of itself; normalized FDOPA binding ratios were assessed for treatment effects in this region.

Changes in regional FDOPA ratios were evaluated using voxel-wise t-tests. Given the post hoc and exploratory nature of these analyses, p-values were not appropriate for designating statistical significance. Rather, effect sizes were computed in the form of Cohen’s d statistic for paired t-tests (d = M/SD for difference scores) and unpaired t-tests (d = (M1−M2)/SDPOOLED).

2.6.2. Differential symptom response to aripiprazole augmentation

Of the 10 MADRS symptoms assessed, it was hypothesized that the symptoms most likely to be affected by the dopaminergic system were lassitude (Demyttenaere et al., 2005) and inability to feel (i.e., anhedonia) (Keedwell et al., 2005). To assess these associations, we compared change scores (Week 16 – Week 10) for the 10 MADRS symptoms between the aripiprazole augmentation groups (responders vs. nonresponders).

3. Results

3.1. Subjects, mood, extrapyramidal movement, and motor activity assessments

Twenty-eight subjects were enrolled. Of those, eight dropped out: two due to pregnancy, three due to poor tolerance for escitalopram side effects, and three without explanation. Six responded to escitalopram monotherapy and exited the trial after Week 8. Of the remaining 14 subjects who entered the aripiprazole augmentation phase (Weeks 9–16), 11 responded (≥ 50% decline in MADRS score, Weeks 10 to 16), and three did not. Sample demographic and disease data are presented in Table 1. The mean doses for the medications were as follows: escitalopram 17.9 mg (SD = 4.3); aripiprazole 7.8 (SD = 3.4).

Table 1.

Subject demographics and illness history

Variable Escitalopram responders (n = 6) Aripiprazole responders (n = 11) Non-responders (n = 3) Dropouts (n = 8) Total (n = 28)
Age, mean (SD) 41.2 (8.1) 44.8 (7.6) 40.0 (10.4) 37.1 (14.1) 41.3 (10.2)
Female, % (n) 67% (4) 91% (10) 100% (3) 75% (6) 82% (23)
Caucasian, % (n) 100% (6) 73% (8) 100% (3) 50% (4) 75% (21)
Number depression episodes, mean (SD) 9.7 (12.3) 4.4 (2.9) 1.3 (0.58) 5.7 (6.4) 5.6 (7.0)
Number failed trials, mean (SD) 2.2 (1.2) 3.3 (1.8) 3.7 (0.58) 2.7 (1.3) 2.9 (1.5)
ECT, % (n) yes 0% (0) 9% (1) 0% (0) 12.5% (1) 7% (2)
Suicide attempt, % (n) yes 33% (2) 18% (2) 0% (0) 25% (2) 21% (6)
Escitalopram max dose, mean (SD) 15.0 (5.5) 18.2 (4.0) 20.0 (0) 16.2 (5.2) 17.1 (4.6)
Aripiprazole max dose, mean (SD) — 7.0 (2.4) 8.3 (2.9) — 7.3 (2.5)*
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*

n = 14

Mean changes in MADRS scores for escitalopram responders, and aripiprazole augmentation responders and nonresponders are depicted in Fig. 2. The mean MADRS score of all subjects entering the aripiprazole augmentation phase was 28.7 (SD = 7.2) at Week 10 and 10.6 (SD = 8.78) at Week 16 (t(13) = 7.3, p < 0.001). The aripiprazole responders had a mean MADRS of 27.9 (SD = 5.6) at Week 10 and a mean MADRS of 6.5 (SD = 3.0) at Week 16 (t(10) = 11.1, p < 0.001). The respective values for the three nonresponders were 31.7 (SD = 12.7) and 25.3 (SD = 5.5) (t(2) = 1.2, p = 0.366). No subject who failed to respond to escitalopram monotherapy experienced a ≥50% reduction in their MADRS score from baseline during the second aripiprazole placebo phase (“placebo 2”; Weeks 8–10).

Fig. 2.

Fig. 2

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Change in mean depression scale scores for escitalopram responders (n = 6), aripiprazole augmentation responders (n = 11), and nonresponders (n = 3).

Changes in scores for the SAS, AIMS, BAS, and finger tapping were evaluated over three time points (Baseline to Week 10 to Week 16) using the non-parametric Friedman’s test. No significant effects were obtained for these analyses (p ≥ 0.06); however, the statistical power for these comparisons was low (supplemental Table 1S). AIMS and SAS scores trended toward improvement in the responders (p = 0.06 and p = 0.12, respectively), while BAS scores increased somewhat in the total sample (p = 0.07), a trend attributable to nonresponders only (p = 0.13).

3.2. FDOPA PET imaging findings

Using a within-subjects, whole brain comparison (paired t-test), there were no significant clusters for the entire group comparison (N = 14); however, for the 11 aripiprazole augmentation responders, there was a treatment effect for a cluster within the right medial caudate. This large volume consisting of 88 voxels was localized to the medial surface of the right caudate extending from the rostral head to the posterior body of the nucleus, as depicted in Fig. 3. Here, the normalized FDOPA ratio significantly increased between scan 1 and 2 (p = 0.029; family-wise error [FWE] multiple comparisons corrected). A similar within-subjects, whole brain analysis assessing for opposite directional change (regions undergoing decreased FDOPA trapping) did not reveal any significant findings.

Fig. 3.

Fig. 3

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A region of increased relative FDOPA uptake was observed following 6 weeks of aripiprazole augmentation (in responders [n=11]; paired t-test thresholded at a cluster level significance of p = 0.001) in the right medial caudate (left = transverse view, right = coronal view; left/right side = patient left/right). This right medial caudate region of increased relative FDOPA uptake spans from the anterior tip through the posterior body of the caudate.

3.3. Post hoc exploratory analyses results

3.3.1. Regional (medial caudate) FDOPA uptake subanalyses

A post hoc exploratory analysis of the medial caudate region was conducted. The change in mean relative FDOPA ratio in the right medial caudate from Week 10 (1.311, SD = 0.172) to Week 16 (1.336, SD = 0.183) for the total sample (t(13) = 2.2) was associated with a Cohen’s d of 0.62, a limited effect. Aripiprazole responders demonstrated an increase in mean relative right medial caudate FDOPA uptake from Week 10 (1.297, SD = 0.176) to Week 16 (1.333, SD = 0.175), (t(10) = 5), with a Cohen’s d of 1.70, which is a large effect. In contrast, the ariprazole nonresponders demonstrated a decrease in mean relative right medial caudate FDOPA uptake: Week 10 (1.363, SD = 0.180) versus Week 16 (1.350, SD = 0.252), (t(2) = 0.29) yielding a more modest Cohen’s d of 0.37. The difference in FDOPA uptake between aripiprazole responders and nonresponders is depicted in Fig. 4: no aripiprazole augmentation antidepressant responders decreased FDOPA uptake (in fact, 10/11 increased right medial caudate FDOPA uptake), whereas, 2/3 aripiprazole augmentation responders decreased FDOPA uptake.

Fig. 4.

Fig. 4

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Percent change in mean FDOPA uptake ratio in the right medial caudate versus percent change in depression score (Δ MADRS) following 6 weeks of aripiprazole augmentation of escitalopram. Notably, 10 of the 11 aripiprazole augmentation responders (open circles) demonstrated increased FDOPA trapping in the right medial caudate region, with no responders demonstrating a decrease in FDOPA trapping in this region. In contrast, 2 of the 3 aripiprazole augmentation nonresponders (darkened circles) had decreased FDOPA trapping. There was 1 outlier (upper right hand corner) that did not conform to this pattern.

Linear correlation between change in right medial caudate uptake and degree of antidepressant response (Δ MADRS) in the aripiprazole augmentation responders (n = 11) was not significant: r = 0.11, p = 0.76. Further, a similar correlation including all 14 subjects (responders and nonresponders) did not achieve statistical significance, in large part as a result of one outlier subject who failed to respond to aripiprazole augmentation, yet increased FDOPA uptake (r = −0.31, p = 0.28).

Corresponding changes in the mean FDOPA uptake ratio from Week 10 to Week 16 in the mirror image template (left medial caudate) were: a) total sample: (t(13) = 0.43) Cohen’s d = 0.11; b) responders: (t(10) = 0.60) Cohen’s d = 0.18; c) nonresponders: (t(2) = 0.87) Cohen’s d = 0.87.

3.3.3. Differential symptom response to aripiprazole augmentation

Of the 10 MADRS symptoms, large differences between augmentation responders and nonresponders in Week 10 versus Week 16 change scores were evident only for lassitude and inability to feel. Mean lassitude change score means were −0.67 (SD = 0.58) for nonresponders and −3.0 (SD = 0.89) for responders (t(12) = 4.2) Cohen’s d = 3.2. Mean inability to feel change score means were −0.33 (SD = 0.58) in nonresponders and −2.91 (SD = 1.22) in responders (t(12) = 3.5) Cohen’s d = 2.9. Mean sleep scores, which deteriorated among nonresponders, also was notably different between responder and nonresponders (2.0, SD = 2.0), and improved somewhat in responders (−1.6, SD = 2.0) (t(12) = 2.8) Cohen’s d = 1.80. The remaining effect size estimates for the other seven MADRS items ranged from 0.20–1.39 (with a mean d of 0.72). Non-parametric (Mann-Whitney U) comparisons of MADRS symptoms yielded the same pattern of results.

4. Discussion

These preliminary results support the hypothesis that aripiprazole antidepressant augmentation is associated with increased FDOPA utilization in the basal ganglia. Exploratory analysis showed relative, increased FDOPA trapping occurred in the right medial caudate of 10 of 11 (91%) of aripiprazole augmentation responders, with no responders demonstrating decreased right medial caudate FDOPA trapping. In contrast, the small subset of aripiprazole augmentation non-responders (n = 3), did not allow direct statistical comparison; however, two of the three non-responders decreased relative, right medial caudate FDOPA trapping.

The FDOPA recordings were obtained during an interval in which striatal FDOPA uptake is at its maximum, and remains fairly constant (60–90 min post-infusion), so as to provide an index of dopamine synthesis capacity. However, the lack of entire dynamic time-series and metabolite-corrected arterial input, omitted for the sake of simplicity, do not enable formal graphical and kinetic analysis of FDOPA trapping. The continuous time-activity curves measured in the striatum are the result of complex mechanisms involving first DOPA conversion to [18F]fluorodopamine, its storage in synaptic vesicles, and ultimately the elimination from brain of deaminated [18F]fluorodopamine metabolites (Kumakura and Cumming, 2009; Matsubara et al., 2011). Additionally, the assay is further complicated by the presence throughout the brain of the plasma metabolite O-methyl-FDOPA. Despite these complexities, the parsimonious explanation for the observations is that aripiprazole antidepressant augmentation occurs in association with increased FDOPA utilization in the right medial caudate.

How might aripiprazole potentiate the uptake and metabolism of FDOPA? Rodent studies ex vivo demonstrate that dopamine D2/3 antagonism/agonism influences the activity of cerebral DOPA decarboxylase (AAADC) (Zhu et al., 1993; Cho et al., 1997; Cumming et al., 1997), the enzyme converting L-DOPA to dopamine, and likewise responsible for the specific signal in FDOPA-PET studies. Similarly, treatment of rats with a monoamine oxidase inhibitor reduced the in vivo decarboxylation of [3H]DOPA, suggesting a feedback inhibition by presynaptic autoreceptors (Cumming et al., 1995). The stimulation in striatal dopamine syntheses evoked by D2/3 antagonists seems to be greater in magnitude than the inhibition evoked by agonists, suggesting a near ceiling effect for autoreceptor tonus (Kumakura and Cumming, 2009). Thus, acute treatment with haloperidol stimulated the utilization of FDOPA in striatum of pigs (Danielsen et al., 2001) and healthy volunteers (Vernaleken et al., 2006), whereas an agonist only slightly reduced [3H]-DOPA utilization in rat striatum (Cumming et al., 1997). Furthermore, Meller et al. (1993) found that autoreceptor regulation of dopamine synthesis was mediated by D3-specific agonists. Hence, a possible mechanism of action of aripiprazole (a purported partial agonist) in increasing striatal FDOPA utilization among aripiprazole augmentation responders might be through net antagonism at striatal (caudate) dopamine autoreceptors, relative to the tonic inhibitory prevailing condition brought about by interstitial dopamine levels. However, other possible explanations could exist.

The established dissociation between occupancy by aripiprazole and receptor antagonism (Grunder et al., 2003) may be further complicated by factors related to individual dopaminergic tonus at autoreceptors. Thus, non-human primate studies with 11C-DOPA PET revealed an inverse relationship between tracer utilization in striatum at baseline, and the decline evoked by challenge with aripiprazole (Ito et al., 2012), suggesting that net agonism at autoreceptors (thus decreasing utilization of exogenous DOPA tracers) was most pronounced in individuals with low basal activation of autoreceptors. Those authors interpreted their findings to support an action of aripiprazole as a stabilizer of dopamine synthesis, with efficacy depending upon individual factors. In this light, the present FDOPA-PET findings suggest rather the opposite scenario in depressed patients responding to aripiprazole augmentation, whereby the therapeutic effect was seemingly consistent with normalizing or stabilizing dopamine synthesis in those individuals with high basal activation of autoreceptors.

Independent of the FDOPA uptake findings, we identified that the two symptoms demonstrating the greatest improvement in antidepressant response in the aripiprazole augmentation responder group were those a priori identified as related to the dopaminergic system, i.e., lassitude and inability to feel. These results further strengthen the argument that aripiprazole augmentation may occur via alteration in dopaminergic activity.

4.1. Role of the caudate in major depression

Numerous studies have demonstrated structural (Krishnan et al., 1992) and functional (Buchsbaum et al., 1986) changes in the caudate nucleus associated with depression. Indeed, the caudate nucleus is proposed to be a key component of the cortico–striato–pallido–thalamic circuit, which is hypothesized to be critical in mood disorders (Price and Drevets, 2010). Martinot et al. (2001) demonstrated that depressed, unmedicated patients with psychomotor slowing (vs. anxious depressives) have decreased relative caudate FDOPA uptake, relative to healthy controls. However, unlike the current treatment effect, their finding was in the left caudate nucleus.

4.2. Medial caudate neuroanatomical localization and right-sided lateralization of findings

The right caudate region manifesting increased relative FDOPA uptake in the aripiprazole-responsive patients is located along the medial edge of the caudate, extending from the anterior body to caudal region of the nucleus. Although the ventral striatum (nucleus accumbens and adjacent striatal regions) is considered to be a central nucleus in the reward system and critical in mood disorders (Nestler and Carlezon, 2006), the medial caudate, especially the portion immediately adjacent to the lateral ventricle, also receives input from regions believed to be critical in depression/mood disorders (e.g., medial prefrontal cortex and amygdala; Ferry et al., 2000; Price and Drevets, 2010).

The lateralized findings (right > left) of this study were surprising. However, several functional neuroimaging studies examining the relationship between dopamine activity and MDD have also observed lateral asymmetry of striatal dopamine function/binding. Thus, in a single photon emission computed tomography (SPECT) study, which employed the selective dopamine transporter imaging agent [99mTc]TRODAT-1, there was greater binding in the left caudate of MDD patients than in non-depressed, matched controls, suggesting an asymmetric (left-versus-right) dopamine activity imbalance in MDD (Brunswick et al., 2003). In a SPECT study using the D2/3 antagonist ligand [123I]-IBZM, Shah et al. (1997) found higher receptor availability in the right striatum of MDD patients than in non-depressed controls, which could indicate lower occupancy by dopamine in a depressed state. Furthermore, they also found an inverse association between right side receptor availability and verbal fluency. Ebert et al. (1994), also using 123I-IBZM SPECT, found an association between antidepressant response to sleep deprivation and reduced post-treatment D2/3 receptor availability on the right side. In contrast to our findings, Martinot et al. (2001) found that psychomotor slowing and affective flattening were associated with decreased FDOPA uptake in the left caudate in depressed subjects. However, most dopamine functional neuroimaging studies have not searched for differences between right and left caudate/striatal activity (Dunlop and Nemeroff, 2007).

4.3 Right medial caudate post hoc findings (Figure 4)

As depicted in Fig. 4, a post hoc analysis of change in mean relative FDOPA uptake in the right medial caudate of both aripiprazole antidepressant responders and non-responders demonstrated an emerging pattern: the vast majority (10/11) of the responders increased right medial caudate FDOPA uptake; whereas, two of the three nonresponders decreased right medial caudate FDOPA uptake. One nonresponder subject was an outlier for this pattern (increased right medial caudate FDOPA uptake in a nonresponse subject). Limited power prevented us from achieving statistically significant separation for this correlation.

To attempt to explain these findings, we hypothesize the possibility that there may exist several variants of treatment-resistant depression identified by this study. The first, and most common, type are seen in the aripiprazole augmentation responder group and are depicted by open circles in Fig. 4. These responders may have clinical depression characterized by dysfunctional dopaminergic homeostasis; they experience enhanced FDOPA uptake (and presumably increased dopaminergic uptake) on aripiprazole augmentation. However, those who fail to respond to aripiprazole antidepressant augmentation may be a heterogenous group: one subset, who may consist of TRD patients with “unresponsive” dysfunctional dopaminergic systems, fail to increase right medial caudate FDOPA and are represented by the dark circles on the lower right in Fig. 4. Another group of aripiprazole antidepressant nonresponders may have “responsive” dopaminergic systems (increase right medial caudate FDOPA uptake) but still fail to demonstrate an antidepressant response, and they are depicted by the dark circle in the right upper corner of Fig. 4.

4.4. Antidepressant exposure alters dopamine agonist receptor binding

There are complex interactions between serotonergic and dopaminergic brain systems (Kapur and Remington, 1996). Numerous animal studies have demonstrated increased dopamine agonist binding following sustained exposure to antidepressants, including tricyclic antidepressants and SSRIs (Klimek and Maj, 1989; Maj et al., 1998; Gershon et al., 2007). Further, studies demonstrate that sustained antidepressant treatment also potentiates the locomotor stimulant effect of systemically-delivered dopamine agonists (Maj et al., 1989). Hence, aripiprazole augmentation may be a two-step process, wherein sustained SSRI treatment “primes” or sensitizes the mesolimbic D2/3 receptors, thus enhancing the pre-synaptic effects of aripiprazole on dopamine synthesis. We have hypothesized an analogous but contrary mechanism in the response of SSRI-treated OCD patients to a challenge with a dopamine D2/3 antagonist (Ersche et al., 2012).

4.5. Alternative explanations

Theoretically, the antidepressant effects of aripiprazole might be completely independent of the dopaminergic system, but perhaps mediated by serotonin receptors (Jordan et al., 2002), usually conceived as the target of SSRIs (Savitz et al., 2009). However, the post hoc exploratory findings that aripiprazole augmentation response is strongly associated with change in depressive symptoms related to dopaminergic function (lassitude and inability to feel) would favor the position that dopaminergic involvement is a key component of the anti-depressant effects.

4.6. Limitations

This preliminary study has several limitations. First, the small sample size and low number of patients who failed to respond to aripiprazole augmentation limit statistical power and complexity of statistical analyses. In particular, the apparent asymmetry of findings in the right caudate might arise from a Type I error in the left caudate, where Cohen’s d was only 0.2, and we likewise found no correlation between change in right caudate in FDOPA uptake with change in depression score in the 11 responders. Because of the critical importance of minimizing factors potentially altering brain dopamine function, we screened more than 100 patients (excluding many patients for smoking and higher age). Second, there was no control group; all FDOPA PET subjects were treated with aripiprazole. Third, the rate of aripiprazole response observed in this study (11/14 or 79%) is considerably higher than those seen in the multicenter trials, i.e. 32–47% (Berman et al., 2007; Marcus et al., 2008; Berman et al., 2009). This is likely attributable to the meticulous screening used in this trial, including the exclusion of multiple patient subsets (e.g., smokers, anxiety disorders, age restriction < 54). Fourth, in this preliminary trial, we obtained static FDOPA ratio images rather than dynamic PET recordings, based on the proven utility of a similar approach in studies of Parkinson’s disease (Dhawan et al., 2002; Jokinen et al., 2009). Finally, it is theoretically possible that the patients thought to be responding to aripiprazole augmentation could, in fact, be simply responding to monotherapy escitalopram. This is possible; however, given the adequate duration of trial (10 weeks), including two periods of placebo aripiprazole (8 and 2 weeks in duration), not likely. Future studies with dynamic PET recordings should afford more quantitative and mechanistic information about the effect of aripiprazole augmentation.

Supplementary Material

01

Acknowledgments

The authors thank Jon Christenson and Lars Couture for image processing, Betsy Thomas, RN, for scheduling and assistance with obtaining scans, Thomas Zeffiro, MD, PhD, of Harvard University School of Medicine for image interpretation, Britt Gott, MS, for editing and formatting the text, and Sudha Patel, MD, for her assistance with clinical assessments. This study was funded by Bristol-Myers Squibb by an investigator-initiated, industry-sponsored (CRC) grant. Bristol-Myers Squibb did not have any involvement in data collection, analysis, interpretation, or any editorial involvement. Forest Pharmaceuticals provided cost-free escitalopram (Lexapro ™) for this study.

Footnotes

Financial disclosures

CRC is on the speaker’s bureau for Pfizer Pharmaceuticals, Merck, and Bristol-Myers Squibb. CRC is currently supported by funding from the National Institute of Mental Health K08 award (1K08MH078156) and YIS K24 award (9K24MH07951006). MAM is an employee of Avid Radiopharmaceuticals. YIS has received honoraria for speaking through Eli Lilly and Co. and has served as a consultant for Bristol-Myers Squibb. JEM has received honoraria for advisory and speaking with Avid Radiopharmaceuticals/Eli Lilly and Co. JTC, PC, MAG, DCP, JLP, MEC, and SG all have no financial relationships to disclose.

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