Sage Journals: Discover world-class research

Abstract

Chronic stress accounts for billions of dollars of economic loss annually in the United States alone, and is recognized as a major source of disability and mortality worldwide. Robust evidence suggests that chronic stress plays a significant role in the onset of severe and impairing psychiatric conditions, including major depressive disorder, bipolar disorder, and posttraumatic stress disorder. Application of molecular imaging techniques such as positron emission tomography and single photon emission computed tomography in recent years has begun to provide insight into the molecular mechanisms by which chronic stress confers risk for these disorders. The present paper provides a comprehensive review and synthesis of all positron emission tomography and single photon emission computed tomography imaging publications focused on the examination of molecular targets in individuals with major depressive disorder, posttraumatic stress disorder, or bipolar disorder to date. Critical discussion of discrepant findings and broad strengths and weaknesses of the current body of literature is provided. Recommended future directions for the field of molecular imaging to further elucidate the neurobiological substrates of chronic stress-related disorders are also discussed. This article is part of the inaugural issue for the journal focused on various aspects of chronic stress.

Keywords

depression posttraumatic stress disorder bipolar disorder positron emission tomography single photon emission computed tomography

Introduction

The experience of chronic psychological stress is associated with a variety of serious physical, financial, and emotional consequences at both individual and societal levels.¹ The World Health Organization has labeled stress as a “worldwide epidemic” in recognition of the magnitude of its deleterious effects.² The American Institute of Stress estimates that the effects of chronic stress cost US companies over 300 billion dollars annually.³ More gravely, stress and resultant changes in affect are associated with increased morbidity and mortality,⁴ including increased rates of mental illness and suicide.⁵ Robust evidence has linked the experience of chronic stress to onset of major depressive disorder (MDD), which is the leading cause of disability worldwide.^1,6,7 Likewise, onset of bipolar (BD) and posttraumatic stress (PTSD) disorders, both of which are associated with substantial emotional, physical, and financial burden,^8,9 has been linked to chronic stress. Unfortunately, the molecular mechanisms by which chronic stress confers risk for mental health problems are poorly understood, hindering the development of critical interventions to resolve and prevent chronic stress-related disorders.

Application of Positron Emission Tomography and Single Photon Emission

Computed tomography (SPECT) has begun to provide information concerning how the brain changes following chronic stress on a molecular level. Positron emission tomography (PET) and SPECT molecular imaging techniques allow for the quantification of biochemical processes, including those known to play a pivotal role in the pathophysiology of psychiatric disorders in the living human brain.¹⁰ Both techniques rely on the injection of a “radiotracer,” a physiologically active compound with affinity for a specific target, which has been tagged with a small amount of radioactive isotope. This review is part of the journal’s inaugural issue, which is designed to comprehensively describe the neurobiological and neuroclinical effects of chronic stress. The role of this review is to summarize the existing molecular imaging work in psychiatric conditions known to be associated with chronic stress—MDD, BD, and PTSD—and recommend directions for future research.

Methods

Separate searches of the PubMed database were conducted for each disorder. In each case, the following standard prompts were used: “positron emission tomography” OR “PET” OR“single photon emission computed tomography” OR “SPECT” OR “single photon emission tomography” OR “SPET”). Distinct specifiers were then added for each of the three disorders: AND (“depression” OR “MDD”), AND (“bipolar disorder” OR “mania”), AND (“posttraumatic stress disorder” OR “PTSD”). Searches for MDD, BD, and PTSD initially yielded 2, 302, 447, and 158 PubMed article results, respectively. Studies were included in this review if they satisfied the following criteria: (1) articles focused on the use of PET or SPECT techniques, (2) articles describing original research, (3) articles presenting in vivo results in human participants, and (4) articles focused on the imaging of specific molecule/receptor types (i.e. excluding glucose metabolism and cerebral blood flow). Following careful review, 126 MDD, 22 BD, and 15 PTSD articles were retained.

Results

Major Depressive Disorder

A substantial body of research supports the assertion that stress, both chronic and acute, is causally related to the onset of MDD.¹¹ Recent research suggests that exposure to chronic or “every day” stress in financial, occupational, or personal settings alone, or in combination with acute stress exposure is more powerfully predictive of MDD than acute stress exposure alone.^12–14 While short-term stress can be adaptive, prolonged, or chronic exposure to stress can lead to long-term dysregulation of many physiological and neurochemical processes. PET and SPECT research has provided more precise insight into the nature of the chronic stress-related alterations associated with the onset and persistence of MDD (Table 1).

Table 1.

Radiotracers used for in vivo molecular imaging in individuals with major depressive disorder.

Molecular target (receptor) MDD	Radiotracer (full name)	Abbreviation(s)	Main findings
Serotonin synthesis	a-[¹¹C]methyl-L-tryptophan	a-[¹¹C]- MTrp	↓Serotonin synthesis in MDD^15–17
	5-hydroxytryptophan (5-HTP) labelled with ¹¹C in the ß position	[ß-¹¹C]5-HTP	↓Serotonin synthesis in MDD^18,19
Serotonin transporter (SERT)	(3-amino-4-(2-dimethylami-nomethyl- phenylsulfanyl)-benzonitrile)	[¹¹C]DASB	↓SERT availability in MDD;^20–22 mixed findings^23,24
	(11)C-(+)-6β -(4Methylthiophenyl)- 1,2,3,5,6alpha,10β hexahydropyrrolo [2,1-a] isoquinoline	[¹¹C]McN5652	↓SERT availability in MDD;^25,26 ↑SERT availability in MDD^27,28
	[123I] 2-((2-((dimethylamino)methyl) phenyl) thio)-5-iodophenylamine (aDaM)	[123I]-ADAM	↓SERT availability in MDD;^29–,32 ↑midbrain SERT availability in suicide attempters³³
	N, N-dimethyl-2-(2-amino-4- [18F]fluorophenylthio)benzylamine (4-[18F]-aDaM)	(4-[¹⁸F]-ADAM)	Suicidal ideation positively correlated with SERT availability³⁴
	Carbon-11 labeled 2β-carbomethoxy-3β- [4′-((Z)-2-iodoethenyl)phenyl]nortropane	[¹¹C]-ZIENT PET	↓SERT availability in MDD suicide attempters³⁵
Serotonin 1A (5HT1A) receptors	carbon11–labeledN-(2-1-4-2-methoxyphenyl)-1piperazinyl)ethyl))- N-(2-pyridyl)-cyclohexanecarboxamide	[¹¹C]WAY-100635	↑5HT1A availability in MDD^26,36–40; ↓5HT1A availability in MDD^41–48
	No-carrier-added 4-(2′-methoxyphenyl)- 1-[2′-(N-2-pyridinyl)-p-[18F] fluorobenzamido]ethylpiperazine)	[¹⁸F]MPPF	↓5HT1A availability in MDD⁴⁹
			(cont.)
Serotonin 1B (5HT1B) receptors	(R-1-[4-(2-methoxy-isopropyl)-phenyl]-3- [2-(4-methyl-piperazin-1-yl)benzyl]- pyrrolidin-2-one)	[¹¹C]P943	↓5HT1B availability in MDD⁵⁰
	(5-methyl-8-(4-methyl-piperazin-1-yl)- 4-oxo-4H-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide)	[¹¹C]AZ10419369	↓5HT1B availability in MDD;⁵¹ ↓5HT1B availability in MDD following therapy⁵²
Serotonin 2A (5HT2A) receptors	123iodinated 4-amino-N-1- [3-(4-fluorophenoxy)propyl]-4-methyl-4- piperidinyl] 5-iodo-2-methoxybenzamide	123I-5-I-R91150	↓5HT2A availability in MDD⁵³
	[18F]altanserin		↓5HT2A availability in MDD^54,55
	((R)-(+)-4 -(l-hydroxy-1- (2,3-dimethoxyphenyl)methyl)-N -2-(4-fluorophenylethyl)piperidine) labeled with 11C	[¹¹C]MDL 100,907	↑5HT2A availability in individuals with a history of MDD⁵⁶
	[¹⁸F]fluoroethylspiperone	[¹⁸F]FESP	↓5HT2A availability in drug-naïve MDD, not different from HC in SSRI responders⁵⁷
	[¹⁸F]setoperone		↓5HT2A availability in MDD;^58,59 ↑5HT2A availability in MDD^60,61
Serotonin receptor type 4 (5HT4)		[¹¹C]SB207145	↓5HT4 availability in healthy individuals with family history of MDD⁶²
SERT/dopamine transporter (DAT)	¹²³I-labelled 2β-carbomethoxy-3 β-(4-iodophenyl)-tropane	[¹²³I]I-ß-CIT	↓SERT/DAT availability in MDD^63–66
		[¹²³I]nor-ß-CIT	↓SERT/DAT availability in MDD^67,68
	(2β-carbomethoxy-3β- (4- iodophenyl)-tropane	[¹²³I-labeled β -CIT	Mixed results^69,64
Dopamine synthesis	[¹⁸F]fluorodopa	[¹⁸F]DOPA	↓Dopamine synthesis⁷⁰
Doapmine synthesis (cont)	¹¹C-labeled 3,4-Dihydroxy-phenyl-L-alanine	L-[¹¹C]DOPA	↓Dopamine synthesis¹⁰²
Dopamine transpoter (DAT)	((99 m)Tc-[2[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]-oct-2-yl]-methyl](2-mercaptoethyl) amino]ethyl] amino]ethane-thiolato(3-)-N2,N2′,S2,S2]oxo-[1R-(exo-exo)]))	[99mTc] TRODAT-1	↓DAT availability in MDD^71–76
		[¹¹C]RTI-32 PET	↓DAT availability in MDD⁷⁷
	[¹²³I]N-fluoropropyl-carbomethoxy-3β- (4-iodophenyl)tropane		↓DAT availability in MDD⁷⁸
Dopamine type 2/3 receptors (D2/3)	[¹²³I]iodo-benzamide	([¹²³I]IBZM)	↑D 2/3 availability in MDD;^62,79 No differences in D 2/3 availability between MDD and HC^80,74,81,82
	[¹²³I]epidepride		↑D 2/3 availability in MDD⁶⁸
	((S)-N-((1-ethyl-2-pyrrolidinyl)methyl)- 5- bromo-2,3-dimethoxybenzamide)	[¹¹C]FLB 457	No differences in D 2/3 availability between MDD and HC⁸³
	[¹¹C]raclopride	[¹¹C]RAC	↑D1 availability in MDD²⁴
Dopamine Type 1 Receptors (D1)	8-chloro-7-hydroxy-3-methyl-5- (7-benzofuranyl)-2,3,4,5-tetrahydro- IH-3-benzazepine)	[¹¹C]NNC-112	↓D1 availability in MDD⁸⁴
	((R)-(+)-8-chloro-2,3,4,5-tetrahydro- 3- methyl-5-phenyl-1H-3-benzazepin-7-ol)	[¹¹C]SCH 23,390	↓D1 availability in MDD with anger⁸⁵
Metabotropic glutamate receptors type 5 (mGluR5)	(3-(6-methyl-pyridin-2-ylethynyl)- cyclohex-2-enone-O-(11) C-methyl-oxime)	[¹¹C]ABP688	↓mGluR5 availability in MDD^86,87
		[¹⁸F]FPEB	No differences in mGluR5 availability between MDD and HC⁸⁸
Translocator protein (TSPO)		[¹¹C]PBR28	No differences in TSPO availability between MDD (mild symptom severity) and HC⁸⁹
	fluorine F 18–labeled N-(2-(2- fluoroethoxy)benzyl)-N- (4-phenoxypyridin-3-yl)acetamide	([¹⁸F]FEPPA)	↑TSPO availability in MDD^90,91
MAO-A		([¹¹C]harmine)	↑MAO-A availability in MDD^92,93
β-Amyloid	F-florbetapir		↑ β-Amyloid availability in MDD⁹⁴
	N-Methyl-[¹¹C]-2-(4′methyaminophenyl)- 6-hydroxybenzothiasole	[¹¹C]PIB-PET	β-Amyloid availability correlated with MDD severity⁹⁵
β2*-nAChR	(¹²³I-IA); [¹²³I]-5-iodo-3-[2(S)-azetidinylmethoxy]pyridine	[¹²³I]5-I-A-85380	No differences in β2*-nAChR between MDD and HC⁹⁶

Note. MDD, major depressive disorder; PET, positron emission tomography; MAO, monoamine oxidase; HC, healthy control.

The majority of existing PET and SPECT research in MDD populations has focused on the functioning of two monoaminergic neurotransmitters: serotonin and dopamine. Focus on monoamine functioning in depression resulted in part from the monoaminergic hypothesis,⁹⁷ which postulates that alterations in the function of monoaminergic neurotransmission play a causal role in the development of MDD.

Serotonin

Between 1991 and 2016, 71 molecular imaging studies meeting the criteria specified above were published. Strong evidence supports the role of the serotonergic (5HT) system, which plays a role in the regulation of sleep, stress responses, and affective cognition⁹⁸ in the development and continuation of depressive symptoms.⁹⁹ However, the exact nature of the relationship between 5HT functioning and MDD is still under debate. Both preclinical and postmortem evidence suggests that serotonergic dysfunction and specifically deficits in serotonin are central to the pathophysiology of MDD.^100,101 In line with such findings, evidence from PET work suggests lower serotonin synthesis in MDD individuals relative to healthy control,^15–19 and that treatment with selective serotonin reuptake inhibitor (SSRI) resulted in increased serotonin synthesis.¹⁶

The serotonin transporter (SERT) plays a key role in modulation of brain 5HT levels via reuptake into presynaptic neurons,⁹⁸ and is the primary target of action for many commonly prescribed antidepressant medications.¹⁰² Interest in SERT has been motivated in part by evidence suggesting that expression of the SERT gene (5HTT) may moderate emotional and behavioral responses to stress,¹⁰³ such that individuals displaying a specific 5HTT polymorphism (associated with decreased serotonergic functioning in preclinical studies^103,104) were more likely to develop MDD and suicidal behavior following stress.¹⁰⁵ Evidence from a recent SPECT study similarly found lower SERT availability in the thalamus and that high levels of life stress interacted to predict depressive symptom severity, suggesting that SERT may play a specific role in the development of depression following chronic stress.¹⁰⁶ Miller et al.²⁵ observed lower SERT availability across brain regions in individuals reporting a history of child abuse who went on to develop MDD, but not PTSD, relative to MDD individuals without an abuse history. Further, support for the relationship between SERT and stress comes from an experimental study of HPA axis dysfunction, as measured by the dexamethasone suppression test,¹⁰⁷ showing an association with reduction in SERT levels. Evidence points to lower SERT availability in multiple brain areas, most commonly the thalamus,^20,29 and midbrain^{21,22,30,31,67} or brainstem,^63,69 areas responsible for regulation of sleep/wake cycles which are frequently disrupted in MDD.

Importantly, SERT levels appear to be related to antidepressant treatment outcome and illness progression.^{32,108,109,110,111} Increase in midbrain SERT availability is associated with depressive symptom remission following antidepressant treatment,^109,111,112 and Amsterdam et al.¹¹⁰ showed a significant increase in both midbrain and medial temporal lobe SERT availability in treatment responders following 12 weeks of cognitive behavioral therapy. Conversely, in participants whose MDD symptoms did not remit following a year of antidepressant use, lower SERT availability was detected in several brain regions in individuals with MDD relative to healthy controls.²⁷

Of note, in vivo evidence for low SERT in MDD is strong but not universal. Some studies have reported no significant differences in SERT availability between MDD and healthy control groups,^{23,28,64,113,114} while others reported higher SERT availability in individuals with MDD relative to controls.^65,113,115 No clear explanation for these discrepant findings is available, though low sample size due to cost in PET and SPECT studies, difficulty in recruiting these patients, and cross-sample variability (e.g. symptom severity, sex, race, medication) likely play a role. Notably, characteristics of some specific radiotracers may have biased findings in some cases. For example, both SPECT tracers, [¹²³I]nor-β-CIT and [¹²³I]β-CIT, have been shown to bind not only to SERT but to norepinephrine (NET) and dopamine (DAT) transporters.¹¹⁶ Thus, depending on the region, quantification of SERT might represent SERT and DAT/NET densities.

A large focus in the serotonergic literature has also been the 5HT1A receptor, which is a post-synaptic G-coupled protein receptor and the most common serotonergic receptor in the brain.¹⁰⁵ The 5HT1A receptor is located both in brain areas with projections from the raphe nuclei (RN), where the serotonergic system is centralized,¹¹⁷ and in the RN itself. Preclinical research has shown that animals with higher numbers of 5HT1A receptors are more vulnerable to stress¹¹⁸ and display more “depressive” behavior (e.g. helplessness¹¹⁹). Similarly, some postmortem studies have shown higher 5HT1A density in select brain regions (e.g. midbrain dorsal RN) of individuals with MDD relative to healthy controls.⁴⁹ Based on evidence from other modalities, it is reasonable to hypothesize observation of similarly increased 5HT1A availability in vivo.

To date all published 5HT1A studies have used PET, with all but one using the 5HT1A radiotracer [¹¹C]WAY-100635 with somewhat mixed findings. Unlike cited preclinical and postmortem studies, there does not appear to be a consensus on whether 5HT1A is up or downregulated in depression: about half the published studies observed lower 5HT1A availability in MDD participants across various brain regions,^41–46 whereas the other half found evidence for higher levels of 5HT1A in MDD, particularly in treatment-resistant individuals,^{26,36–39,47,48,120,121} and with only one study reporting no 5HT1A differences between MDD participants and controls.⁴⁰ Interestingly, downregulation in 5HT1A appears to be associated with treatment response following SSRI treatment.^39,121

Importantly, a specific, testable explanation for the observed variability in 5HT1A findings has been proposed. In molecular imaging, there are various ways to quantify receptor availability, one of which is by the use of a reference tissue, which should be a region that is devoid of the target molecule (commonly the cerebellum). This method has been implemented in the studies that report lower 5HT1A availability in MDD; however, it appears that the cerebellum is not devoid of 5HT1A and there is evidence of lower cerebellar 5HT1A availability in the control relative to the MDD groups,⁹⁸ which would bias the results and lead to an underestimation of the true 5HT1A density in MDD. Illustrating this point, Hesselgrave and Parsey¹²² showed that the same data set showed lower 5HT1A availability in MDD when analyses were completed using the cerebellum as reference, and the opposite finding when the outcome measure was a blood derived input function. It has also been suggested that 5HT1A level varies temporally over the course of MDD, possibly in part as a function of antidepressant exposure.¹²² At present, all that can be concluded is that the preponderance of evidence suggests 5HT1A is elevated in MDD.

Like 5HT1A, the 5HT1B receptor is an autoreceptor present in the terminal regions of serotonergic neurons and plays a role in regulating, specifically decreasing when activated, the amount of serotonin in the synapse.⁹⁸ Both clinical¹²³ and preclinical¹²⁴ studies have shown that 5HT1B agonists have antidepressant properties, suggesting that unlike 5HT1A, lower levels of 5HT1B may be associated with MDD symptom experience. Although limited, evidence is somewhat consistent with this hypothesis with two reports of lower 5HT1B availability in the ventral striatum and pallidum⁵⁰ and the anterior cingulate cortex (ACC), subgenual prefrontal cortex (PFC), and hippocampus,⁵¹ respectively, but another report of lower 5HT1B availability in the dorsal brainstem following cognitive behavioral therapy for MDD.⁵²

The 5HT2A receptor has received significant molecular imaging research attention, largely because SSRIs are known to act directly on 5HT2A receptors, leading to receptor downregulation.¹²⁵ Importantly, the 5HT2A receptor has proven responsive to stress exposure; 5HT2A levels have been shown to increase following exposure to chronic stress in preclinical studies.^126,127 Depressive behavior following stress has also been shown to increase in response to 5HT2A agonists,^128,129 further implicating upregulated 5HT2A in the pathophysiology of MDD. In vivo molecular imaging studies, however, have shown mixed results. There are several reports of downregulated^{53–55,57,58,60} 5HT2A in MDD across several brain regions. However, there are also studies of no significant differences between untreated MDD participants and controls,^59,130 and two showed higher levels of 5HT2A in the basal ganglia¹³¹ and frontal, parietal, and occipital cortices⁵⁶ of unmedicated MDD participants relative to controls. The reports of higher 5HT2A density in MDD are in agreement with studies showing a reduction in cortical 5HT2A availability following treatment with tricyclic antidepressants.^61,130 In attempting to account for mixed findings concerning 5HT2A in MDD, Ruhe et al.⁹⁸ suggested that individuals with MDD may have lower 5HT2A availability in the hippocampus due to HPA axis dysregulation and higher 5HT2A availability in other areas (e.g. the frontal cortex), a pattern that has been shown in animals exposed to chronic stress. However, this proposed explanation has not yet been directly tested.¹³²

Finally, a single PET study investigated the relationship between MDD risk and availability of the 5HT4 receptor,⁶² which has been implicated in recent preclinical studies as a potential target for rapidly acting antidepressant agents.¹³³ The authors reported that healthy individuals with a family history of MDD have lower 5HT4 availability in the striatum, which was inversely correlated with the number of first degree relatives with MDD. These findings implicate the 5HT4 receptor as a potential target subserving familial risk for MDD, though replication and exploration of this receptor system in individuals with MDD is warranted.

Dopamine

Another monoaminergic neurotransmitter implicated in the pathophysiology of MDD is dopamine, which is known to be associated with emotion regulation, attention, motivation, and reward.¹³⁴ Dopaminergic circuits contribute to the regulation of concentration and memory functioning, as well as the ability to experience pleasure, all of which are impaired in MDD.¹³⁵ Dopaminergic dysfunction (i.e. reduced D2 receptor function), specifically in the nucleus accumbens, has also been linked directly to the experience of chronic stress, and subsequent development of depressive symptoms (anhedonia) in preclinical studies.^80,136

As with serotonin, early molecular imaging of the dopamine system sought to examine the neurotransmitter’s synthesis in the brain, speculating in part based on results from clinical studies,¹³⁷ that less dopamine synthesis would be observed in depressed individuals.⁹⁸ This was verified by some PET studies in limited brain regions.^19,138 A much larger number of studies have examined the functioning of dopamine transmitters (DAT) in MDD but have produced incongruent results. Specifically, genetic research has suggested that a DAT gene polymorphism, which increases DAT availability, is associated with higher risk for MDD.^70,139 Several postmortem studies, however, have observed lower brain-wide DAT availability in MDD individuals. Findings in the molecular imaging literature are similarly mixed. Although there are reports of higher DAT availability in the striatum,^71,140 basal ganglia,⁷² and other brain areas⁷³ of MDD participants, others reported no significant differences between MDD and healthy control (HC),^74,75 and three reported lower DAT availability in MDD in the striatum.^76,78,141 Furthermore, Meyer et al.⁷⁶ reported that a downregulation in DAT availability was related to more severe depressive symptoms. However, they did not detect a significant change in DAT availability before and after bupropion antidepressant therapy,⁷⁶ suggesting that bupropion treatment did not appear to target this system or this system may not be significantly involved in MDD pathophysiology.

Measuring DAT with SPECT has also yielded some mixed results.^{28,63,67–69,77,108,109} However, not all of these studies characterized their results as indicative of DAT availability because, as noted above, SPECT DAT tracers are recognized to have affinity for SERT and NET as well. Results of these studies should therefore be interpreted with caution. Furthermore, Camardese et al.⁶⁶ highlighted the heterogeneity in presentation of MDD symptoms that can meet diagnosis and the potential effects of pharmacological treatment history and drug abuse as potential confounds affecting the observed variability in findings. As with SERT, inconsistent findings make it difficult to form a conclusion concerning the relationship between DAT and MDD at present.

The majority of neuroimaging studies investigating dopamine receptor availability have focused primarily on D2/D3 receptors, in part due to these receptors being targets for antidepressant and antipsychotic therapy.¹³⁶ Evidence from other modalities implicates possible downregulation of D2/3 receptors in MDD. Epigenetic studies have presented evidence for a link between chronic stress, D2 downregulation, and the development of depression.⁶⁶ Similarly, preclinical studies have shown downregulation of D3 in animals experiencing stress and depression. However, of the 14 studies which have examined D2/3 availability using PET and SPECT in individuals with MDD, all but 3 failed to observe differences in both medicated^{44,81,142,143} and unmedicated^{26,43,73,79,142} MDD participants relative to HCs. The remaining three showed higher D2/3 availability in MDD in the striatum,^82,131 and in the case of Lehto et al.,⁷⁷ a positive correlation between MDD symptom severity and D2/3 availability in the temporal cortex. However, although in vivo evidence suggests no specific D2/3 dysregulation in MDD, alterations treatment with SSRIs appears to influence D2/3 availability. For example, Montgomery et al.²⁴ reported lower D2/3 availability in the striatum of MDD participants using SSRIs, while two other studies observed increased D2/3 in the basal ganglia¹³⁶ and striatum⁸³ of SSRI treatment responders but not non-responders. Of note, while only two published studies have examined the D1 receptor in vivo in MDD, both found lower D1 availability in the striatum of MDD relative to control groups.^85,144

Glutamate

More recently, there has been a major focus on the glutamatergic system in MDD. Glutamate is the primary excitatory neurotransmitter in the brain, with 80%–90% of synapses in the human brain being glutamatergic. Dysfunction of the glutamate system is thought to play a role in MDD⁸⁴ and there is currently an intensive focus on the glutamate system as a target for novel treatments for MDD.⁸⁴ Part of this focus has been on metabotropic glutamate receptors (mGluRs), G-protein-coupled receptors that mediate neuromodulatory effects of glutamate.¹⁴⁵ Indeed, mGluR5 antagonists have consistently shown antidepressant effects in animal models of depression.^146–151 Lower levels of mGluR5 protein expression was also found in postmortem PFC tissue of individuals with MDD;¹⁵² however, another study did not detect differences using autoradiography.⁸⁶ To date, there are four PET imaging studies that report on mGluR5 availability in MDD. Two smaller scale studies found lower levels of mGluR5 in various brain regions of those with unmedicated MDD including the PFC, ACC, and insula.^152,153 A recent PET study focusing on late-life MDD found no differences in mGluR5 availability between older adults with MDD and matched controls.⁸⁷ Similarly, a recent study by our group found no differences in mGluR5 availability in a large group of unmedicated MDD individuals compared to HCs. As part of the same study, we used MRS to assess measures of glutamate and found a negative correlation between mGluR5 availability and MRS measures of glutamate in the ACC.¹⁵⁴ It is possible, therefore, that higher levels of glutamate are associated with a downregulation of mGluR5 in MDD. Furthermore, we recently observed that rapid downregulation of mGluR5 is associated with a reduction of somatic anxiety symptoms in MDD participants, suggesting this might be a treatment target for anxiety in MDD.¹⁵³ Further work will be required to definitively determine whether mGluR5 is a viable treatment target for symptoms of MDD.

Inflammation

Convergent evidence indicates that inflammation plays a significant role in MDD.^88,155,156 Inflammatory mechanisms have been proposed to underlie the link between chronic stress and depression,³³ and meta-analyses have confirmed elevated inflammatory markers in individuals with MDD.^157–160 However, the specific role of inflammation in the brain is less clear. It is possible to measure neuroinflammation with PET and radioligands that bind to the translocator protein (TSPO), which is upregulated on activated microglia, the immune cells of the brain.¹⁶¹ To date, there are two published PET studies investigating TSPO in depression. The first found no difference in TSPO availability between depressed individuals with symptoms of mild severity and controls.¹⁶² The second larger study showed elevated microglial activation in medication-free depression of moderate to severe severity, specifically in the PFC, ACC, and insula.⁸⁹ This finding has recently been replicated in a similar sample of medication-free depressed individuals.⁹⁰ Interestingly, this study found elevated TSPO in depressed individuals with versus without current suicidal thinking, suggesting a role for neuroinflammation in suicidal ideation specifically. Indeed, the heterogeneity in MDD symptomatology may play a role in the expression of neuroinflammation in MDD and account for divergent findings. PET and the 40+ existing TSPO radioligands provide a unique opportunity for clarifying the role of neuroinflammation in the pathophysiology of MDD and evaluating the use of anti-inflammatory medications in treating its symptoms.

Other Neurotransmitters

In addition to those reviewed above, PET and SPECT have been used to measure other systems such as monoamine oxidase (MAO-A), β-Amyloid, nicotinic acetylcholine receptors (β₂*-nAChR), and γ-aminobutyric acid (GABA)—benzodiazepine receptors (GABA_A-BZR). MAO-A is an enzyme known to be responsible for the regulation of brain monoamine levels.⁹¹ Higher MAO-A availability is observed in MDD participants relative to HC,^91,92 which would be in line with the studies showing lower monoamine neurotransmission in MDD.

β-Amyloid deposition in the brain, which is associated with the development of dementia, has been shown to correlate with history of lifetime MDD episode in postmortem work.⁹³ A single PET study by Wu et al.⁹³ showed higher β-Amyloid levels in depressed, but cognitively normal, older adults relative to age-matched HCs in multiple brain regions. A recent study by Yasuno et al.⁹⁴ looking at older adults without clinical MDD also reported a positive correlation between β-Amyloid availability averaged across the brain and depressive symptom severity. The cholinergic system has long been identified to be dysregulated in MDD,^95,163–166 with the hypothesis of excesses in acetylcholine levels contributing to the experiences of depression. Specific to the neuroimaging literature, the β₂*-nAChR has been identified as potentially relevant to MDD symptom expression,¹⁶⁷ although clinical trials with targets to downregulate β₂*-nAChR did not prove efficacious for treatment of MDD. Combined in vivo/postmortem study from our group verified that β₂*-nAChR does not appear to be dysregulated in MDD; however, elevations in acetylcholine levels might indeed play a role in depression.¹⁶⁸ Finally, a single study examined GABA_A-BZR availability in MDD and found no differences in availability between MDD and control groups.⁹⁶

PET and SPECT Literature: Suicidal behavior

Importantly, while suicidal behavior is most frequently investigated as an associated feature of MDD, evidence from clinical research suggests the existence of meaningful neurobiological differences between suicide attempters and non-attempters.¹⁶⁹ For example, platelet studies showed that suicidal individuals had higher number for 5HT2A binding sites compared both to MDD non-attempters and HCs.¹⁶⁹ Similarly, variation in the DRD2 gene affecting D2 receptor expression has been consistently associated with risk for suicidal behavior, but not for MDD.³⁵ To date, seven published studies, all focused on the serotonergic system, have explicitly examined associations with current or historical suicidal behavior (ideation or attempt). Five studies focused on SERT availability in MDD participants with suicidal behavior with interesting if mixed results. For example, Yeh et al. observed a positive correlation between SERT availability and suicidal ideation across brain regions³³ while two other studies observed lower SERT availability in the midbrain¹⁷⁰ and putamen¹⁷⁰ of MDD participants with a history of suicide attempts compared to both healthy controls and MDD non-attempters. In combination, these findings suggest that lower midbrain SERT availability might distinguish between MDD individuals with and without risk for suicide. Notably, Oquendo et al.¹⁷¹ failed to confirm midbrain SERT availability as a predictor of attempts in a recent longitudinal study. They did, however, observe that increased 5HT1A availability in the RN predicted both suicidal ideation and lethality of suicidal behavior.¹⁷¹ In a cross-sectional study, Sullivan et al. also found that 5HT1A availability in the RN correlated positively with the lethality of attempt.⁹⁰ Thus, 5HT1A availability in the RN serve as a marker for suicide risk. Of note, a single PET study in high-lethality suicide attempters across psychiatric diagnoses found lower serotonin synthesis in the orbital and ventromedial PFC of attempters relative to HCs.¹⁷² These promising results underscore the need for more molecular imaging work in suicidal individuals.

Bipolar Disorder

Relationship Between BD and Chronic Stress

Stress is also thought to play a significant role in the development of bipolar disorder (BD). Stress can trigger the first manic/hypomanic episode, predict episode recurrence, and lead to less favorable outcomes.^173–177 Thus, there is significant interest in stress as a target for treatment and prevention strategies in BD. Molecular imaging can provide invaluable information on the molecular mechanisms underlying the link between stress and BD. To date, 22 PET and SPECT studies have been performed in BD (Table 2), and like MDD, the majority (n=14) have focused on the serotonergic system.

Table 2.

Radiotracers used for in vivo molecular imaging in individuals with bipolar disorder.

Molecular target (receptor) BD	Radiotracer (full name)	Abbreviation(s)	Major findings
SERT (serotonin transporter)	trans-1,2,3,5,6,10- -hexahydro-6-[4-(methylthio) phenyl]pyrrolo-[2,1-a]-isoquinoline	[¹¹C](+)-McNeil 5652	↓SERT availability in BD¹⁷⁸
	[¹¹C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile	[¹¹C]DASB	Mixed findings^65,34
	[(123)I]-2-((2-((dimethylamino)methyl)phenyl)thio)- 5-iodophenylamine	[¹²³I]-ADAM	↓SERT availability in euthymic BD^179–184
Serotonin 2A receptor (5HT2A)	[¹⁸F]-setoperone		Mixed findings^185,186
Serotonin type 1A receptor (5HT1A)	[N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2- pyridinyl) cyclohexane carboxamide]	[Carbonyl-C-11]WAY-100635	No differences in 5HT2A availability in euthymic BD;¹⁸⁷ ↑5HT2A availability in BD depression¹²³
	[¹⁸F]trans- 4-ﬂuoro-N-(2-[4-(2-methoxyphenyl) piperazino]-ethyl)-N- (2-pyridyl) cyclohexanecarboxamid	[¹⁸F]FCWAY	↓5HT2A availability in BD depression¹⁸⁸
Dopamine transporter (DAT)	((99 m)Tc-[2[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]-oct-2-yl]-methyl](2-mercaptoethyl) amino]ethyl]amino]ethane-thiolato(3-)-N2,N2′,S2,S2]oxo-[1R-(exo-exo)]))	[99mTc]TRODAT-1	↑DAT availability in depressed¹⁸⁹ and euthymic BD¹⁹⁰
	[O-methyl-¹¹C]b -CFT	[¹¹C]CFT	↓DAT availability in BD across mood states
Dopamine type 2 teceptor (D2)	[¹¹C]raclopride.	[¹¹C]RAC	No differences in D2 availability in manic BD¹⁹¹
Translocator protein (TSPO)	[1-(2-chlorophenyl)-N-methyl-N-(1-methyl propyl)-3-isoquinoline carboxamide]	[¹¹C]-(R)-PK11195	↑TSPO availability in euthymic BD
β2*-nAChR	5-iodo-3-(2(S) azetidinylmethoxy) pyridine	[¹²³I]5IA	No differences in β2*-nAChR availability between depressed BD, euthymic BD, and HC¹⁹²
Muscarinic type 2 (M2) receptor	(fluorodopa F 18 [3-(3-[3-fluoroprop- ly]thio)-1,2,5-thiadiazol-4-yl]-1,2,5,6-tetrahydro-1- methylpyridine)	[¹⁸F]FP-TZTP	↓M2 availability in depressed BD^193,194

Note. BP, bipolar disorder.

PET and SPECT Literature: BD

Serotonin

Serotoninergic function has long been thought to be central to the development of bipolar disorder.⁵⁸ Prange et al.¹⁹⁵ proposed what they termed the “permissive hypothesis of 5HT function” in bipolar disorder, which stated that deficient serotonergic functioning underlies bipolar disorder, and that manic and depressive episodes specifically would be marked by low 5HT. Supporting this proposal, a recent meta-analysis confirmed two gene SNPs related to the production of tryptophan hydroxylase-2, a rate-limiting enzyme for 5HT in the brain, are consistently associated with the development of bipolar disorder.¹⁹⁶ However, existing PET and SPECT imaging evidence has not yet substantiated the permissive hypothesis. It appears that there is a variability in SERT availability across mood states in BD.⁹⁸ During euthymia, there is lower SERT availability consistently measured across studies.^{179–182,184,197} During depression, studies appear to diverge in their findings, with reports of no differences in SERT availability in BD compared to HC,¹⁸⁴ lower SERT availability in thalamus, putamen, amygdala of depressed BD participants,³⁴ and higher SERT availability in the thalamus compared to MDD participants, but lower availability in the RN relative to controls.¹⁷⁸ No studies investigating SERT availability in manic BD participants have been published to date.

Both 5HT1A and 5HT2A are target receptors for medications used to treat BD (e.g. lamotrigine¹⁹⁸ and ziprasidone,¹⁹⁹ respectively). Further, genetic studies have found that the presence of specific SNPs in the 5HT1A gene predict both MDD and BD,²⁰⁰ suggesting a possible similar pattern of 5HT1A upregulation in both disorders. By contrast, a postmortem study observed decreased 5HT2A mRNA levels in the hippocampal region of BD individuals relative to MDD and HC.²⁰¹ Quantitation of 5HT1A and 5HT2A receptors in BD in vivo has led to divergence in findings,^187,188,202 including lower and higher receptor availability during depression, and no differences during euthymia.¹⁸⁷ 5HT2A availability has been examined in bipolar mania only, with observations of lower availability relative to HC in all cortical regions,¹⁸⁵ and no alterations in 5HT2A availability following three to five weeks treatment with mood stabilizers.¹⁸⁶ More research across mood states is needed to increase understanding of the potential involvement of both receptors in BD. Of note, researchers have observed that while serotonin modulation plays a role in antidepressant action in bipolar depression, based on examination of the most effective agents for BD depression, it is not sufficient for symptom relief.¹⁹⁸ It is therefore crucial that molecular imaging research in BD examine other receptor systems.

Dopamine

Dopaminergic dysfunction is also implicated in the development and expression of BD.⁹⁸ Researchers have suggested that increased dopaminergic function underlies mania, while the opposite is true for depressive episodes in BD.²⁰³ Many antipsychotic drugs are commonly prescribed to treat mania block dopamine receptors, decreasing levels of dopamine in the brain.²⁰⁴ Indeed drugs known to increase levels of dopamine (e.g. some tricyclic antidepressants) have also been shown to induce mania in BD individuals.^205,206 Two postmortem studies have observed upregulation of D2 in the dlPFC of BD.^207,208 However, to date, only one molecular imaging study has examined D2 in BD during mania, finding no differences in D2 receptor availability in the striatum of manic BD participants relative to HCs.¹⁹¹ The remainder of molecular imaging studies have focused on DAT, dysfunction of which, genetic research suggests, is associated with risk for BD.^209,210 Interestingly, DAT findings in BD diverge based on imaging modality used. More specifically, two studies using SPECT and [^99mTc]TRODAT-1 (a non-selective DAT tracer⁹⁸) observed higher DAT availability in the striatum of both depressed¹⁸⁹ and euthymic¹⁹⁰ BD participants relative to HC. By contrast, using PET and a DAT selective tracer ([¹¹C]CFT), Anand et al.²⁰⁸ observed lower striatal DAT in BD across mood states relative to HC. As with serotonin, more research is needed to further clarify the relationship between dopaminergic neurotransmission and BD.

Inflammation

Mounting evidence suggests that inflammation plays a key role in BD as well as MDD.²¹¹ For example, pro-inflammatory cytokines have been shown to be elevated in the blood of BD individuals, during periods of mania, depression, and euthymia, suggesting that low-grade inflammation may be a trait marker of BD.²¹² Preliminary evidence suggests the presence of inflammation in the brain as well as the periphery in BD, with one postmortem study showing upregulation of markers of neuroinflammation in the frontal cortex in BD.²¹³ One study has investigated neuroinflammation in vivo using PET to date. Using [¹¹C](R)PK11195, Haarman et al. reported elevated TSPO levels in the right hippocampus of euthymic-medicated BD participants compared to controls.²¹⁴ Whether these medications impact neuroinflammation and whether level of measurable neuroinflammation differs across mood states remains to be determined.

Other Neurotransmitters

Cholinergic neurotransmitter systems have also been implicated in the pathophysiology of BD.¹⁹³ Both muscarinic agonists and acetylcholinesterase inhibitors increase cholinergic neurotransmission, and have been shown to increase depressive and decrease manic symptoms.¹⁹³ They have also been found to elicit erratic emotional responding—similar to that manifested in BD—when administered to HCs.²¹⁵ Additionally, CHRM2, which encodes for muscarinic receptors (M2) is one of several candidate genes shown to be expressed more in the ACC of BD individuals relative to HC in a recent postmortem study. Three molecular imaging studies have examined the availability of muscarinic (mACh) and nicotinic (nACh) receptors in BD. Cannon et al. first showed lower M2 availability in the ACC of depressed BD participants relative to HC.¹⁹³ They then showed that variation in the gene that encodes for M2, specifically, presence of the TT allele, was associated with lower M2 availability in the ACC of BD participants, and with more severe lifetime BD symptoms.¹⁹⁴ However, we did not find lower β₂*-nAChR in depressed BD participants compared to euthymic BD and HC individuals, although variability in ACh levels between depression and euthymia may interfere with receptor availability quantification.¹⁹² Alterations in ACh levels were not taken into account in the Cannon et al. studies; therefore, the role of the cholinergic receptors in the pathophysiology of BD needs further research.

Posttraumatic Stress Disorder

Relationship Between PTSD and Chronic Stress

PTSD is a psychiatric condition, which by definition occurs in direct response to acute stress exposure (i.e. exposure to trauma). However, while approximately 80% of individuals will be exposed to a traumatic event capable of conferring PTSD (per the DSM-5^6,21), only 8%–15% of the general population will go on to develop PTSD.⁸ One reliable predictor of developing PTSD following trauma exposure is historical exposure to chronic stress.²¹⁷ As with MDD and BD, molecular imaging has the potential to provide crucial insights into the pathophysiology of PTSD and specifically its relationship to chronic stress (Table 3).

Table 3.

Radiotracers used for in vivo molecular imaging in individuals with posttraumatic stress disorder.

Molecular target (receptor)	Radiotracer (full name)	Abbreviation(s)	Studies utilizing this tracer in vivo
Neurokinin 1 Receptor (NK1)	(2 S,3 S)-N-[[2-[11C]Methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]phenyl]methyl]-2-phenyl-piperidin-3-amine	[¹¹C]GR205171
Serotonin transpoter (SERT)	[¹¹C]2-(2-(Dimethylaminomethyl)phenylthio)-5-fluoromethylphenylamine	[¹¹C]AFM	↓SERT availability in MDD²¹⁸
	[¹¹C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)- benzonitrile	[¹¹C]DASB	↓SERT availability in MDD^219,220
Serotonin 1B receptor (5HT1B)	(R-1-[4-(2-methoxy-isopropyl)-phenyl]-3-[2-(4-methyl-piperazin-1-yl)benzyl]-pyrrolidin-2-one)	[¹¹C]P943	↓5HT1B in trauma exposed HC⁵⁰
Serotonin 1A receptor (5HT1A)	carbon11–labeledN-(2-(1-(4-(2-methoxyphenyl)-1piperazinyl)ethyl))- N-(2-pyridyl)- cyclohexanecarboxamide	[carbonyl-C-¹¹]WAY-100635	↑5HT1A availability in MDD²²¹
	(N-{2-[4-(2-methoxyphenyl)piperazino]}-N-(2-pyridinyl)trans-4-fluorocyclohexanecarboxamide)	[¹⁸F]CWAY	No differences in 5HT1A availability in MDD²²²
Dopamine transporter (DAT)	((99 m)Tc-[2[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]-oct-2-yl]-methyl](2-mercaptoethyl) amino]ethyl]amino]ethane-thiolato(3-)-N2,N2′,S2,S2]oxo-[1R-(exo-exo)]))	[99mTC]-TRODAT-1	↑DAT availability in PTSD²²³
GABA_A-BZR	[¹²³I]iomazenil		↑ GABAA-BZR availability in PTSD²²⁴
	[¹¹C]flumazenil		↑ GABAA-BZR availability in PTSD²²⁵
Cannabinoid receptor 1 (CB1)	([¹¹C]JHU75528)	[¹¹C]OMAR	↑CB1 availability in PTSD^226,227
Norepinephrine Transporter (NET)	[¹¹C]methylreboxetine	([¹¹C]MRB)	↓NET availability in PTSD relative to HC, but not trauma controls²²⁸
ß2*-nAChR	(¹²³I-5-IA; [¹²³I]-5-iodo-3-[2(S)-azetidinylmethoxy]pyridine)	[¹²³I]5-IA-85380 ([¹²³I]5-IA)	↑ ß2*-nAChR availability in PTSD²²⁹
K- Opioid Receptor		[¹¹C]LY2795050	↓KOR availability associated with severity of loss symptoms in trauma survivors

PET and SPECT Literature: PTSD

Serotonin

As was the case with MDD and BD, altered serotonergic function has been implicated in the development of PTSD.²⁰³ More specifically, in contrast to reductions observed in MDD models, preclinical studies have reported increased 5HT synthesis in PTSD in multiple brain regions.^231–233 As in MDD, presence of the short SERT gene allele is a risk factor for PTSD, although a recent meta-analysis suggests that risk only extends to highly trauma exposed individuals.²³⁴ Published imaging data suggest lower SERT availability in PTSD as well as correlations between SERT and severity of PTSD-related symptomatology.^218–220

Focusing on presynaptic serotonin receptors, preclinical evidence suggests that alterations in 5HT1A function are associated with attentional bias to threat-related stimuli,²³⁵ and exposure to stress reduces functioning of the 5HT1B receptor.²³⁶ In line with preclinical findings, Sullivan et al.²²² observed upregulation of 5HT1A in the amygdala, RN, and all cortical regions of individuals with PTSD with and without comorbid MDD relative to HCs. Of note, an earlier study by Bonne et al.²²¹ observed no differences in 5HT1A availability in PTSD participants. However, Sullivan et al.²²² argued that characteristics of the PET tracer used and issues with the analytic approach used might have contributed to the Bonne’s null result. Further, consistent with preclinical evidence, there is a finding of lower 5HT1B availability in trauma-exposed control participants relative to HCs with no previous trauma exposure.⁵⁰ Earlier age of trauma exposure appears to be associated with both lower 5HT1B availability and PTSD symptom severity, suggesting that 5HT1B availability may be affected by trauma exposure, particularly during development.

Dopamine

Dopaminergic hyper-functioning has also been implicated in the development of PTSD, and specifically in the experience of hyperarousal symptoms.²³⁷ More specifically, a DAT gene polymorphism has been shown to be associated with risk for developing PTSD following trauma exposure.²³⁸ In keeping, researchers found higher availability of DAT in the striatum of PTSD participants relative to trauma-exposed control subjects.²²³

GABA_A-BZR

Evidence has shown that exposure to trauma/acute stress is associated with reduction in GABA_A benzodiazepine receptor (GABA_A-BZR) density,²³⁹ which plays an important role in modulating nervous stress response in the central nervous system.²²⁵ In vivo quantification is in line with the animal studies reporting lower PFC GABA_A-BZR availability in individuals with combat-related or nonrelated PTSD relative to HCs.^224,225

Other Neurotransmitters

Other neurotransmitters have also been examined in trauma-related psychopathology: cannabinoid receptor 1 (CB1), NET, β₂*-nAChR, and mGluR5. In line with preclinical reports of an association between chronic stress and altered CB1,^240,241 Neumeister et al.²²⁶ reported elevated CB1 availability brain-wide in PTSD participants relative to both trauma-exposed controls and HCs. In an research domain criteria approach to examine the pathophysiology of PTSD, we reported that trauma and PTSD-related symptomology was associated with higher amygdalar CB1 availability.²²⁷ NET has also been implicated in the development of anxiety-related disorders like PTSD.²⁴² A single PET study by Pietrzak et al.²⁴³ found lower NET availability in PTSD in the locus coeruleus relative to healthy controls. However, no significant differences in NET availability were observed in the trauma-exposed control group (compared to PTSD and HC groups).²²⁸ β₂*-nAChRs availability, which has been implicated in regulation of memory and arousal which function abnormally in PTSD,²⁴⁴ appears to be upregulated in the mesiotemporal cortex of PTSD individuals relative to HCs. This receptor also appears to be implicated in the re-experiencing symptoms in PTSD.²²⁹ Finally, mGluR5 has emerged as a target of interest in PTSD²⁴⁵ due to its role in fear conditioning and emotion regulation. In a recent pilot study, we observed increased mGluR5 availability in PTSD participants relative to HC across cortical regions. MGluR5 availability was also correlated with severity of PTSD avoidance symptoms. The cause of this dysregulation is not clear; however, postmortem examination and preclinical data suggest deficits in glucocorticoid functioning may be impacting mGluR5 density. Based on this preliminary evidence, CB1, NET, β2*-nACh, and mGluR5 may all play roles in the pathophysiology of PTSD; however, the limited numbers of studies preclude firm conclusions.

Discussion

In the last 20 years, molecular imaging has made a substantial contribution to the understanding of the neurobiological alterations underlying chronic stress-related disorders. The reviewed studies have enriched our understanding of how and why existing psychotherapeutic agents affect neurotransmitter function and have implicated novel targets for optimizing treatment efficacy.²⁴⁶ To begin, they have confirmed the presence of in vivo alterations in serotonergic and dopaminergic functioning in at least some subgroups of MDD, BD, and PTSD individuals and provided preliminary evidence that other neurotransmitter systems play a role in these disorders.²⁴⁷ Areas of overlap between molecular imaging evidence and other research modalities (e.g. lower SERT in MDD) lend confidence to assertions concerning the role of some receptors and psychiatric diagnoses. Areas of discrepancy, however, encourage critical examination of explanations for such incongruity like that proposed and tested by Hesselgrave and Parsey¹²² to explain discrepant in vivo 5HT1A results in MDD.

While PET and SPECT have been confirmed as powerful and highly useful clinical research tools,²²⁸ as it stands, the molecular imaging literature on MDD, BD, and PTSD raises as many questions as it answers. One exciting novel application of molecular imaging with the potential to reduce variability in findings is transdiagnostic research. As noted, the experience of chronic stress conveys risk for complex and highly comorbid psychiatric diagnoses (e.g. MDD and PTSD). Heterogeneous symptom presentation within wide and overlapping diagnostic categories makes the systematic study of these disorders by obtaining a “representative sample” extremely challenging. Transdiagnostic designs could eliminate a significant source of error by basing analyses on the presence or absence of a specific symptoms in lieu of diagnosis (i.e. using research domain criteria²⁴⁸). In a recent example, Pietrzak et al.²⁴⁹ examined the availability of Kappa-opioid receptors (KORs) in individuals with a range of trauma-related pathology (including MDD and PTSD). Instead of examining the relationship between diagnostic status and receptor density, they used principal components analysis to group symptoms into transdiagnostic “threat” and “loss” categories, and observed that low KOR availability in the amygdalar-ACC-ventral striatal circuit was associated with severe loss, but not threat symptoms, suggesting the use of molecular imaging to investigate the relationship between receptor availability and transdiagnostic aspects of chronic stress-related psychopathology may be an important next step.

In summary, molecular imaging has provided unique insight into the neurobiological underpinnings of chronic stress-related disorders. Despite inconsistencies in specific findings, the wide-reaching impact of chronic stress, and subsequent disorders like MDD, BD, and PTSD, is evident. The ability to confirm preclinical and postmortem findings, and to quantify the action of pharmacological agents in vivo has allowed for identification of biomarkers to improve risk assessment, progress toward optimization of pharmacotherapy, and identification of promising new treatment targets.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Schmidt

Sterlemann

Muller

. Chronic stress and individual vulnerability. Ann N Y Acad Sci 2008; 1148: 174–183.

Organization WH. Task shifting: rational redistribution of tasks among health workforce teams: global recommendations and guidelines. 2007. http://apps.who.int/iris/handle/10665/43821. Accessed May 16, 2017.

Rosch

. The quandary of job stress compensation. Health Stress 2001; 3(1): 1–4.

Kopp

Rethelyi

. Where psychology meets physiology: chronic stress and premature mortality—the Central-Eastern European health paradox. Brain Res Bull 2004; 62(5): 351–367.

Paykel

. Life stress, depression and attempted suicide. J Human Stress 1976; 2(3): 3–12.

Insel

Cuthbert

Garvey

Murray

CJL

Lopez

. Alternative projections of mortality and disability by cause 1990–2020: the global burden of disease study. Lancet 1997; 349: 1498–1504.

US Department of Health and Human Services. National Strategy for Suicide Prevention: Goals and Objectives for Action. Rockville. The Yale Textbook of Public Psychiatry. 2016; 349: 111.

Kessler

. Posttraumatic stress disorder: the burden to the individual and to society. J Clin Psychiatry 2000; 61(suppl 5): 4–12.

Kupfer

. The increasing medical burden in bipolar disorder. JAMA 2005; 293(20): 2528–2530.

10.

Mier

. Advantages in functional imaging of the brain. Front Hum Neurosci 2015; 9: 249.

11.

McEwen

. Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Ann N Y Acad Sci 2004; 1032: 1–7.

12.

Cohen

Janicki-Deverts

Miller

. Psychological stress and disease. JAMA 2007; 298(14): 1685–1687.

13.

McGonagle

Kessler

. Chronic stress, acute stress, and depressive symptoms. Am J Community Psychol 1990; 18(5): 681–706.

14.

Thoits

. Stress and health: major findings and policy implications. J Health Soc Behav 2010; 51(Suppl): S41–53.

15.

Frey

Skelin

Sakai

Nishikawa

Diksic

. Gender differences in α-[11 C] MTrp brain trapping, an index of serotonin synthesis, in medication-free individuals with major depressive disorder: a positron emission tomography study. Psychiatry Res Neuroimaging 2010; 183(2): 157–166.

16.

Berney

Nishikawa

Benkelfat

Debonnel

Gobbi

Diksic

. An index of 5-HT synthesis changes during early antidepressant treatment: α-[11 C] methyl-l-tryptophan PET study. Neurochem Int 2008; 52(4): 701–708.

17.

Rosa-Neto

Diksic

Okazawa

. Measurement of brain regional α-[11C] Methyl-L-Tryptophan trapping as a measure of serotonin synthesis in medication-free patients with major depression. Arch Gen Psychiatry 2004; 61(6): 556–563.

18.

Agren

Reibring

Hartvig

. Low brain uptake of L [11C] 5-hydroxytryptophan in major depression: a positron emission tomography study on patients and healthy volunteers. Acta Psychiatrica Scandinavica 1991; 83(6): 449–455.

19.

Ågren

Reibring

Hartvig

. PET studies with L-[11C] 5-HTP and L-[11C] dopa in brains of healthy volunteers and patients with major depression. Clin Neuropharmacol 1992; 15(Part A): 235A–236A.

20.

Reimold

Batra

Knobel

. Anxiety is associated with reduced central serotonin transporter availability in unmedicated patients with unipolar major depression: a [11C]DASB PET study. Mol Psychiatry 2008; 13(6): 606–613, 557.

21.

Hahn

Haeusler

Kraus

. Attenuated serotonin transporter association between dorsal raphe and ventral striatum in major depression. Hum Brain Mapp 2014; 35(8): 3857–3866.

22.

Selvaraj

Murthy

Bhagwagar

. Diminished brain 5-HT transporter binding in major depression: a positron emission tomography study with [11C]DASB. Psychopharmacology (Berl) 2011; 213(2–3): 555–562.

23.

Miller

Hesselgrave

Ogden

. Positron emission tomography quantification of serotonin transporter in suicide attempters with major depressive disorder. Biol Psychiatry 2013; 74(4): 287–295.

24.

Montgomery

Stokes

Kitamura

Grasby

. Extrastriatal D 2 and striatal D 2 receptors in depressive illness: pilot PET studies using [11 C] FLB 457 and [11 C] raclopride. J Affect Disord 2007; 101(1): 113–122.

25.

Miller

Kinnally

Ogden

Oquendo

Mann

Parsey

. Reported childhood abuse is associated with low serotonin transporter binding in vivo in major depressive disorder. Synapse 2009; 63(7): 565–573.

26.

Moses-Kolko

Wisner

Price

. Serotonin 1A receptor reductions in postpartum depression: a positron emission tomography study. Fertil Steril 2008; 89(3): 685–692.

27.

Miller

Oquendo

Ogden

Mann

Parsey

. Serotonin transporter binding as a possible predictor of one-year remission in major depressive disorder. J Psychiatr Res 2008; 42(14): 1137–1144.

28.

Ruhe

Booij

Reitsma

Schene

. Serotonin transporter binding with [123I]beta-CIT SPECT in major depressive disorder versus controls: effect of season and gender. Eur J Nucl Med Mol Imaging 2009; 36(5): 841–849.

29.

Huang

. Association study of serotonin transporter availability and SLC6A4 gene polymorphisms in patients with major depression. Psychiatry Res 2013; 212(3): 216–222.

30.

Newberg

Amsterdam

Wintering

. 123I-ADAM binding to serotonin transporters in patients with major depression and healthy controls: a preliminary study. J Nucl Med 2005; 46(6): 973–977.

31.

Newberg

Amsterdam

Wintering

Shults

. Low brain serotonin transporter binding in major depressive disorder. Psychiatry Res 2012; 202(2): 161–167.

32.

Blasi

De Virgilio

Papazacharias

. Converging evidence for the association of functional genetic variation in the serotonin receptor 2a gene with prefrontal function and olanzapine treatment. JAMA Psychiatry 2013; 70(9): 921–930.

33.

Köhler

Benros

Nordentoft

. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry 2014; 71(12): 1381–1391.

34.

Oquendo

Hastings

Huang

Y-Y

. Brain serotonin transporter binding in depressed patients with bipolar disorder using positron emission tomography. Arch Gen Psychiatry 2007; 64(2): 201–208.

35.

Mandelli

Serretti

. Gene environment interaction studies in depression and suicidal behavior: an update. Neurosci Biobehav Rev 2013; 37(10): 2375–2397.

36.

Sargent

Kjaer

Bench

. Brain serotonin1A receptor binding measured by positron emission tomography with [11C] WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry 2000; 57(2): 174–180.

37.

Parsey

Olvet

Oquendo

Huang

Y-Y

Ogden

Mann

. Higher 5-HT1A receptor binding potential during a major depressive episode predicts poor treatment response: preliminary data from a naturalistic study. Neuropsychopharmacology 2006; 31(8): 1745–1749.

38.

Parsey

Oquendo

Ogden

. Altered serotonin 1A binding in major depression: a [carbonyl-C-11] WAY100635 positron emission tomography study. Biol Psychiatry 2006; 59(2): 106–113.

39.

Gray

Milak

DeLorenzo

. Antidepressant treatment reduces serotonin-1A autoreceptor binding in major depressive disorder. Biol Psychiatry 2013; 74(1): 26–31.

40.

Mickey

Ducci

Hodgkinson

Langenecker

Goldman

Zubieta

J-K

. Monoamine oxidase A genotype predicts human serotonin 1A receptor availability in vivo. J Neurosci 2008; 28(44): 11354–11359.

41.

Lothe

Saoud

Bouvard

Redouté

Lerond

Ryvlin

. 5-HT 1A receptor binding changes in patients with major depressive disorder before and after antidepressant treatment: a pilot [18 F] MPPF positron emission tomography study. Psychiatry Res Neuroimaging 2012; 203(1): 103–104.

42.

Drevets

Frank

Price

. PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 1999; 46(10): 1375–1387.

43.

Hirvonen

Karlsson

Kajander

. Decreased brain serotonin 5-HT1A receptor availability in medication-naive patients with major depressive disorder: an in-vivo imaging study using PET and [carbonyl-11C] WAY-100635. Int J Neuropsychopharmacol 2008; 11(4): 465–476.

44.

Saijo

Takano

Suhara

. Effect of electroconvulsive therapy on 5-HT1A receptor binding in patients with depression: a PET study with [11C] WAY 100635. Int J Neuropsychopharmacol 2010; 13(6): 785–791.

45.

Meltzer

Price

Mathis

. Serotonin IA receptor binding and treatment response in late-life depression. Neuropsychopharmacology 2004; 29(12): 2258–2265.

46.

Karlsson

Hirvonen

Kajander

. Research letter: psychotherapy increases brain serotonin 5-HT 1A receptors in patients with major depressive disorder. Psychol Med 2010; 40(03): 523–528.

47.

Bhagwagar

Montgomery

Grasby

Cowen

. Lack of effect of a single dose of hydrocortisone on serotonin 1A receptors in recovered depressed patients measured by positron emission tomography with [11 C] WAY-100635. Biol Psychiatry 2003; 54(9): 890–895.

48.

Bhagwagar

Rabiner

Sargent

Grasby

Cowen

. Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with & lsqb; 11C] WAY-100635. Mol Psychiatry 2004; 9(4): 386–392.

49.

Stockmeier

Shapiro

Dilley

Kolli

Friedman

Rajkowska

. Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression—postmortem evidence for decreased serotonin activity. J Neurosci 1998; 18(18): 7394–7401.

50.

Murrough

Henry

. Reduced ventral striatal/ventral pallidal serotonin1B receptor binding potential in major depressive disorder. Psychopharmacology 2011; 213(2–3): 547–553.

51.

Tiger

Farde

Rück

. Low serotonin 1B receptor binding potential in the anterior cingulate cortex in drug-free patients with recurrent major depressive disorder. Psychiatry Res Neuroimaging 2016; 253: 36–42.

52.

Tiger

Rück

Forsberg

. Reduced 5-HT 1B receptor binding in the dorsal brain stem after cognitive behavioural therapy of major depressive disorder. Psychiatry Res Neuroimaging 2014; 223(2): 164–170.

53.

Baeken

De Raedt

Bossuyt

. The impact of HF-rTMS treatment on serotonin 2A receptors in unipolar melancholic depression. Brain Stimul 2011; 4(2): 104–111.

54.

Biver

Wikler

Lotstra

Damhaut

Goldman

Mendlewicz

. Serotonin 5-HT2 receptor imaging in major depression: focal changes in orbito-insular cortex. Br J Psychiatry 1997; 171(5): 444–448.

55.

Mintun

Sheline

Moerlein

Vlassenko

Huang

Snyder

. Decreased hippocampal 5-HT 2A receptor binding in major depressive disorder: in vivo measurement with [18 F] altanserin positron emission tomography. Biol Psychiatry 2004; 55(3): 217–224.

56.

Bhagwagar

Hinz

Taylor

Fancy

Cowen

Grasby

. Increased 5-HT 2A receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [11 C] MDL 100,907. Am J Psychiatry 2006; 163(9): 1580–1587.

57.

Messa

Colombo

Moresco

. 5-HT2A receptor binding is reduced in drug-naive and unchanged in SSRI-responder depressed patients compared to healthy controls: a PET study. Psychopharmacology 2003; 167(1): 72–78.

58.

Yatham

Liddle

Shiah

-S . Brain serotonin2 receptors in major depression: a positron emission tomography study. Arch Gen Psychiatry 2000; 57(9): 850–858.

59.

Meyer

Kapur

Houle

. Prefrontal cortex 5-HT2 receptors in depression: an [18F] setoperone PET imaging study. Am J Psychiatry 1999; 156(7): 1029–1034.

60.

Meyer

McMain

Kennedy

. Dysfunctional attitudes and 5-HT2 receptors during depression and self-harm. Am J Psychiatry 2003; 160(1): 90–99.

61.

Yatham

Liddle

Dennie

. Decrease in brain serotonin 2 receptor binding in patients with major depression following desipramine treatment: a positron emission tomography study with fluorine-18–labeled setoperone. Arch Gen Psychiatry 1999; 56(8): 705–711.

62.

Madsen

Torstensen

Holst

. Familial risk for major depression is associated with lower striatal 5-HT4 receptor binding. Int J Neuropsychopharmacol 2014; 18: pyu034.

63.

Staley

Sanacora

Tamagnan

. Sex differences in diencephalon serotonin transporter availability in major depression. Biol Psychiatry 2006; 59(1): 40–47.

64.

Meyer

Wilson

Sagrati

. Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C] DASB positron emission tomography study. Am J Psychiatry 2004; 161(5): 826–835.

65.

Cannon

Ichise

Rollis

. Elevated serotonin transporter binding in major depressive disorder assessed using positron emission tomography and [11 C] DASB; comparison with bipolar disorder. Biol Psychiatry 2007; 62(8): 870–877.

66.

Camardese

Di Giuda

Di Nicola

. Imaging studies on dopamine transporter and depression: a review of literature and suggestions for future research. J Psychiatr Res 2014; 51: 7–18.

67.

Joensuu

Tolmunen

Saarinen

. Reduced midbrain serotonin transporter availability in drug-naive patients with depression measured by SERT-specific [(123)I] nor-beta-CIT SPECT imaging. Psychiatry Res 2007; 154(2): 125–131.

68.

Neumeister

Willeit

Praschak-Rieder

. Dopamine transporter availability in symptomatic depressed patients with seasonal affective disorder and healthy controls. Psychol Med 2001; 31(08): 1467–1473.

69.

Malison

Price

Berman

. Reduced brain serotonin transporter availability in major depression as measured by [123 I]-2β-carbomethoxy-3β-(4-iodophenyl) tropane and single photon emission computed tomography. Biol Psychiatry 1998; 44(11): 1090–1098.

70.

Mill

Asherson

Browes

D’Souza

Craig

. Expression of the dopamine transporter gene is regulated by the 3′ UTR VNTR: evidence from brain and lymphocytes using quantitative RT PCR. Am J Med Genet 2002; 114(8): 975–979.

71.

Amsterdam

Newberg

Soeller

Shults

. Greater striatal dopamine transporter density may be associated with major depressive episode. J Affect Disord 2012; 141(2): 425–431.

72.

Brunswick

Amsterdam

Mozley

Newberg

. Greater availability of brain dopamine transporters in major depression shown by [99mTc] TRODAT-1 SPECT imaging. Am J Psychiatry 2003; 160(10): 1836–1841.

73.

Yang

Yeh

Yao

. Greater availability of dopamine transporters in patients with major depression—a dual-isotope SPECT study. Psychiatry Res Neuroimaging 2008; 162(3): 230–235.

74.

Hsieh

Lee

Yeh

. Distribution volume ratio of serotonin and dopamine transporters in euthymic patients with a history of major depression—a dual-isotope SPECT study. Psychiatry Res Neuroimaging 2010; 184(3): 157–161.

75.

Árgyelán

Szabó

Kanyó

. Dopamine transporter availability in medication free and in bupropion treated depression: a 99m Tc-TRODAT-1 SPECT study. J Affect Disord 2005; 89(1): 115–123.

76.

Meyer

Krüger

Wilson

. Lower dopamine transporter binding potential in striatum during depression. Neuroreport 2001; 12(18): 4121–4125.

77.

Lehto

Tolmunen

Joensuu

. Midbrain binding of [123 I] nor-β-CIT in atypical depression. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30(7): 1251–1255.

78.

Lou

Huang

Shi

. SPECT imaging of dopamine transporters with 99mTc-TRODAT-1 in major depression and Parkinson’s disease. J Neuropsychiatry Clin Neurosci 2011; 23(1): 63–67.

79.

Parsey

Oquendo

Zea-Ponce

. Dopamine D 2 receptor availability and amphetamine-induced dopamine release in unipolar depression. Biol Psychiatry 2001; 50(5): 313–322.

80.

Papp

Klimek

Willner

. Parallel changes in dopamine D 2 receptor binding in limbic forebrain associated with chronic mild stress-induced anhedonia and its reversal by imipramine. Psychopharmacology 1994; 115(4): 441–446.

81.

de Kwaasteniet

Pinto

Ruhe

van Wingen

Booij

Denys

. Striatal dopamine D 2/3 receptor availability in treatment resistant depression. PloS One 2014; 9(11): e113612.

82.

Meyer

McNeely

Sagrati

. Elevated putamen D 2 receptor binding potential in major depression with motor retardation: an [11 C] raclopride positron emission tomography study. Am J Psychiatry 2006; 163(9): 1594–1602.

83.

Larisch

Klimke

Vosberg

Löffler

Gaebel

Müller-Gärtner

H-W

. In vivo evidence for the involvement of dopamine-D 2 receptors in striatum and anterior cingulate gyrus in major depression. Neuroimage 1997; 5(4): 251–260.

84.

Sanacora

Treccani

Popoli

. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 2012; 62(1): 63–77.

85.

Dougherty

Bonab

Ottowitz

. Decreased striatal D1 binding as measured using PET and [11C] SCH 23,390 in patients with major depression with anger attacks. Depress Anxiety 2006; 23(3): 175–177.

86.

Matosin

Fernandez-Enright

Frank

. Metabotropic glutamate receptor mGluR2/3 and mGluR5 binding in the anterior cingulate cortex in psychotic and nonpsychotic depression, bipolar disorder and schizophrenia: implications for novel mGluR-based therapeutics. J Psychiatry Neurosci 2014; 39(6): 407–416.

87.

DeLorenzo

Sovago

Gardus

. Characterization of brain mGluR5 binding in a pilot study of late-life major depressive disorder using positron emission tomography and [ 11C] ABP688. Transl Psychiatry 2015; 5(12): e693.

88.

Zunszain

Hepgul

Pariante

Inflammation and depression. In: Philip J

Cowen

Trevor

Sharp

Jennifer YF

Lau

(eds). Behavioral Neurobiology of Depression and Its Treatment, Berlin, Germany: Springer, 2012, pp. 135–151.

89.

Setiawan

Wilson

Mizrahi

. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry 2015; 72(3): 268–275.

90.

Holmes S, Hinz R, Gregory C, et al. Microglial activation in anterior cingulate in major depression and a role for inflammation in suicidal thinking: a PET study. Biol Psychiatry. Under Review.

91.

Meyer

Ginovart

Boovariwala

. Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry 2006; 63(11): 1209–1216.

92.

Meyer

Wilson

Sagrati

. Brain monoamine oxidase A binding in major depressive disorder: relationship to selective serotonin reuptake inhibitor treatment, recovery, and recurrence. Arch Gen Psychiatry 2009; 66(12): 1304–1312.

93.

K-Y

Hsiao

Chen

C-S

. Increased brain amyloid deposition in patients with a lifetime history of major depression: evidenced on 18F-florbetapir (AV-45/Amyvid) positron emission tomography. Eur J Nucl Med Mol Imaging 2014; 41(4): 714–722.

94.

Yasuno

Kazui

Morita

. High amyloid-β deposition related to depressive symptoms in older individuals with normal cognition: a pilot study. Int J Geriatr Psychiatry 2016; 31(8): 920–928.

95.

Mineur YS, Mose TN, Blakeman S, Picciotto MR. Hippocampal α7 nicotinic acetylcholine receptors contribute to modulation of depression-like behavior in C57BL/6 J mice. Br J Pharmacol. 8 April 2017.

96.

Croarkin

Levinson

Daskalakis

. Evidence for GABAergic inhibitory deficits in major depressive disorder. Neurosci Biobehav Rev 2011; 35(3): 818–825.

97.

Schildkraut

. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 1965; 122(5): 509–522.

98.

Ruhé

Visser

Frokjaer

Haarman

BBC

Klein

Booij

Molecular imaging of depressive disorders. In: Rudi AJO

Dierckx

Andreas

Otte

Erik FJ

de Vries

Aren

van Waarde

Johan A

den Boer

(eds). PET and SPECT in Psychiatry, Berlin, Germany: Springer, 2014, pp. 93–172.

99.

Cai

Chang

. Molecular signatures of major depression. Curr Biol 2015; 25(9): 1146–1156.

100.

Domínguez-López

Howell

Gobbi

. Characterization of serotonin neurotransmission in knockout mice: implications for major depression. Rev Neurosci 2012; 23(4): 429–443.

101.

Kambeitz

Howes

. The serotonin transporter in depression: meta-analysis of in vivo and post mortem findings and implications for understanding and treating depression. J Affect Disord 2015; 186: 358–366.

102.

Pirker

Asenbaum

Kasper

. β-CIT SPECT demonstrates blockade of 5HT-uptake sites by citalopram in the human brain in vivo. J Neural Transm Gen Sect 1995; 100(3): 247–256.

103.

Bennett

Lesch

Heils

. Early experience and serotonin transporter gene variation interact to influence primate CNS function. Mol Psychiatry 2002; 7(1): 118.

104.

Caspi

Sugden

Moffitt

. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003; 301(5631): 386–389.

105.

Zhang

Zhu

. Molecular, functional, and structural imaging of major depressive disorder. Neurosci Bull 2016; 32(3): 273–285.

106.

Lin

Lee

Chen

. Serotonin transporter availability may moderate the association between perceiving stress and depressive tendencies—A SPECT with 5-HTTLPR genotyping study. Prog Neuropsychopharmacol Biol Psychiatry 2015; 61: 24–29.

107.

Tsai

McDonald

Rosenberg

Stamoulis

Kleinman

. Discordant radiologic and histological dimensions of the zone of provisional calcification in fetal piglets. Pediatr Radiol 2013; 43(12): 1606–1614.

108.

Yeh

Kuo

. Disproportionate reduction of serotonin transporter may predict the response and adherence to antidepressants in patients with major depressive disorder: a positron emission tomography study with 4-[18F]-ADAM. Int J Neuropsychopharmacol 2015; 18(7): pyu120.

109.

Laasonen-Balk

Viinamaki

Kuikka

Husso-Saastamoinen

Lehtonen

Tiihonen

. 123I-beta-CIT binding and recovery from depression. A six-month follow-up study. Eur Arch Psychiatry Clin Neurosci 2004; 254(3): 152–155.

110.

Amsterdam

Newberg

Newman

Shults

Wintering

Soeller

. Change over time in brain serotonin transporter binding in major depression: effects of therapy measured with [(123) I]-ADAM SPECT. J Neuroimaging 2013; 23(4): 469–476.

111.

Lanzenberger

Kranz

Haeusler

. Prediction of SSRI treatment response in major depression based on serotonin transporter interplay between median raphe nucleus and projection areas. Neuroimage 2012; 63(2): 874–881.

112.

Rominger

Cumming

Brendel

. Altered serotonin and dopamine transporter availabilities in brain of depressed patients upon treatment with escitalopram: a [123 I] β-CIT SPECT study. Eur Neuropsychopharmacol 2015; 25(6): 873–881.

113.

Reivich

Amsterdam

Brunswick

Yann Shiue

. PET brain imaging with [11C](+)McN5652 shows increased serotonin transporter availability in major depression. J Affect Disord 2004; 82(2): 321–327.

114.

Catafau

Perez

Plaza

. Serotonin transporter occupancy induced by paroxetine in patients with major depression disorder: a 123I-ADAM SPECT study. Psychopharmacology (Berl) 2006; 189(2): 145–153.

115.

Ichimiya

Suhara

Sudo

. Serotonin transporter binding in patients with mood disorders: a PET study with [11 C](+) McN5652. Biol Psychiatry 2002; 51(9): 715–722.

116.

Baldwin

Zea-Ponce

Laurelle

. Evaluation of the monoamine uptake site ligand [131I] methyl 3β-(4-Iodophenyl)-tropane-2β-carboxylate ([123I] β-CIT) in non-human primates: pharmacokinetics, biodistribution and SPECT brain imaging coregistered with MRI. Nucl Med Biol 1993; 20(5): 597–606.

117.

Savitz

Drevets

. Neuroreceptor imaging in depression. Neurobiol Dis 2013; 52: 49–65.

118.

Richardson-Jones

Craige

Guiard

. 5-HT 1A autoreceptor levels determine vulnerability to stress and response to antidepressants. Neuron 2010; 65(1): 40–52.

119.

Naudon

El Yacoubi

Vaugeois

J-M

Leroux-Nicollet

Costentin

. A chronic treatment with fluoxetine decreases 5-HT 1A receptors labeling in mice selected as a genetic model of helplessness. Brain Res 2002; 936(1): 68–75.

120.

Parsey

Ogden

Miller

. Higher serotonin 1A binding in a second major depression cohort: modeling and reference region considerations. Biol Psychiatry 2010; 68(2): 170–178.

121.

Miller

Hesselgrave

Ogden

. Brain serotonin 1A receptor binding as a predictor of treatment outcome in major depressive disorder. Biol Psychiatry 2013; 74(10): 760–767.

122.

Hesselgrave

Parsey

. Imaging the serotonin 1A receptor using [11C] WAY100635 in healthy controls and major depression. Phil Trans R Soc B 2013; 368(1615): 20120004.

123.

Tatarczyńska

Antkiewicz-Michaluk

Kłodzińska

Stachowicz

Chojnacka-Wójcik

. Antidepressant-like effect of the selective 5-HT 1B receptor agonist CP 94253: a possible mechanism of action. Eur J Pharmacol 2005; 516(1): 46–50.

124.

Redrobe

Bourin

. Evidence of the activity of lithium on 5-HT1B receptors in the mouse forced swimming test: comparison with carbamazepine and sodium valproate. Psychopharmacology 1999; 141(4): 370–377.

125.

Carr

Lucki

. The role of serotonin receptor subtypes in treating depression: a review of animal studies. Psychopharmacology 2011; 213(2–3): 265–287.

126.

Couch

Anthony

Dolgov

. Microglial activation, increased TNF and SERT expression in the prefrontal cortex define stress-altered behaviour in mice susceptible to anhedonia. Brain Behav Immun 2013; 29: 136–146.

127.

Benekareddy

Vadodaria

Nair

Vaidya

. Postnatal serotonin type 2 receptor blockade prevents the emergence of anxiety behavior, dysregulated stress-induced immediate early gene responses, and specific transcriptional changes that arise following early life stress. Biol Psychiatry 2011; 70(11): 1024–1032.

128.

Alam

Huang

Shahzad

. Percutaneous coronary intervention vs. coronary artery bypass graft surgery for unprotected left main coronary artery disease in the drug-eluting stents era–an aggregate data meta-analysis of 11,148 patients. Circ J 2013; 77(2): 372–382.

129.

Couch

Trofimov

Markova

. Low-dose lipopolysaccharide (LPS) inhibits aggressive and augments depressive behaviours in a chronic mild stress model in mice. J Neuroinflammation 2016; 13(1): 108.

130.

Attar-Lévy

Martinot

J-L

Blin

. The cortical serotonin 2 receptors studied with positron-emission tomography and [18 F]-setoperone during depressive illness and antidepressant treatment with clomipramine. Biol Psychiatry 1999; 45(2): 180–186.

131.

D’haenen

Bossuyt

. Dopamine D 2 receptors in depression measured with single photon emission computed tomography. Biol Psychiatry 1994; 35(2): 128–132.

132.

Dwivedi

Mondal

Payappagoudar

Rizavi

. Differential regulation of serotonin (5HT) 2A receptor mRNA and protein levels after single and repeated stress in rat brain: role in learned helplessness behavior. Neuropharmacology 2005; 48(2): 204–214.

133.

Vidal

Castro

Pilar-Cuellar

. Serotonin 5-HT4 receptors: a new strategy for developing fast acting antidepressants? Curr Pharm Des 2014; 20(23): 3751–3762.

134.

Nutt

. Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry 2008; 69(suppl E1): 4–7.

135.

Dunlop

Nemeroff

. The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry 2007; 64(3): 327–337.

136.

Klimke

Larisch

Janz

Vosberg

Müller-Gärtner

H-W

Gaebel

. Dopamine D 2 receptor binding before and after treatment of major depression measured by [123 I] IBZM SPECT. Psychiatry Res Neuroimaging 1999; 90(2): 91–101.

137.

Bowers

Heninger

Gerbode

. Cerebrospinal fluid 5-hydroxyindoleacetic acid and homovanillic acid in psychiatric patients. Int J Neuropharmacol 1969; 8(3): 255–262.

138.

Martinot

M-LP

Bragulat

Artiges

. Decreased presynaptic dopamine function in the left caudate of depressed patients with affective flattening and psychomotor retardation. Am J Psychiatry 2001; 158(2): 314–316.

139.

Opmeer

Kortekaas

Aleman

. Depression and the role of genes involved in dopamine metabolism and signalling. Prog Neurobiol 2010; 92(2): 112–133.

140.

Hsiao

M-C

Lin

K-J

Liu

C-Y

Schatz

. The interaction between dopamine transporter function, gender differences, and possible laterality in depression. Psychiatry Res Neuroimaging 2013; 211(1): 72–77.

141.

Sarchiapone

Carli

Camardese

. Dopamine transporter binding in depressed patients with anhedonia. Psychiatry Res Neuroimaging 2006; 147(2): 243–248.

142.

Shah

Ogilvie

Goodwin

Ebmeier

. Clinical and psychometric correlates of dopamine D 2 binding in depression. Psychol Med 1997; 27(06): 1247–1256.

143.

Ebert

Loew

Feistel

Pirner

. Dopamine and depression—striatal dopamine D2 receptor SPECT before and after antidepressant therapy. Psychopharmacology 1996; 126(1): 91–94.

144.

Cannon

Klaver

Peck

Rallis-Voak

Erickson

Drevets

. Dopamine type-1 receptor binding in major depressive disorder assessed using positron emission tomography and [ 11C] NNC-112. Neuropsychopharmacology 2009; 34(5): 1277–1287.

145.

Krystal

Mathew

D’Souza

Garakani

Gunduz-Bruce

Charney

. Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists. CNS Drugs 2010; 24(8): 669–693.

146.

Brodkin

Busse

Sukoff

Varney

. Anxiolytic-like activity of the mGluR5 antagonist MPEP: a comparison with diazepam and buspirone. Pharmacol Biochem Behav 2002; 73(2): 359–366.

147.

Pałucha

Brański

Szewczyk

Wierońska

Kłak

Pilc

. Potential antidepressant-like effect of MTEP, a potent and highly selective mGluR5 antagonist. Pharmacol Biochem Behav 2005; 81(4): 901–906.

148.

Belozertseva

Kos

Popik

Danysz

Bespalov

. Antidepressant-like effects of mGluR1 and mGluR5 antagonists in the rat forced swim and the mouse tail suspension tests. Eur Neuropsychopharmacol 2007; 17(3): 172–179.

149.

Need

Baez

Witkin

. Metabotropic glutamate 5 receptor antagonism is associated with antidepressant-like effects in mice. J Pharm Exp Ther 2006; 319(1): 254–259.

150.

Tatarczyńska

Kłodzińska

Chojnacka-Wójcik

. Potential anxiolytic and antidepressant like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist. Br J Pharmacol 2001; 132(7): 1423–1430.

151.

Pilc

Kłodzińska

Brański

. Multiple MPEP administrations evoke anxiolytic-and antidepressant-like effects in rats. Neuropharmacology 2002; 43(2): 181–187.

152.

Deschwanden

Karolewicz

Feyissa

. Reduced metabotropic glutamate receptor 5 density in major depression determined by [11C] ABP688 PET and postmortem study. Am J Psychiatry 2011; 168(7): 727–734.

153.

Esterlis I. Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C]ABP688 and PET imaging study in depression. Mol Psychiatry. Under Review.

154.

Abdallah CG, Jonas Hannestad, Graeme F Mason, Sophie E Holmes, Nicole DellaGioia, Gerard Sanacora, et al. mGluR5 and glutamate involvement in MDD: a multimodal imaging study [published online ahead of print April 4, 2017]. Biol Psychiatr: Cognit Neurosci Neuroimaging. 2017.

155.

Dantzer

O’Connor

Freund

Johnson

Kelley

. From inflammation to sickness and depression: when the immune system subjugates the brain. Nature Rev Neurosci 2008; 9(1): 46–56.

156.

Bufalino

Hepgul

Aguglia

Pariante

. The role of immune genes in the association between depression and inflammation: a review of recent clinical studies. Brain Behav Immun 2013; 31: 31–47.

157.

Zorrilla

Luborsky

McKay

. The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behav Immun 2001; 15(3): 199–226.

158.

Howren

Lamkin

Suls

. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 2009; 71(2): 171–186.

159.

Dowlati

Herrmann

Swardfager

. A meta-analysis of cytokines in major depression. Biol Psychiatry 2010; 67(5): 446–457.

160.

Haapakoski

Mathieu

Ebmeier

Alenius

Kivimäki

. Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder. Brain Behav Immun 2015; 49: 206–215.

161.

Kraft

Harry

. Features of microglia and neuroinflammation relevant to environmental exposure and neurotoxicity. Int J Environ Res Public Health 2011; 8(7): 2980–3018.

162.

Hannestad

DellaGioia

Gallezot

J-D

. The neuroinflammation marker translocator protein is not elevated in individuals with mild-to-moderate depression: a [(11)C]PBR28 PET study. Brain Behav Immun 2013; 33: 131–138.

163.

Mineur

Obayemi

Wigestrand

. Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety-and depression-like behavior. Proc Natl Acad Sci U S A 2013; 110(9): 3573–3578.

164.

Caldarone

Harrist

Cleary

Beech

King

Picciotto

. High-affinity nicotinic acetylcholine receptors are required for antidepressant effects of amitriptyline on behavior and hippocampal cell proliferation. Biol Psychiatry 2004; 56(9): 657–664.

165.

Janowsky

Davis

El-Yousef

Sekerke

. A cholinergic-adrenergic hypothesis of mania and depression. Lancet 1972; 300(7778): 632–635.

166.

Overstreet

Rezvani

Janowsky

. Genetic animal models of depression and ethanol preference provide support for cholinergic and serotonergic involvement in depression and alcoholism. Biol Psychiatry 1992; 31(9): 919–936.

167.

Dilsaver

. Pathophysiology of “cholinoceptor supersensitivity” in affective disorders. Biol Psychiatry 1986; 21(8–9): 813–829.

168.

Saricicek

Esterlis

Maloney

. Persistent β2*-nicotinic acetylcholinergic receptor dysfunction in major depressive disorder. Am J Psychiatry 2012; 169(8): 851–859.

169.

Pandey

Davis

. Interaction of antidepressant drugs with phosphoinositide turnover in human platelets and rat brain. Clin Neuropharmacol 1992; 15(Suppl 1 Pt A): 202A–203A.

170.

Nye

Purselle

Plisson

. Decreased brainstem and putamen SERT binding potential in depressed suicide attempters using [11C]-zient PET imaging. Depress Anxiety 2013; 30(10): 902–907.

171.

Oquendo

Galfalvy

Sullivan

. Positron emission tomographic imaging of the serotonergic system and prediction of risk and lethality of future suicidal behavior. JAMA Psychiatry 2016; 73(10): 1048–1055.

172.

Leyton

Paquette

Gravel

. α-[11 C] Methyl-l-tryptophan trapping in the orbital and ventral medial prefrontal cortex of suicide attempters. Eur Neuropsychopharmacol 2006; 16(3): 220–223.

173.

Ellicott

Hammen

Gitlin

Brown

Jamison

. Life events and the course of bipolar disorder. Am J Psychiatry 1990; 147(9): 1194–1198.

174.

Malkoff-Schwartz

Frank

Anderson

. Social rhythm disruption and stressful life events in the onset of bipolar and unipolar episodes. Psychol Med 2000; 30(5): 1005–1016.

175.

Cohen

Hammen

Henry

Daley

. Effects of stress and social support on recurrence in bipolar disorder. J Affect Disord 2004; 82(1): 143–147.

176.

Bender

Alloy

. Life stress and kindling in bipolar disorder: review of the evidence and integration with emerging biopsychosocial theories. Clin Psychol Rev 2011; 31(3): 383–398.

177.

Horesh

Apter

Zalsman

. Timing, quantity and quality of stressful life events in childhood and preceding the first episode of bipolar disorder. J Affect Disord 2011; 134(1): 434–437.

178.

Yeh

Chen

. Suicidal ideation modulates the reduction in serotonin transporter availability in male military conscripts with major depression: a 4-[18F]-ADAM PET study. World J Biol Psychiatry 2015; 16(7): 502–512.

179.

Chou

Y-H

Hsieh

W-C

Chen

L-C

Lirng

J-F

Wang

S-J

. Association between the serotonin transporter and cytokines: implications for the pathophysiology of bipolar disorder. J Affect Disord 2016; 191: 29–35.

180.

Chou

Y-H

Lin

C-L

Wang

S-J

. Aggression in bipolar II disorder and its relation to the serotonin transporter. J Affect Disord 2013; 147(1): 59–63.

181.

Chou

Y-H

Wang

S-J

Lirng

J-F

. Impaired cognition in bipolar I disorder: the roles of the serotonin transporter and brain-derived neurotrophic factor. J Affect Disord 2012; 143(1): 131–137.

182.

Chou

Wang

Lin

Mao

Lee

Liao

. Decreased brain serotonin transporter binding in the euthymic state of bipolar I but not bipolar II disorder: a SPECT study. Bipolar Disord 2010; 12(3): 312–318.

183.

Hsieh W, Jou Y, Lin J, Wang S, Chou Y. The effect of cortisol and BDNF on serotonin transporter in bipolar I disorder. Paper presented at: 16 Annual conference in bipolar disorders, International Society for Bipolar Disorders, Wiley, 2014.

184.

Miller

Everett

Oquendo

Ogden

Mann

Parsey

. Positron emission tomography quantification of serotonin transporter binding in medication free bipolar disorder. Synapse 2016; 70(1): 24–32.

185.

Yatham

Liddle

Erez

. Brain serotonin-2 receptors in acute mania. Br J Psychiatry 2010; 196(1): 47–51.

186.

Yatham

Liddle

Lam

. A positron emission tomography study of the effects of treatment with valproate on brain 5 HT2A receptors in acute mania. Bipolar Disord 2005; 7(s5): 53–57.

187.

Sargent

Rabiner

Bhagwagar

. 5-HT 1A receptor binding in euthymic bipolar patients using positron emission tomography with [carbonyl-11 C] WAY-100635. J Affect Disord 2010; 123(1): 77–80.

188.

Nugent

Bain

Carlson

. Reduced post-synaptic serotonin type 1A receptor binding in bipolar depression. Eur Neuropsychopharmacol 2013; 23(8): 822–829.

189.

Amsterdam

Newberg

. A preliminary study of dopamine transporter binding in bipolar and unipolar depressed patients and healthy controls. Neuropsychobiology 2007; 55(3–4): 167–170.

190.

Chang

Yeh

Chiu

. Higher striatal dopamine transporters in euthymic patients with bipolar disorder: a SPECT study with [99mTc] TRODAT 1. Bipolar Disord 2010; 12(1): 102–106.

191.

Yatham

Liddle

Lam

. PET study of the effects of valproate on dopamine D2 receptors in neuroleptic-and mood-stabilizer-naive patients with nonpsychotic mania. Am J Psychiatry 2002; 159(10): 1718–1723.

192.

Hannestad

Cosgrove

DellaGioia

. Changes in the cholinergic system between bipolar depression and euthymia as measured with [123 I] 5IA single photon emission computed tomography. Biol Psychiatry 2013; 74(10): 768–776.

193.

Cannon

Carson

Nugent

. Reduced muscarinic type 2 receptor binding in subjects with bipolar disorder. Arch Gen Psychiatry 2006; 63(7): 741–747.

194.

Cannon

Klaver

Gandhi

. Genetic variation in cholinergic muscarinic-2 receptor gene modulates M2 receptor binding in vivo and accounts for reduced binding in bipolar disorder. Mol Psychiatry 2011; 16(4): 407–418.

195.

Prange

Wilson

Lynn

Alltop

Stikeleather

. L-tryptophan in mania: contribution to a permissive hypothesis of affective disorders. Arch Gen Psychiatry 1974; 30(1): 56–62.

196.

Gao

Jia

Qiao

. TPH2 gene polymorphisms and bipolar disorder: a meta-analysis. Am J Med Genet B Neuropsychiatr Genet 2016; 171B(2): 145–152.

197.

Chou

P-H

Tseng

W-J

Chen

L-M

Lin

C-C

Lan

T-H

Chan

C-H

. Late onset bipolar disorder: a case report and review of the literature. J Clin Gerontol Geriatr 2015; 6(1): 27–29.

198.

Fountoulakis

Kelsoe

Akiskal

. Receptor targets for antidepressant therapy in bipolar disorder: an overview. J Affect Disord 2012; 138(3): 222–238.

199.

Mamo

Kapur

Shammi

. A PET study of dopamine D2 and serotonin 5-HT2 receptor occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone. Am J Psychiatry 2004; 161(5): 818–825.

200.

Kishi

Yoshimura

Fukuo

. The serotonin 1A receptor gene confer susceptibility to mood disorders: results from an extended meta-analysis of patients with major depression and bipolar disorder. Eur Arch Psychiatry Clin Neurosci 2013; 263(2): 105–118.

201.

López-Figueroa

Norton

López-Figueroa

. Serotonin 5-HT 1A, 5-HT 1B, and 5-HT 2A receptor mRNA expression in subjects with major depression, bipolar disorder, and schizophrenia. Biol Psychiatry 2004; 55(3): 225–233.

202.

Lan

Hesselgrave

Ciarleglio

. Higher pretreatment 5 HT1A receptor binding potential in bipolar disorder depression is associated with treatment remission: a naturalistic treatment pilot PET study. Synapse 2013; 67(11): 773–778.

203.

Berk

Dodd

Kauer-Sant’Anna

. Dopamine dysregulation syndrome: implications for a dopamine hypothesis of bipolar disorder. Acta Psychiatrica Scandinavica 2007; 116(s434): 41–49.

204.

El-Mallakh

Wyatt

. The Na, K-ATPase hypothesis for bipolar illness. Biol Psychiatry 1995; 37(4): 235–244.

205.

Peet

. Induction of mania with selective serotonin re-uptake inhibitors and tricyclic antidepressants. Br J Psychiatry 1994; 164(4): 549–550.

206.

Bottlender

Rudolf

Strauss

Möller

H-J

. Antidepressant-associated maniform states in acute treatment of patients with bipolar-I depression. Eur Arch Psychiatry Clin Neurosci 1998; 248(6): 296–300.

207.

Zhan

Kerr

Lafuente

. Altered expression and coregulation of dopamine signalling genes in schizophrenia and bipolar disorder. Neuropathol Appl Neurobiol 2011; 37(2): 206–219.

208.

Anand

Barkay

Dzemidzic

. Striatal dopamine transporter availability in unmedicated bipolar disorder. Bipolar Disord 2011; 13(4): 406–413.

209.

Greenwood

Schork

Eskin

Kelsoe

. Identification of additional variants within the human dopamine transporter gene provides further evidence for an association with bipolar disorder in two independent samples. Mol Psychiatry 2006; 11(2): 125–133.

210.

Greenwood

Alexander

Keck

. Evidence for linkage disequilibrium between the dopamine transporter and bipolar disorder. Am J Med Genet 2001; 105(2): 145–151.

211.

Anderson

Maes

. Bipolar disorder: role of immune-inflammatory cytokines, oxidative and nitrosative stress and tryptophan catabolites. Curr Psychiatry Rep 2015; 17(2): 1–9.

212.

Rosenblat

McIntyre

. Bipolar disorder and inflammation. Psychiatr Clin North Am 2016; 39(1): 125–137.

213.

Rao

Harry

Rapoport

Kim

H-W

. Increased excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients. Mol Psychiatry 2010; 15(4): 384–392.

214.

Haarman

Riemersma-Van der Lek

de Groot

. Neuroinflammation in bipolar disorder—a [(11)C]-(R)-PK11195 positron emission tomography study. Brain Behav Immun 2014; 40: 219–225.

215.

Post

Ketter

Denicoff

. The place of anticonvulsant therapy in bipolar illness. Psychopharmacology 1996; 128(2): 115–129.

216.

Association AP. DSM 5. Washington, DC: American Psychiatric Association; 2013.

217.

Davidson

Baum

. Chronic stress and posttraumatic stress disorders. J Consult Clin Psychol 1986; 54(3): 303.

218.

Murrough

Huang

. Reduced amygdala serotonin transporter binding in posttraumatic stress disorder. Biol Psychiatry 2011; 70(11): 1033–1038.

219.

Frick

Ahs

Linnman

. Increased neurokinin-1 receptor availability in the amygdala in social anxiety disorder: a positron emission tomography study with [11C] GR205171. Transl Psychiatry 2015; 5: e597.

220.

Frick

Åhs

Palmquist

ÅM

. Overlapping expression of serotonin transporters and neurokinin-1 receptors in posttraumatic stress disorder: a multi-tracer PET study. Mol Psychiatry 2015; 21(10): 1400–1407.

221.

Bonne

Bain

Neumeister

. No change in serotonin type 1A receptor binding in patients with posttraumatic stress disorder. Am J Psychiatry 2005; 162(2): 383–385.

222.

Sullivan

Ogden

Huang

Y-Y

Oquendo

Mann

Parsey

. Higher in VIVO Serotonin 1A binding in posttraumatic stress disorder: a pet study with [11C] way 100635. Depress Anxiety 2013; 30(3): 197–206.

223.

Hoexter

Fadel

Felício

. Higher striatal dopamine transporter density in PTSD: an in vivo SPECT study with [99mTc] TRODAT-1. Psychopharmacology 2012; 224(2): 337–345.

224.

Bremner

Innis

Southwick

Staib

Zoghbi

Charney

. Decreased benzodiazepine receptor binding in prefrontal cortex in combat-related posttraumatic stress disorder. Am J Psychiatry 2000; 157(7): 1120–1126.

225.

Geuze

Van Berckel

Lammertsma

. Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder. Mol Psychiatry 2008; 13(1): 74–83.

226.

Neumeister

Normandin

Pietrzak

. Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study. Mol Psychiatry 2013; 18(9): 1034–1040.

227.

Pietrzak

Huang

Corsi-Travali

. Cannabinoid type 1 receptor availability in the amygdala mediates threat processing in trauma survivors. Neuropsychopharmacology 2014; 39(11): 2519–2528.

228.

Redpath

Cooper

Lawrie

. Imaging symptoms and syndromes: similarities and differences between schizophrenia and bipolar disorder. Biol Psychiatry 2013; 73: 495–496.

229.

Czermak

Staley

Kasserman

. β2 Nicotinic acetylcholine receptor availability in post-traumatic stress disorder. Int J Neuropsychopharmacol 2008; 11(3): 419–424.

230.

Krystal

Neumeister

. Noradrenergic and serotonergic mechanisms in the neurobiology of posttraumatic stress disorder and resilience. Brain Res 2009; 1293: 13–23.

231.

Bruening

Hetzenauer

. The anxiety like phenotype of 5 HT1A receptor null mice is associated with genetic background specific perturbations in the prefrontal cortex GABA–glutamate system. J Neurochem 2006; 99(3): 892–899.

232.

Amato

Bankson

Yamamoto

. Prior exposure to chronic stress and MDMA potentiates mesoaccumbens dopamine release mediated by the 5-HT1B receptor. Neuropsychopharmacology 2007; 32(4): 946–954.

233.

Mitsushima

Yamada

Takase

Funabashi

Kimura

. Sex differences in the basolateral amygdala: the extracellular levels of serotonin and dopamine, and their responses to restraint stress in rats. Eur J Neurosci 2006; 24(11): 3245–3254.

234.

Gressier

Calati

Balestri

. The 5 HTTLPR polymorphism and posttraumatic stress disorder: a meta analysis. J Trauma Stress 2013; 26(6): 645–653.

235.

Klemenhagen

Gordon

David

Hen

Gross

. Increased fear response to contextual cues in mice lacking the 5-HT1A receptor. Neuropsychopharmacology 2006; 31(1): 101–111.

236.

Bolaños-Jiménez

de Castro

Seguin

. Effects of stress on the functional properties of pre-and postsynaptic 5-HT 1B receptors in the rat brain. Eur J Pharmacol 1995; 294(2): 531–540.

237.

Charney

Deutch

Krystal

Southwick

Davis

. Psychobiologic mechanisms of posttraumatic stress disorder. Arch Gen Psychiatry 1993; 50(4): 294–305.

238.

Segman

Cooper-Kazaz

Macciardi

. Association between the dopamine transporter gene and posttraumatic stress disorder. Mol Psychiatry 2002; 7(8): 903.

239.

Weizman

Laor

Karp

. Alteration of platelet benzodiazepine receptors by stress of war. Am J Psychiatry 1994; 151(5): 766–767.

240.

Hill

Gorzalka

. The endocannabinoid system and the treatment of mood and anxiety disorders. CNS Neurol Disord Drug Targets 2009; 8(6): 451–458.

241.

Anasetti

Martin

Storb

. Treatment of acute graft-versus-host disease with a nonmitogenic anti-CD3 monoclonal antibody. Transplantation 1992; 54(5): 844–851.

242.

Görena MZ, Cabadakb H. Noradrenaline and post-traumatic stress disorder. In Colin R Martin, Victor R Preedy, & Vinood B Patel, eds. Comprehensive Guide to Post-Traumatic Stress Disorder. Springer International Publishing; 2015. https://www.ncbi.nlm.nih.gov/pubmed/?term=Pietrzak+RH%2C+Gallezot+J-D%2C+Ding+Y-S%2C+Henry+S%2C+Potenza+MN%2C+Southwick+SM%2C+Krystal+JH%2C+Carson+RE%2C+Neumeister+A.+Association+of+posttraumatic+stress+disorder+with+reduced+in+vivo+norepinephrine+transporter+availability+in+the+locus+coeruleus. Accessed May 18, 2017.

243.

Pietrzak

Gallezot

J-D

Ding

Y-S

. Association of posttraumatic stress disorder with reduced in vivo norepinephrine transporter availability in the locus coeruleus. JAMA Psychiatry 2013; 70(11): 1199–1205.

244.

Levin

McClernon

Rezvani

. Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology 2006; 184(3–4): 523–539.

245.

Averill

Purohit

Averill

Boesl

Krystal

Abdallah

. Glutamate dysregulation and glutamatergic therapeutics for PTSD: evidence from human studies. Neurosci Lett 2016; 169: 147–155.

246.

Ring

. The value of positron emission tomography in psychopharmacology. Human Psychopharmacology: Clinical and Experimental 1995; 10(2): 79–87.

247.

Parsey

Mann

. Applications of positron emission tomography in psychiatry. Semin Nucl Med 2003; 33(2): 129–135.

248.

Cuthbert

. The RDoC framework: facilitating transition from ICD/DSM to dimensional approaches that integrate neuroscience and psychopathology. World Psychiatry 2014; 13(1): 28–35.

249.

Pietrzak

Naganawa

Huang

. Association of in vivo κ-opioid receptor availability and the transdiagnostic dimensional expression of trauma-related psychopathology. JAMA Psychiatry 2014; 71(11): 1262–1270.

Neurobiology of Chronic Stress-Related Psychiatric Disorders: Evidence from Molecular Imaging Studies

Abstract

Keywords

Introduction

Application of Positron Emission Tomography and Single Photon Emission

Methods

Results

Major Depressive Disorder

Serotonin

Dopamine

Glutamate

Inflammation

Other Neurotransmitters

PET and SPECT Literature: Suicidal behavior

Bipolar Disorder

Relationship Between BD and Chronic Stress

PET and SPECT Literature: BD

Serotonin

Dopamine

Inflammation

Other Neurotransmitters

Posttraumatic Stress Disorder

Relationship Between PTSD and Chronic Stress

PET and SPECT Literature: PTSD

Serotonin

Dopamine

GABAA-BZR

Other Neurotransmitters

Discussion

Footnotes

Declaration of Conflicting Interests

Funding

References

GABA_A-BZR