This study is the first, to our knowledge, to compare the effects of CD on depression-related symptoms and neurophysiologic characteristics between unmedicated RMDD subjects and healthy controls. The CD induced greater increases in depressive, anxiety, and anhedonic symptoms in RMDD subjects than those in controls. In both groups, AMPT administration resulted in increased metabolism in the anteroventral striatum and decreased metabolism in the OFC. The most significant positive correlation between AMPT-induced changes in depression ratings and corresponding increases in metabolism appeared in the ventromedial frontal polar cortex.
Administration of AMPT evoked significantly more depressive symptoms in the RMDD group than in controls, although, in contrast to most previous studies,25
we found a minor but statistically significant effect of AMPT on mood in the healthy controls. The RMDD subjects described their CD-associated depressive symptoms as qualitatively similar to those experienced during major depressive episodes. Moreover, RMDD subjects, but not controls, showed increased anhedonia ratings under AMPT. These findings suggested that depressive and anhedonic responses during CD reflected a biological vulnerability in some RMDD subjects. It is noteworthy that AMPT-induced anxiety symptoms were nearly as prominent as AMPT-induced depressive symptoms, although none of the RMDD subjects had a comorbid anxiety disorder. This observation appears consistent with evidence from family and twin studies showing important nonspecific genetic and environmental factors underlying both depression and anxiety,26,27
and from studies of the pathological DA depletion state of Parkinson disease, which showed increased rates of anxiety as well as depressive symptoms.28
Although our study assessed the neurophysiologic effects of AMPT in unmedicated RMDD subjects, another study reported that AMPT-induced depressive symptoms were associated with decreased activity in the OFC, thalamus, dorsolateral PFC, and temporal cortex in medicated RMDD subjects.12
The previous study had a more balanced sex ratio (9 women and 9 men) but did not include a control group. Although we also found that AMPT resulted in reduced OFC metabolism in unmedicated RMDD subjects, we additionally demonstrated that this effect extended to healthy controls. We also demonstrated that, under AMPT, metabolism increased in both the RMDD and control groups in the anteroventral striatum, a region not specifically assessed by Bremner et al.12
Our results differed from theirs in the dorsolateral PFC, where we observed no significant change in metabolism under AMPT, and in the thalamus and temporal cortex, where we found that metabolism increased in RMDD in the right thalamus and left superior temporal gyrus. Although these differences in the results across studies may be accounted for by the differential sex proportions in the study samples (our sample was predominantly female), they may also reflect other experimental design differences. Bremner et al administered diphenhydramine hydrochloride as an active placebo, although this drug may have influenced cerebral metabolism via antihistaminergic and anticholinergic effects. They also studied RMDD subjects receiving NRI antidepressants, so the metabolic changes they observed may have included effects of CD on NRI-induced changes in catecholaminergic function. Finally, they included cigarette smokers, subjects with past alcohol or cocaine dependence, and RMDD subjects in remission for as little as 2 weeks.
A difference between our study and all previous studies of AMPT effects in mood disorders was that we used a slightly lower, body weight–adjusted dose to reduce risk of adverse reactions (eg, dystonia). Although some previous studies observed adverse events in response to AMPT doses greater than 4 g,29
none of our subjects experienced serious adverse effects. Nevertheless, this lower AMPT dose may have influenced the sensitivity for detecting differences between groups.
Some limitations of our methods warrant comment. Healthy controls with a latent vulnerability to MDD could not be definitively excluded, so AMPT-induced mood symptoms in some controls might reflect undetected risk factors for depression. We also did not include a “positive” control group with psychiatric conditions other than MDD (eg, anxiety disorders), which would have helped to evaluate the specificity of the results for MDD. In addition, the specificity of our results was limited by AMPT’s effects of reducing the synthesis of norepinephrine as well as DA and of inducing sedation. Furthermore, sedation may have been interpreted as a mood-lowering effect by subjects, potentially reducing the specificity of mood ratings and interfering with the subject and rater blinding to the drug condition. However, the previous study of CD in unmedicated RMDD subjects demonstrated that AMPT resulted in significantly greater effects on the depressed mood and anxiety items of the depression rating scale than did the sedative diphenhydramine (administered as an active placebo).5
In our study, the effect of sedation was partly controlled by comparison with healthy subjects, who experienced a degree of sedation similar to that experienced by RMDD subjects. In addition, our cross-sectional design could not establish whether the depressive response to AMPT in RMDD reflected an endophenotypic vulnerability to depression or a consequence of illness.
Finally, although the PET-fludeoxyglucose technique allowed us to address our primary aim of assessing neurophysiologic responses to CD by using measures that were unaffected by nonspecific changes in cerebral blood flow and vascular tone, this method could not provide specific biochemical information about catecholamine concentrations. Instead, we relied on the observation that AMPT produced a similar rise in serum prolactin levels in the RMDD and control samples to indicate that the AMPT effect on catecholamine synthesis was similar across groups.30
Nevertheless, a more selective method for assessing the depth of CD on intrasynaptic DA concentrations would potentially be afforded by measures obtained with PET using carbon 11–labeled raclopride; these measures are sensitive to endogenous DA levels.31
The generalizability of our results was limited by the small size and predominantly female sex composition of our samples. Moreover, a selection bias may have been introduced by requiring that RMDD subjects be in remission without medications for 3 months or longer, potentially explaining the relatively small number of past depressive episodes (mean [SD], 2.7 [1.4]).
Effects of AMPT in unmedicated RMDD subjects hold particular interest for elucidating the role of central catecholamine systems in conferring depressive vulnerability and maintaining symptom remission. Both our study and the other study that characterized AMPT effects in unmedicated RMDD patients5
observed that CD induced reemergence of depressive symptoms. These data suggest that MDD is associated with persistent vulnerability for developing depressive responses to reduced catecholamine neurotransmission. The variable mood response to CD across individuals () further suggests that genetic and/or pathophysiologic variation exists in the dependence on catecholaminergic function for maintaining remission. The positive relationship between AMPT-induced changes in regional glucose metabolism in the ventromedial frontal polar cortex () across diagnostic groups suggests qualitatively similar relationships between AMPT-induced mood change and associated alterations in local metabolic rates in both groups. However, we identified several other brain regions that showed metabolic changes that differed in direction in RMDD subjects vs controls (). These latter observations suggest that RMDD is additionally associated with specific neural responses to CD. Taken together, our findings indicate that both qualitative and quantitative differences exist in the neurophysiologic response to AMPT between RMDD subjects and controls.
We hypothesized that vulnerability to CD arises because reduced dopaminergic function would disinhibit limbic-cortical-striatal-pallidal-thalamic circuits implicated in depression.16
Dopaminergic projections from the substantia nigra and ventral tegmental area to the striatum, amygdala, and PFC compose an important inhibitory input into these structures.16,32
In the striatum, dopaminergic projections synapse onto axon terminals of afferent glutamatergic neurons, and DA release inhibits glutamate release from these neurons.14
Reducing DA input into the striatum thus disinhibits efferent neural transmission from the striatum.33
The AMPT-induced elevation of anteroventral striatal metabolism was compatible with this hypothesis ( and and ). Metabolism increased 8.5% and 8.6% in the RMDD group vs 4.4% and 4.6% in controls in the left and right anteroventral striatum, respectively, although the differences between groups were not significant (P
In other regions of the limbic-cortical-striatal-pallidal-thalamic circuitry, however, AMPT-induced metabolic changes differed significantly between groups (), and these changes correlated with the depressive and anhedonic responses to AMPT in the RMDD sample (). The interaction analyses () showed that, under AMPT, metabolism increased in RMDD subjects but decreased or remained unchanged in controls in the ventromedial frontal polar cortex, sgACC, midcingulate cortex, superior temporal gyrus, ventral striatum, and thalamus. In these regions, metabolism reportedly is elevated in currently depressed patients with MDD vs controls.16,34,35
Moreover, in RMDD samples imaged under tryptophan depletion,20,36
the depressive relapse induced putatively by reduced central serotonergic function also was associated with increased metabolism in the frontal polar cortex, sgACC, superior temporal gyrus, ventral striatum, and thalamus. Conversely, physiologic activity decreases in these regions after antidepressant treatment (reviewed by Drevets et al34
) or deep brain stimulation of the sgACC.37
These regions, along with the hypothalamus () and amygdala, share extensive anatomic interconnections to form part of an extended visceromotor network that modulates autonomic, neuroendocrine, and experiential aspects of emotional behavior.38
The central dopaminergic and noradrenergic systems participate in modulating anxiety responses to stress or threat (reviewed by Charney and Drevets39
). For example, in the anterior cingulate cortex, which receives extensive dopaminergic innervation,40
AMPT-induced metabolic changes correlated positively with anxiety ratings (). Reduced DA transmission to the accumbens also may dysregulate stress or anxiety responses because DA release in this region correlated inversely with anxiety ratings in healthy humans during amphetamine challenge.22
Dopaminergic projections from the ventral tegmental area to the accumbens play major roles in learning associations between operant behaviors or sensory stimuli and reward and in mediating reinforcing properties of drugs of abuse and natural rewards.41
Reduced dopaminergic transmission into the accumbens during CD may partly underlie the anhedonic response to AMPT in RMDD (). The mechanisms by which CD resulted in anhedonia in RMDD subjects, but not controls, also may involve differential effects on the sgACC and ventromedial frontal polar cortex function ( and ) because medial PFC neurons stimulate phasic DA release from the ventral tegmental area in rats.42
The AMPT-induced depressive symptoms may additionally or alternatively relate to reductions in norepinephrine synthesis. Dysfunction of the central noradrenergic system has been hypothesized to play a role in the pathophysiologic mechanisms of MDD on the basis of evidence of decreased norepinephrine metabolism, increased activity of tyrosine hydroxylase, and decreased density of norepinephrine transporter in the locus ceruleus in depressed patients.43
In addition, decreased neuronal counts in the locus ceruleus, increased α2
-adrenergic receptor density, and decreased α1
-adrenergic receptor density have been found in the brains of depressed suicide victims post mortem.44
An abnormality that conceivably may confer vulnerability to CD is the reduction in OFC metabolism in RMDD subjects under placebo. This baseline abnormality may reflect the neuropathologic changes found in the OFC post mortem in MDD.45
During depressive episodes, OFC metabolism is elevated to an extent that correlates inversely with depression severity, suggesting that this region functions to modulate symptoms.46
In contrast, depressive relapse under CD was associated with reduced OFC function, consistent with evidence that catecholaminergic transmission is necessary for optimal PFC function.47
Impaired baseline OFC function in RMDD thus may increase vulnerability for developing depressive symptoms during CD-associated reductions in OFC function. Compatible with this hypothesis, OFC activity is decreased in depressed vs nondepressed subjects with Parkinson disease.48,49
In conclusion, RMDD subjects manifest a diathesis to develop depressive relapse and altered visceromotor network physiologic processes as a result of decreased catecholaminergic neurotransmission. The association between depressive symptoms and metabolic changes supports hypotheses that dysmodulation of limbic-cortical-striatal-pallidal-thalamic circuits underlies the pathophysiologic mechanisms of depression,46
and that reduced catecholaminergic function constitutes one pathway through which dysmodulation of this circuit may arise. Our results encourage further research to characterize the neural and behavioral responses to AMPT as possible endophenotypic markers of depression and to elucidate the genetic factors that modulate these responses.50