Molecular tools for assessing human depression by positron emission tomography

European Neuropsychopharmacology (2009) 19, 611–628

w w w. e l s e v i e r. c o m / l o c a t e / e u r o n e u r o

REVIEW

Molecular tools for assessing human depression by positron emission tomography Donald F. Smith a,⁎, Steen Jakobsen b a b

Center for Psychiatric Research, Psychiatric Hospital of Aarhus University, 8240 Risskov, Denmark PET Center, Aarhus University Hospital, 8000 Aarhus C, Denmark

Received 22 October 2008; received in revised form 11 March 2009; accepted 2 April 2009

KEYWORDS Depression; Major depressive disorder; Unipolar depression; Bipolar depression; Positron emission tomography; PET brain imaging; Neuroreceptor; Neurotransmission; Human

Abstract We review reports published over the past 5 years on positron emission tomography (PET) of neurotransmission in depressive disorders. The molecular tools of PET neuroimaging are compounds labeled with a positron-emitting nuclide. PET radioligands have been used in recent years to study several aspects of monoaminergic and cholinergic neurotransmission in the brain of depressed subjects and healthy controls. The value of kinetic parameters of certain PET radioligands has often been reported to be lower in depressed subjects than in healthy ones, but there is usually no reliable relationship between the binding potential of the neuroreceptor or transporter and the clinical condition of depressed subject. In addition, many recent PET studies have noted either higher binding potentials in depressed subjects or no difference between binding potentials of depressed and healthy subjects. In our view, recent research has neither proved nor refuted the idea that neuromolecular processes that can be assessed by the radioligands currently available for PET studies of humans are causally related to depressive disorders. The future success of PET research for understanding molecular mechanisms in depressive disorders may therefore require the invention and development of further molecular tools for studying a wider range of neuronal events in the living human brain. © 2009 Elsevier B.V. and ECNP. All rights reserved.

1. Introduction Depression causes inner chaos and desperation that requires prompt attention and appropriate care. Success in discovering new, more effective antidepressant therapies may require detailed information on how molecules in the brain can cause and cure depressive disorders in humans. The ⁎ Corresponding author. E-mail address: [email protected] (D.F. Smith).

living brain of humans can now be studied by positron emission tomography PET (Laruelle et al., 2002; Lammertsma, 2002), and that technology has become increasingly popular in psychiatric research. PET makes use of the radioactive decay of positron-emitting nuclides to derive an image of physiological and pharmacological events in a living organ such as the brain. Three types of studies characterize PET research in psychiatry, namely blood flow studies (Ravnkilde et al., 2003; Videbech et al., 2002; Fitzgerald et al., 2006), metabolic studies (Mayberg, 2003; Drevets et al., 2002), and molecular studies. Most molecular PET

0924-977X/$ - see front matter © 2009 Elsevier B.V. and ECNP. All rights reserved. doi:10.1016/j.euroneuro.2009.04.005

612 studies of human depression are based on the monoamine hypothesis (Schildkraut et al., 1968; Schildkraut and Kety, 1967), despite the need for exploring other strategies (Hindmarch, 2002; Berton and Nestler, 2006). The molecular tools for PET studies of human depression are positronlabeled compounds that can identify some aspect of neurotransmission (Fig. 1 and Table 1). This review presents a concise, factual account of PET studies that have used a molecular tool to assess some aspect of neurotransmission in the brain of depressed humans. Only articles published after 2002 are reviewed here (Table 2); excellent reviews of most molecular PET studies published before then are readily available elsewhere (Stockmeier, 2003; Smith et al., 2003;

D.F. Smith, S. Jakobsen Hesse et al., 2004; Sheline et al., 2004; Meyer, 2007; Dunlop and Nemeroff, 2007; Kasper et al., 2002).

2. Serotonergic neurotransmission 2.1. Serotonin synthesis α-[11C]MTrp 2.1.1. Medication-free patients Rosa-Neto et al. estimated the rate of serotonin synthesis in brain regions of medication-free depressed outpatients

Figure 1 Structural drawings of the molecular tools used for PET neuroimaging of depression from January 2003 to December 2008. See Table 1 of review for chemical names.

Molecular tools for assessing human depression by positron emission tomography

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Figure 1 (continued ).

and healthy, age- and sex-matched subjects by PET with α-[11C]MTrp (Rosa-Neto et al., 2004). The kinetic analysis was carried out with data obtained from venous blood

and time-radioactivity curves from 48 brain regions socalled regions-of-interest (ROIs) using a graphical method that assumes irreversible trapping of radioligand in brain

Table 1 Alphabetical list of the molecular tools used for PET neuroimaging of depression during the past 5 years (January 2003– March 2008). PET radioligand Chemical name 18

[ F]Altanserin [11C]DASB [18F]FCWAY [18F]FESP [11C]FLB 457

3-(2-(4-(4-Fluorobenzoyl)-1-piperidinyl)ethyl)-2,3-dihydro-2-thioxo-4(1H)quinazolinone 3-Amino-4-[[2-[(dimethylamino) methyl] phenyl]thio]benzonitrile N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl] ethyl]-N-2-pyridinyl-trans-4-fluorocyclohexylcarboxamide 3-(2-Fluoroethyl)-8-[4-(4-fluorophenyl)-4-oxobutyl]-1-phenyl-1,3,8-triazaspiro[4.5] decan-4-one 5-Bromo-N-[[(2S)-1-ethyl-2-pyrrolidinyl] methyl]-2,3-dimethoxybenzamide

[18F]Fluoro-Ldopa [18F]FP-TZTP

3-(3-(3-Flouropropyl)thio)-1,2,5-thiadiazol- 4-yl)-1,2,5,6-tetrahydro-1-methylpyridine

[11C]Harmine

7-Methoxy-1-methyl-9H-[3,4-b]indole

[11C]McNeil 5652 [11C]MDL 100,907 [18F]MPPF

(6S,10bR)-1,2,3,5,6,10b-Hexahydro-6-[4-(methylthio)phenyl]-pyrrolo[2,1-a] isoquinoline (R)-1-[2-(4-Fluorophenyl)ethyl]-(4-(2,3-dimethoxyphenyl)-4-piperidinemethano

2-Fluoro-5-hydroxy-L-tyrosine

Site-of-action Serotonin type 2A receptor Serotonin transporter Serotonin type 1A receptor Serotonin type 2 receptor Dopamine type D2 receptor Dopamine synthesis Muscarinic type 2 receptor Monoamine oxidase type A Serotonin transporter

Serotonin type 2A receptor 4-Fluoro-N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylbenzamide Serotonin type 1A receptor α-[11C]MTrp α-Methyl-L-tryptophan Serotonin synthesis [11C]Raclopride 3,5-Dichloro-N-[[(2S)-1-ethyl-2-pyrrolidinyl] methyl]-2-hydroxy-6-methoxybenzamide Dopamine type D2 receptor [11C]RTI-32 Methyl-((1R)-2-exo-3-exo)-8- methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2- Catecholamine carboxylate transporter 8-Chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol Dopamine type D1 [11C]SCH 23,390 receptor 6-[2-[4-(4-Fluorobenzoyl)-1-piperidinyl]ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2a] Serotonin type 2 [18F]Setoperone pyrimidin-5-one receptor [11C]WAYN-[2-[4-(2-Methoxyphenyl)-1-piperazinyl] ethyl]-N-2-pyridinyl-cyclohexylcarboxamide Serotonin type 1A 100635 receptor

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Table 2 Neuronal target

Radioligand Medication status

Serotonin synthesis

α-[11C] MTrp

Serotonin transporter

Diagnostic procedure

Subjects

Regions-of-interest

Outcome

Reference

SCID1

17 depressed & 17 healthy

SCID

19 depressed & 41 healthy

Distribution volume by graphical analysis with plasma input function

SCID

18 depressed bipolar & 41 healthy

9–18% less trapping in temporal & cingulated cortex of depressed 27% less binding in amygdale, midbrain & anterior cingulated of non-remitted depressed than healthy 16–27% less binding in depressed bipolar

Rosa-Neto et al., 2004

[11C]McNeil Medication- Distribution volume by 5652 free graphical analysis with plasma input function

Distribution volume by graphical analysis with plasma input function

DSM-IV criteria

25 depressed & 43 healthy

Frontal & temporal cortex, cingulate, thalamus & caudate Anterior cingulate cortex, amygdala, putamen, hippocampus, midbrain & thalamus Anterior cingulate cortex, amygdala, putamen, hippocampus, midbrain & thalamus Anterior cingulate cortex, amygdala, putamen, hippocampus, midbrain & thalamus Frontal, occipital & cingulate cortex, thalamus & pons Prefrontal & cingulate cortex, caudate, putamen, thalamus & midbrain Cerebral cortex, subcortex, & brainstem Thalamus, striatum, cingulated cortices, & raphe Thalamus, striatum, cingulate cortex & raphe

18 – 22% less binding in midbrain & amygdala of depressed

Parsey et al., 2006a

15–20% more binding in left frontal & right cingulate cortex of depressed No difference in binding between groups

Reivich et al., 2004

No difference in binding between groups

Bhagwagar et al., 2007

10 – 16% more binding in depressed bipolar

Cannon et al., 2006b

14–27% more binding in both depressed groups

Cannon et al., 2007

Cerebral cortex & thalamus

20–60% more binding in depressed

Boileau et al., 2008

[11C]DASB

Quantification

Medication- Graphical analysis with free plasma input function

Distribution volume by SCID compartmental model with plasma input function Medication- Graphical reference tissue SCID free model

SCID

Multilinear reference tissue model

SCID

SCID

Graphical reference tissue SCID model

20 depressed & 20 healthy

24 recovered depressive & 20 healthy 18 depressed bipolar & 37 healthy 18 depressed unipolar, 18 depressed bipolar & 34 healthy 7 depressed Parkinson patients & 7 healthy

Oquendo et al., 2007

Meyer et al., 2004a

D.F. Smith, S. Jakobsen

Distribution volume by graphical analysis with plasma input function Multilinear reference tissue model

4 depressed & 4 healthy

Miller et al., 2008

Serotonin type [11C]WAY1A receptor 100635

Medication- Simplified reference free tissue model Distribution volume by graphical analysis with plasma input function

SCID

SCID

10 depressed & 19 healthy 37 depressed & 35 healthy

Midbrain, thalamus & amygdala Striatum

21% less binding in thalamus of depressed No difference in binding between groups

Reimold et al., 2008 Meyer et al., 2004b

12 depressed & 12 healthy

Striatum, thalamus, midbrain, prefrontal cortex & anterior cingulate Cerebral cortex

High dose SSRI3 blocks 84– 98% of serotonin transporters in striatum, midbrain & cerebral cortex 17% less binding in recovered depressed

Voineskos et al., 2007

Bhagwagar et al., 2004

Dorsal raphe nucleus, hippocampus, mesial temporal cortex, anterior cingulate & occipital cortex Cerebral cortex, hippocampus, amygdala & raphe nucleus Cerebral cortex, hippocampus, amygdala & raphe nucleus Dorsal raphe nucleus & multiple regions of cerebral cortex

37% less binding in dorsal raphe of depressed elderly

Meltzer et al., 2004

Cortical binding correlated with anxiety

Sullivan et al., 2005

16–30% more binding in depressed

Parsey et al., 2006b

19% less binding in depressed

Hirvonen et al., 2008

14 recovered depressed & 18 healthy 17 depressed elderly & 17 healthy elderly

Distribution volume by SCID compartmental model with plasma input function

28 depressed

Distribution volume by SCID compartmental model with plasma input function

28 depressed & 43 healthy

Two-tissue compartmental model with cerebellar white matter reference tissue Simplified reference tissue model Simplified reference tissue model Distribution volume by graphical analysis with reference tissue Medication- Simplified reference free & tissue model with medicated cerebellar grey minus vermis as reference tissue

SCID

21 depressed & 15 healthy

DSM-IV criteria SCID

16 depressed & 8 healthy 14 euthymic depressive 14 depressed & 17 healthy

Mesiotemporal cortex & raphe Cerebral cortex, hippocampus & raphe Entire brain by SPM2

26–43% less binding in depressed No effect of hydrocortisone on binding No difference in binding between groups

Drevets et al., 2007 Bhagwagar et al., 2003 Mickey et al., 2008

15 depressed

Raphe nucleus, hippocampus, amygdala, posterior cingulate & cerebral cortex

No reliable effect of antidepressant drug on binding

Moses-Kolko et al., 2007

SCID

SCID

Molecular tools for assessing human depression by positron emission tomography

Multilinear reference DSM-IV tissue model criteria Medication- Graphical reference tissue SCID free & model medicated Medicated Graphical reference tissue SCID model

(continued on next page)

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616

Table 2 (continued) Neuronal target

Radioligand Medication status

Quantification

Diagnostic procedure

Subjects

Regions-of-interest

Outcome

Reference

Beck depression inventory SCID

45 epileptics & 10 healthy

Hippocampus

18% less binding in depressed epileptics

Theodore et al., 2007

8 remitted depressive

No effect of tryptophan depression on binding

Praschak-Rieder et al., 2004

Medication- Multicompart-mental free model with plasma input function

DSM-IV criteria

46 depressed & 29 healthy

29% less binding in hippocampus of depressed

Mintun et al., 2004

Multicompart-mental model with plasma input function

DSM-IV criteria

16 depressed & 9 healthy

39% less binding in hippocampus of depressed

Sheline et al., 2004

Medication- Distribution volume by free graphical analysis with plasma input function Medication- Ratio model during [18F] Setoperone free pseudo-equilibrium

SCID

20 recovered depressive and 20 healthy 22 depressed & 22 healthy

Frontal, temporal & cingulate cortex, hippocampus & midbrain Cerebral cortex, hippocampus & anterior cingulate cortex Cerebral cortex, hippocampus & anterior cingulate cortex Cerebral cortex

Bhagwagar et al., 2006

[18F]FESP

19 drug-naïve Cerebral cortex & depressed, 15 SSRI- striatum treated remitted & 20 healthy Mini6 medicated Entire brain via SPM International depressed, 6 Neuropsych- unmedicated iatric depressed, & 8 Interview healthy

More binding in some cortical regions of recovered depressed 21–29% more binding in depressed with high dysfunctional attitude score 20–26% less binding in cerebral cortex of depressed

20% less striatal uptake in retarded depressed

Bragulat et al., 2007

Serotonin type [18F]FCWAY Medication- Ratio model during free constant infusion 1A receptor [18F]MPPF

Serotonin type [18F] 2 receptor Altanserin

Medicated

Simplified reference tissue model

[11C]MDL 100,907

Integrated radioactivity DSM-IV from 90–120 min in target criteria region Multi-time graphical reference tissue model

Cerebral cortex

Meyer et al., 2003

Messa et al., 2003

D.F. Smith, S. Jakobsen

Dopamine synthesis

Medicated & medicationfree [18F]Fluoro- Medicated L-dopa & medicationfree

SCID

[11C]SCH 23,390 [11C]NNC112

Dopamine D2/3 [11C] receptor Raclopride

[11C]FLB 457

Catecholamine [11C]RTI-32 transporter

Histamine H1 receptor

[11C] Doxepin

MAO type A

[11C] Harmine

Muscarinic type 2 receptor

[18F]FPTZTP

Medicationfree Medicationfree

Simplified reference tissue model Multilinear reference tissue model

Medication- Simplified reference free tissue model Medicated Simplified reference tissue model Ratio model during constant infusion Medication- Distribution volume by free compartmental model with plasma input function Medication- Simplified reference free tissue model

SCID SCID

SCID DSM-IV criteria SCID SCID

DSM-IV criteria

Medicated

Graphical analysis with DSM-IV average plasma input criteria function Medication- Two-tissue compartmental SCID free model with plasma input function Medication- Distribution volume by free compartmental model with plasma input function

DSM-IV criteria

10 depressed & 10 healthy 18 depressed & 19 healthy 21 depressed & 21 healthy 9 depressed & 16 healthy 7 depressed & 8 healthy 7 depressed & 7 healthy

Striatum Accumbens, caudate, putamen, amygdala & cerebral cortex Striatum Caudate & putamen Striatum

Amygdala, hippocampus, frontal cortex, brain stem, anterior cingulate cortex & thalamus 8 depressed Frontal cortex, Parkinson patients, anterior cingulate, 12 non-depressed amygdala, caudate, Parkinson patients putamen, substantia & 7 healthy nigra, & thalamus, 10 depressed & 10 Cerebral cortex and healthy thalamus 17 depressed & 17 healthy

Cerebral cortex, hippocampus, striatum, thalamus & midbrain 16 bipolar Frontal & occipital depressed, 17 cortex, cingulate unipolar depressed gyrus, Hippocampus, & 23 healthy amygdale & striatum

13% less binding in depressed Dougherty et al., 2006 14% less binding in middle Cannon et al., caudate of depressed 2008 7–11% more binding in depressed No difference in binding between groups 8% less binding in dorsal striatum of depressed No difference in binding between groups

Meyer et al., 2006b Kuroda et al., 2006 Montgomery et al., 2007 Montgomery et al., 2007

32–90% less binding in anterior cingulate, thalamus & amygdala of depressed

Remy et al., 2005

20–30% less binding in frontal & cingulate cortices of depressed 20–30% more binding in depressed

Kano et al., 2004

12–16% less binding in cingulate of bipolar depressed

Cannon et al., 2006a

Meyer et al., 2006a

Molecular tools for assessing human depression by positron emission tomography

Dopamine D1 receptor

1

SCID = Structured Clinical Interview for DSM-IV Axis I Disorders. SPM = Statistical Parametric Mapping. 3 SSRI = Selective serotonin reuptake inhibitor. 2

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618 tissue (Patlak et al., 1983). The Hamilton Depression Scale (Hamilton, 1960) and Beck Depression Inventory (Beck et al., 1961) were used to measure the severity and symptoms of depression. In females, the rate of serotonin synthesis in left and right cingulate cortex and left mesial temporal lobe was lower in depressed patients than in healthy subjects. In males, the left cingulate cortex showed a lower rate of serotonin synthesis in depressed patients than in healthy subjects. The level of serotonin synthesis noted in cingulate cortex was, however, not correlated with depression scores of patients. In summary, α-[11C]MTrp accumulation was reduced in certain brain regions of depressed patients, but failed to correlate with depression scores.

2.2. Serotonin transport [11C]McNeil 5652 2.2.1. Medication-free patients Miller et al. used [11C]McNeil 5652 to study binding by serotonin transporters in the brain of healthy subjects and patients with major depressive disorder (Miller et al., 2008). The patients received no psychotropic drugs for at least 2 weeks prior to PET scanning. Accumulation of [11C]McNeil 5652 in six brain regions was assessed by a graphical method using the cerebellum as reference tissue. After PET scanning, the patients were treated with an antidepressant drug and were followed to determine treatment efficacy. Compared with healthy subjects, the accumulation of [11C]McNeil 5652 was reduced in amygdala, midbrain, and anterior cingulate cortex of patients who failed to show remission, defined as at least 50% reduction on the Hamilton Depression Scale, after 1 year of antidepressant treatment. Oquendo et al. carried out a PET study with [11C]McNeil 5652 in which they determined whether binding by the serotonin transporter differs between healthy subjects and depressed patients with bipolar disorder (Oquendo et al., 2007). Their study also examined possible relationships between serotonin transporter genotypes and [11C]McNeil 5652 binding. The depressed patients had a major depressive episode at the time of the study and were without antidepressant and antimanic medication for several weeks before PET scanning. Arterial blood samples were drawn and used for obtaining a metabolite-corrected plasma time-activity curve and for estimating the volume of distribution of [11C]McNeil 5652 by a two-compartment kinetic model. Data analysts did not know the diagnosis of each participant when identifying regions-of-interest: midbrain, amygdala, hippocampus, thalamus, putamen, and anterior cingulate cortex. The binding potential of the serotonin transporter towards [11C]McNeil 5652 was 16–27% lower in brain regions of patients with bipolar disorder than in healthy subjects. No correlation was, however, found between the binding potential of the serotonin transporter and either the clinical status of depressed, bipolar patients or the triallelic genotype of their transporter. Parsey et al. examined binding by the serotonin transporter by PET with [11C]McNeil 5652 (Parsey et al., 2006a). A relatively large group of patients with a current major depressive episode was compared with healthy subjects. Strict inclusion criteria were employed, including no drug

D.F. Smith, S. Jakobsen abuse of any kind in depressed patients and healthy subjects, and no use of psychotropic medication by patients for at least 2 weeks before the study. Arterial blood samples were obtained and were used with regional time–radioactivity curves for estimating the distribution volume of [11C]McNeil 5652, and thereby the binding potential of serotonin transporters, in selected brain regions, with cerebellum as reference tissue. Compared with healthy subjects, depressed patients had reduced binding potentials in amygdala as well as in midbrain, including the raphe nucleus. Further analysis of the data showed that reduction in the binding potential of serotonin transporters was most pronounced in depressed patients who had never received antidepressant medication. The severity of depression was, however, not correlated with the binding potential of serotonin transporters, as shown by [11C]McNeil 5652-PET, in any brain region. Reivich et al. used [11C]McNeil 5652 to see whether binding by the serotonin transporter differed between a small group of depressed outpatients and healthy subjects (Reivich et al., 2004). The patients had not received psychotropic medication for at least 5 half-lives of drugs or at least 2 weeks for MAOIs and 3 weeks for fluoxetine. Arterial blood sampling provided data for metabolite-corrected plasma input functions which, together with PET data, gave estimates of distribution volumes of [11C]McNeil 5652 in selected brain regions. The binding of [11C]McNeil 5652 was greater in left frontal cortex and right cingulate cortex of depressed subjects than healthy ones, while no reliable difference was found for occipital cortex, thalamus and pons. In summary, low binding of [11C]McNeil 5652 in brain regions of depressed patients may be linked with poor antidepressant response, but not with depression severity. [11C]DASB

2.2.2. Medication-free patients Meyer et al. conducted a PET study using [11C]DASB to determine whether an abnormality in the 5-HT transporter is present during depression (Meyer et al., 2004a). They recruited a relatively large group of medication-free subjects that were in the midst of a major depressive episode as well as an age-matched group of healthy subjects. The binding potential of [11C]DASB was estimated in several brain regions by a reference region method, using cerebellum as reference tissue. Meyer et al. found that a major depressive episode had no reliable effect on the binding potential of [11C]DASB in any brain region, although a positive correlation was noted between the magnitude of negative thinking and the binding potential of [11C]DASB in several brain regions in depressed patients but not in healthy subjects. Bhagwagar et al. used [11C]DASB to determine whether abnormalities in the serotonin transporter are present in the brain of recovered depressed patients, to explore the notion that a molecular disorder of that transporter may be a trait characteristic (Bhagwagar et al., 2007). They recruited 24 recovered, depressed men who had not received antidepressant medication for at least 3 months before the study. Arterial blood samples were obtained and used for estimating the binding of [11C]DASB in brain regions. A thorough statistical analysis revealed no difference in the binding of [11 C]DASB in brain regions of male patients who had

Molecular tools for assessing human depression by positron emission tomography recovered from depression versus healthy men with no current or past history of depression. Cannon et al. used [11C]DASB to compare the binding properties of the serotonin transporter in brain regions of healthy subjects and in patients with either unipolar- or bipolar-depression (Cannon et al., 2007; Cannon et al., 2006b). The depressive subjects received no psychotropic drugs for at least 3 weeks prior to PET scanning. Regional binding potentials of [11C]DASB were estimated without arterial sampling by a reference tissue method with the cerebellum as reference tissue (Ichise et al., 2003). Compared to healthy subjects, unipolar-depressives and bipolar-depressives showed increased binding potentials of [11C]DASB in some brain regions, including the thalamus, striatum, insular cortex, and cingulate cortex. In addition, the binding potential of [11C]DASB in midbrain periaqueductal gray matter was greater in unipolar-depressives than in bipolar-depressives. Cannon et al. noted that the severity of depression in unipolar patients correlated negatively with the binding potentials of [11C]DASB in thalamus, insular cortex, and cingulate cortex, which seems paradoxical in light of their finding of higher binding potentials in depressed patients than in healthy subjects (Cannon et al., 2007). Boileau et al. determined whether alterations of [11C] DASB binding accompany symptoms of depression in Parkinson patients who receive antiparkinson medication but who never received an antidepressant drug (Boileau et al., 2008). They estimated the binding potential of [11C]DASB in selected brain regions using the reference-tissue method with cerebellar cortex as reference region, and compared findings in Parkinson patients with those obtained in a group of healthy subjects. Parkinson patients showed increased binding of [11C]DASB in prefrontal cortical regions, and the severity of depression in Parkinson patients, as reflected by scores on the Hamilton Depression Scale, correlated with [11C]DASB binding in the orbitofrontal cortex. Reimold et al. used PET to explore relationships between depression, anxiety and binding of [11C]DASB by serotonin transporters in a study of drug-free patients suffering from unipolar depression and healthy subjects matched to patients in terms of age, smoking status and genotype (Reimold et al., 2008). A weighting procedure was used to account for confounding effects of several variables, and the weights were used in the calculation of binding potentials. They found that the binding potential of [11C]DASB in thalamus was reliably lower in depressed patients than in healthy subjects, whereas no difference between groups was observed for amygdala and midbrain. Further exploratory analysis showed less binding of [11C]DASB in left putamen, right insula, anterior cingulate, and cingulate gyrus of depressed patients than healthy subjects. The reduced binding potential of [11C]DASB in thalamus of depressed subjects correlated negatively with their self-reported state-of-anxiety, but failed to be correlated self-reported depression severity. In summary, binding of [11C]DASB in brain regions of drugfree depressed patients may be elevated, reduced, or no different from that of healthy subjects. 2.2.3. Medicated patients Meyer et al. used [11 C]DASB in healthy subjects and depressed patients to measure occupancy of the 5-HT

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transporter during prolonged treatment with an antidepressant drug (Meyer et al., 2004b). The study examined whether SSRIs produce a dose-dependent occupancy of the 5-HT transporter in the human brain. All subjects were [11C]DASBPET scanned in medication-free, i.e. baseline, condition in order to obtain an estimate of their regional binding potentials. Healthy subjects then received a low dose of SSRI while depressed subjects received either the usual treating daily dose or a higher daily dose of SSRI. Treatment continued for 4 weeks. Thereafter, all subjects underwent [11C]DASB-PET scanning 6–13 h after the last dose of SSRI as well as blood sampling to determine the concentration of antidepressant drug in serum. A reference tissue method was used to estimate the binding potential of [11C]DASB in selected brain regions. The baseline regional binding potential of [11C]DASB was similar in healthy and depressed subjects. SSRIs in the low-to-moderate dose-range produced a dose-dependent increase in the occupancy of the 5-HT transporter, but transporter occupancy failed to exceed ca. 85% at the highest doses used in the study. The degree of occupancy of the striatal 5-HT transporter produced by the SSRIs failed to correlate reliably with the clinical response observed during the experiment in depressed patients. Voineskos et al. used [11C]DASB to estimate the degree to which high doses of an antidepressant drug occupy the 5-HT transporter in depressed patients (Voineskos et al., 2007). Using a reference region method, the binding potential of [11C]DASB in brain regions of healthy subjects provided baseline values for estimating the occupancy of the 5-HT transporter in brain regions of patients that received an antidepressant for at least 4 weeks. High dose treatment with venlafaxine, citalopram or sertraline produced occupancy of greater than 75% in the 5-HT transporter in the thalamus, striatum, anterior cingulate and prefrontal cortex. In summary, [11C]DASB-PET can determine the occupancy of 5-HT transporters in brain regions of depressed patients in antidepressant therapy.

2.3. Serotonin type 1A receptor [11C]WAY-100635 2.3.1. Medication-free patients Bhagwagar et al. used [11C]WAY-100635 to determine whether the reduction of binding to cerebral 5-HT1A receptors persists after recovery from depression (Bhagwagar et al., 2004). They studied men who had experienced at least two episodes of major depression, but who were euthymic and free of psychotropic drugs for at least 8 months. PET data were assessed by the simplified reference tissue compartmental model with the cerebellum as reference tissue. Compared to a group of age-matched healthy males who had never been depressed, the recovered depressed subjects showed an average reduction of 17% in the binding potential of [11C]WAY-100635. No reliable relationship was found between the binding potential values and the clinical variables of the recovered depressed subjects. Meltzer et al. used [11C]WAY-100635 to assess 5-HT1A receptors in brain regions of elderly depressed patients and age-matched healthy subjects (Meltzer et al., 2004).

620 Particular attention was given to evaluating 5-HT1A receptors in the dorsal raphe nucleus, even though that region is small and non-distinct anatomically, making it difficult to identify in PET and magnetic resonance images. Dynamic arterial blood samples were obtained and plasma data were corrected for radiolabeled metabolites of [11C]WAY-100635. The volume-of-distribution of the radiotracer in brain regions was estimated from time-activity data, and binding potential of [11C]WAY-100635 was calculated using cerebellar hemispheres as reference region. Of the brain regions studied, i.e. dorsal raphe nucleus, lateral orbitofrontal cortex, pregenual cingulated, subgenual cingulated, hippocampus, mesial temporal cortex, and occipital cortex, the binding potential of [11C]WAY-100635 was reliably lower only in the dorsal raphe nucleus of elderly depressed patients compared with elderly healthy subjects. A positive relationship was observed between [11C]WAY-100635 binding potential in dorsal raphe nucleus and Hamilton Depression Rating in the elderly depressed patients, such that more severe depression correlated with higher binding potentials. Sullivan et al. performed a PET study with [11C]WAY100635 to explore possible relationships between 5-HT1A receptors, major depressive disorder, and anxiety (Sullivan et al., 2005). They used unipolar depressed patients fulfilling the DSM-IV criteria of current major depressive episode and being able to refrain from taking antidepressant medication for at least 14 days before PET scanning. Symptoms of depression and anxiety were assessed by rating scales. The binding potential of 5-HT1A receptors was estimated from metabolite-corrected arterial input functions and time– radioactivity curves of brain regions. Principal component analysis of anxiety items on the rating scales provided measures of three anxiety types, named somatic, motoric and psychic. Regression analysis found that the binding potential of 5-HT1A receptors correlated positively with psychic anxiety and negatively with somatic anxiety in the anterior cingulate cortex, body of the cingulated cortex, medial and orbital prefrontal cortex, whereas no reliable correlation was found between anxiety and the binding potential of 5-HT1A receptors in amygdala, hippocampus or raphe nucleus in the unipolar depressed patients. Parsey et al. examined the binding potential of 5-HT1A receptors by PETusing [11C]WAY-100635 in patients with a major depressive episode and in healthy subjects (Parsey et al., 2006b). Arterial blood samples were obtained from all participants during PET scanning, and metabolite-corrected plasma curves were used to estimate regional distribution volumes of [11C]WAY-100635 and binding potentials of 5-HT1A receptors by compartment models. This study included genotyping to determine whether the allelic composition of the C-1019G polymorphism of the promoter region of the 5-HT1A gene can account for individual differences in the binding potential of 5-HT1A receptors. No reliable difference in regional binding potentials of 5-HT1A receptors was found between all depressed patients and healthy subjects, and no correlation was found between regional binding potentials and the severity of depression as assessed by the Hamilton Depression Scale and the Beck Depression Inventory. However, classifying depressed patients as either antidepressant-naïve or antidepressantexperienced showed that antidepressant-naïve patients had higher regional binding potentials of 5-HT1A receptors than antidepressant-experienced patients and healthy subjects.

D.F. Smith, S. Jakobsen Genotyping failed to account for differences in 5-HT1A receptor binding potentials between groups of antidepressant-naïve, antidepressant-experience, and healthy subjects, although an association was found between relatively high binding potentials of 5-HT1A receptors in the dorsal raphe nucleus and the C-1019G allele in patients as well as in healthy subjects. Hirvonen et al. used [11C]WAY-100635 to determine whether binding by the 5-HT1A receptor is abnormal in depressed people (Hirvonen et al., 2008). The severity of depression was assessed by the Hamilton Depression Scale, and the subjects had received neither psychotherapy nor psychoactive drugs during the preceding 4 months, had no comorbidity, and had no severe somatic illnesses. Arterial blood samples were obtained for measuring plasma radioactivity and metabolites for calculating the binding potential of the radiotracer in brain regions. The binding potential of [11C]WAY-100635 was, on average, 19% lower in brain regions of depressed patients than in non-depressed, healthy subjects. No reliable correlation was found between the binding potential of [11C]WAY-100635 in the depressed patients and their clinical condition. Drevets et al. also reported the results of a recent study on the binding potential of [11C]WAY-100635 in depressed outpatients compared to healthy subjects (Drevets et al., 2007). PET data analysis was focused on the raphe region and the mesiotemporal cortex, i.e. hippocampus, amygdala, and adjacent parahippocampal and periamygdaloid regions, with cerebellum as reference region. The binding potential of [11C]WAY-100635 was, on average, 26% lower in the mesiotemporal cortex and 43% lower in the raphe of depressed patients than of healthy subjects, and there was no reliable correlation between the [11C]WAY-100635 binding potential and clinical condition of patients. Bhagwagar et al. used [11C]WAY-100635 and PET to examine whether an adrenal hormone affects the binding of 5-HT1A receptors in patients who had recovered from a major depressive episode (Bhagwagar et al., 2003). The patients included in the study had been euthymic and free of psychotropic drugs for at last 6 months. Each patient was PET scanned with [11C]WAY-100635 in the morning after taking either 100 mg of hydrocortisone or placebo in a double-blind, randomized, crossover design. The binding potential of 5-HT1A receptors in brain regions-of-interest was estimated by a simplified reference tissue compartment model, with cerebellum as reference tissue. No effect of hydrocortisone was observed on the binding potential of 5-HT1A receptors, as measured by [11C]WAY-100635-PET, in any brain region of euthymic, medication-free patients recovered from depression. Mickey et al. used [11C]WAY-100635 in a recent PETstudy to determine whether there are reliable relationships between depression and the binding potential of 5-HT1A receptors (Mickey et al., 2008). This study determined also the genotype of MAO-A in each subject. Healthy subjects were compared with drug-free individuals seeking treatment for moderateto-severe major depressive disorder. PET scans used the method of continuous infusion after bolus injection of the tracer. The binding potential of 5-HT1A receptors toward [11C]WAY-100635 was assessed by Logan graphical analysis using cerebellum, without vermis, as reference region. Region-of-interest analysis and statistical parametric mapping were used to assess results. Binding potentials varied similarly with genotype in the depressed and healthy subjects, and no

Molecular tools for assessing human depression by positron emission tomography reliable relationships were found between depression and regional binding potentials of 5-HT1A receptors. In summary, [11C]WAY-100635 binding failed to show consistent differences between depressed patients and healthy subjects, and no reliable correlation appeared between [11C] WAY-100635 binding and the clinical condition of patients. 2.3.2. Medicated patients Moses-Kolko et al. used [11C]WAY-100635 to see whether the binding potential of 5-HT1A receptors is affected by antidepressant treatment with an SSRI and/or a dual reuptake inhibitor (Moses-Kolko et al., 2007). They recruited patients with recurrent major depressive disorder and PET-scanned them with [11C]WAY-100635 under baseline, unmedicated condition. Then, the depressed patients were treated with either citalopram, venlafaxine, or a combination of both drugs. PET scanning with [11C]WAY-100635 took place again after at least 7 weeks of treatment. Arterial blood samples were obtained from some patients to provide metabolitecorrected data for kinetic analysis, whereas the simplified reference region method was used for assessing the binding of [11C]WAY-100635 in brain regions of all patients. The results showed no reliable effect of antidepressant drug treatment on the binding potential of 5-HT1A receptors. Extensive statistical analysis indicated, however, that the binding of [11C]WAY100635 in orbital cortex was higher prior to antidepressant treatment in non-responders than in responders. In summary, [11C]WAY-100635 binding was unaffected by treatment with an antidepressant drug. [18F]FCWAY 2.3.3. Medication-free patients Theodore et al. used [18F]FCWAY to study 5-HT1A receptor binding in a group of patients that had temporal lobe epilepsy for an average of 20 years and a group of healthy subjects (Theodore et al., 2007). Symptoms of depression in the patients were assessed by the Beck Depression Inventory, and none of the patients took antidepressant medication at the time of the study. The volume-of-distribution of [18F]FCWAY in hippocampal regions was lower in epileptic patients than in healthy subjects, with an inverse relationship in patients between the score on the self-rated depression inventory and the hippocampal volume-of-distribution of [18F]FCWAY. In summary, [18F]FCWAY accumulation was reduced in hippocampus of depressed, epileptic patients compared with healthy subjects.

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mixture caused symptoms of depression to reappear in most of the patients. However, no reliable difference was found for the binding potential of [18F]MPPF in brain regions after consuming the tryptophan-deficient mixture compared with the placebo mixture containing tryptophan. In summary, [18F]MPPF binding was unaffected by tryptophan-deficient mixture in remitted patients given antidepressant drug therapy.

2.4. Serotonin type 2 receptor [18F]Altanserin 2.4.1. Medication-free patients Mintun et al. explored the notion that [18F]altanserin binding is abnormal in the brain of depressed subjects (Mintun et al., 2004). They recruited a relatively large group of depressed outpatients of age 20–85 years and receiving no psychotropic drugs. The depressed subjects were PETscanned, along with a group of healthy subjects, with [18F]altanserin. Arterial blood samples were obtained for kinetic analysis of nine regions-ofinterest using a four-compartment model (Sheline et al., 2002). The binding potential of [18F]altanserin in brain regions differed reliably between depressed outpatients and healthy subjects only in the hippocampus, and there was no correlation between the binding potential of [18F]altanserin in any brain region and the severity of depression in the outpatients. Sheline et al. carried out a similar study to see whether the binding of [18F]altanserin to serotonin type 2A receptors is altered in brain regions of depressed subjects aged above 49 years and receiving no psychotropic drugs (Sheline et al., 2004). The depressed subjects were classified as having either early-onset depression or late-onset depression. A group of healthy subjects was included for comparison with the depressed ones. Arterial blood samples were obtained and the binding potential of [18F]altanserin in nine brain regions was determined by a four-compartment kinetic analysis (Sheline et al., 2002). The binding potential of [18 F]altanserin was lower only in the hippocampus of depressed subjects versus healthy subjects. Neither the type nor the severity of depression was reliably related to the binding potential of [18F]altanserin in any brain region. In summary, [18 F]altanserin binding was reduced in hippocampus of depressed patients, but was not correlated to depression severity. [11C]MDL 100,907

18

[ F]MPPF 2.3.4. Medicated patients Praschak-Rieder et al. used [18F]MPPF to estimate the binding potential of 5-HT1A receptors in the brain of eight remitted patients receiving citalopram as antidepressant therapy (Praschak-Rieder et al., 2004). A tryptophan-deficient amino acid mixture and an amino acid mixture containing tryptophan were given to each patient, in a double-blind, counter-balanced order, on days of PET scanning. The effect of the mixtures on each patients' mood was assessed, and the binding potential of [18F]MPPF was estimated in selected brain regions by the simplified reference region method. As expected (Delgado et al., 1990), the tryptophan-deficient

2.4.2. Medication-free patients Bhagwagar et al. carried out a PETstudy with [11C]MDL 100,907 to assess 5-HT2A receptors in patients who had recovered from depression compared with healthy subjects (Bhagwagar et al., 2006). All patients had been euthymic and medication-free for at least 6 months at the time of the study. Arterial blood samples were obtained and the concentration of [11C]MDL 100,907 in plasma was used to estimate the binding potential of 5-HT2A receptors in cortical regions. 5-HT2A-binding potentials were higher in frontal, occipital and parietal cortical regions in patients who had recovered from depression than in healthy subjects, although no correlation was found in patients between the binding potential of 5-HT2A receptors in

622 frontal cortex and any clinical characteristic such as age at illness onset, lifetime duration of illness, number of depression episodes, and duration of euthymia. In summary, [11C]MDL 100,907 binding was increased in cortical regions of remitted, depressive patients, but no correlation was found between 5-HT2A receptor binding and their clinical characteristics. [18F]Setoperone 2.4.3. Medication-free patients Meyer et al. estimated the binding potential of 5-HT2 receptors with [18F]setoperone in patients having a major depressive episode secondary to major depressive disorder and in age-matched, healthy subjects (Meyer et al., 2003). This study focused on possible relationships between dysfunctional attitudes and the status of 5-HT2 receptors in cerebral cortex. The patients had received no psychotropic drugs for at least 4 weeks plus 5 half-lives of any medication. Regional binding potentials and parametric maps were constructed by a reference-region method, using the cerebellum as reference tissue. The binding potential of 5-HT2 receptors in frontal cortex correlated with the level of dysfunctional attitudes measured in the depressed patients, but failed to be related to other measures of depression such as suicidal ideation, scores on the Hamilton Depression Scale, number of previous episodes, duration of depression, and past use of antidepressant drugs. In summary, [18F]seroperone binding in frontal cortex correlated with dysfunctional attitudes of depressed patients. [18F]FESP 2.4.4. Medicated and medication-free patients Messa et al. assessed primarily the binding of 5-HT2 receptors in cortical regions by [18F]FESP-PET, although the radioligand has also affinity for dopamine D2 sites (Messa et al., 2003). The study included healthy subjects and two groups of patients with unipolar depressive disorder, namely those who had never received an antidepressant drug and those who were in remission during paroxetine treatment. An estimate of 5-HT2A receptor binding was obtained by a reference region method using cerebellum as reference tissue. Compared with healthy subjects, depressed patients that had never received antidepressant medication had less binding of [18F]FESP in cortical brain regions, whereas no difference was found in the regional binding of [18F]FESP between remitted, depressed patients receiving paroxetine and healthy subjects. In summary, [18F]FESP binding in cortical regions was lower in medication-free, depressed patients than in healthy subjects and remitted, depressive patients given an antidepressant drug.

3. Dopaminergic neurotransmission 3.1. Dopamine synthesis [18F]Fluoro-L-dopa 3.1.1. Medicated and medication-free patients Bragulat et al. used [18F]fluoro-L-dopa to see whether uptake in mainly dopaminergic brain regions differs between healthy

D.F. Smith, S. Jakobsen subjects and patients in a major depressive episode (Bragulat et al., 2007). The depressed patients were subdivided on the basis of clinical assessment into two groups: high motor retardation or high impulsivity. Some patients in each group were medicated with either fluoxetine or venlafaxine. Parametric images of rate constants reflecting the uptake of [18F]fluoro-L-dopa in brain tissue were prepared and were then assessed using SPM99 software. Compared with healthy subjects, depressed patients with high motor retardation showed reduced uptake of [18F]fluoro-L-dopa in striatal regions, i.e. caudate, putamen, accumbens, parahippocampus and brainstem, along with elevated uptake in subgenual cingulate cortex. Depressed patients with high impulsivity had lower [18F]fluoro-L-dopa uptake than healthy subjects in anterosuperior cingulate and hypothalamic–pituitary regions, and higher uptake of [18F]fluoro-L-dopa in parahippocampus. In summary, [18F]fluoro-L-dopa uptake in striatal regions was reduced in depressed patients with marked motor retardation.

3.2. Dopamine D1 receptor [11C]SCH 23,390 3.2.1. Medication-free subjects Dougherty et al. performed a PET study with [11C]SCH 23,390 to see whether dopamine D1 receptors in the brain differed between patients with major depression with anger attacks and age-matched, healthy subjects (Dougherty et al., 2006). The patients had refrained from psychotropic drugs for at least 3 weeks before PET scanning. Regions-of-interest were drawn for cerebellum and left and right striatum on PET images by a person who did not know the clinical condition of the participants in the study. Time-radioactivity concentration curves were obtained and the reference tissue method was used to estimate the binding potential of striatal regions towards [11C]SCH 23,390. Binding by dopamine D1 receptors was lower in striatal regions of depressed patients with anger attacks than in healthy subjects. In summary, [11C]SCH 23,390 binding was reduced in striatal regions of depressed patients with anger attacks. [11C]NNC-112 3.2.2. Medication-free subjects Cannon et al. used [11C]NNC-112 for PET to compare dopamine D1 receptors in striatal and extrastriatal regions of depressed subjects and healthy controls (Cannon et al., 2008). The depressed subjects had taken no medication likely to affect cerebral function within 3–8 weeks prior to the study. Values for regional binding potentials of [11C]NNC112 were obtained from time-activity data, without arterial sampling, using a multilinear reference-tissue model with cerebellum as reference region. Segmenting the striatum into five regions in each hemisphere allowed for assessment of laterality in receptor binding. In addition, PET data from several extrastriatal regions were assessed. The binding potential of [11C]NNC-112 in the middle caudate of the left hemisphere was the only region with a reliable difference between depressed subjects and healthy controls; an inverse correlation was found between illness duration and binding potential of [11C]NNC-112 in the left middle caudate of

Molecular tools for assessing human depression by positron emission tomography depressed subjects, whereas the binding potential of [11C] NNC-112 failed to be correlated with severity of depression, anxiety or anhedonia. In summary, [11C]NNC-12 binding to dopamine D1 receptors was reduced in a striatal region of depressed subjects.

3.3. Dopamine D2/3 receptor 11

[ C]Raclopride 3.3.1. Medication-free patients Meyer et al. carried out a PET study with [11C]raclopride in depressed subjects (Meyer et al., 2006b). They used [11C] raclopride to look for a possible relationship between motor retardation and extracellular dopamine in brain regions. Drug-free, non-smoking depressed subjects experiencing a major depression and age-matched, non-smoking, healthy subjects were PET scanned, and the binding potentials of [11C]raclopride in regions of the striatum were estimated by the simplified reference tissue method. The binding potential of [11C]raclopride in striatal regions was reliably higher in depressed subjects than in healthy ones. In addition, depressed subjects with the most marked motor retardation had the highest binding potentials of [11C]raclopride in striatal regions, whereas binding potentials failed to be reliably correlated with any other clinical variable. In summary, [11C]raclopride binding may be elevated in striatal regions of drug-free depressed patients, but fails to correlate with clinical condition.

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between the regional binding potentials of [11C]raclopride and the clinical conditions of the patients. In summary, [11C]raclopride binding may be lower than normal under certain conditions in striatal regions of partiallyrecovered, depressed patients given an antidepressant drug. [11C]FLB 457 3.3.3. Medication-free patients Montgomery et al. examined whether dopaminergic function is abnormal in untreated, depressed subjects by a PET study of [11C]FLB 457 binding in brain regions of depressed patients and age-matched healthy subjects (Montgomery et al., 2007). The depressed subjects had not taken any psychotropic medication for at least 3 months prior to the study. Arterial blood sampling was done throughout the scan, and an arterial input function with metabolite correction was used in the kinetic data analysis to estimate the total volume-of-distribution of [11C]FLB 457 in seven brain regions. No reliable difference was found for the total volume-of-distribution of [11C]FLB 457 in brain regions of depressed subjects compared with healthy subjects, and the cerebral kinetics of [11C]FLB 457 were unrelated to the severity of depression. In summary, [11C]FLB 457 accumulation in brain regions was unaffected by depression.

4. Catecholaminergic neurotransmission [11C]RTI-32

4.1. Medication-free patients 3.3.2. Mediated patients Kuroda et al. used [11C]raclopride to determine whether repetitive transcranial magnetic stimulation (rTMS) affects central dopaminergic mechanisms in depressed subjects (Kuroda et al., 2006). The depressed patients of this study had previously been either resistant to antidepressant drug therapy or discontinued it due to adverse side effects. They were, however, allowed an SSRI and a benzodiazepine during the study. Each depressed subject was PETscanned twice, once before rTMS and again 1 day after 10 sessions of rTMS given over the left dorsolateral prefrontal cortex. A group of healthy subjects was PET-scanned once with [11C]raclopride for comparison with findings obtained in the depressed subjects. Regions-of-interest were drawn to assess striatal regions and the binding potentials of [11C]raclopride were determined by the simplified reference tissue method. No reliable difference in the regional binding potentials of [11C]raclopride was found between depressed and healthy subjects. Moreover, rTMS failed to affect the binding potential of [11C]raclopride reliably in striatal regions of the brain in depressed subjects, regardless of the therapeutic effect of the treatment. Montgomery et al. recently reported a PET study of [11C] raclopride binding in the brain of healthy subjects and partially-recovered, depressed patients who continued taking a SSRI (Montgomery et al., 2007). They administered [11C] raclopride as a constant infusion and mapped striatal and cerebellar regions-of-interest for kinetic data analysis. Evidence was obtained of a lower binding potential of [11C] raclopride in the dorsal striatum of patients taking a SSRI than of controls depending, however, on the selection of data in the statistical analysis. No correlations were found

Remy et al. used [11C]RTI-32 to see whether ligand binding by central catecholamine transporters differed in Parkinson patients who were either depressed or non-depressed (Remy et al., 2005). The depressed Parkinson patients had received no antidepressant medication for at least 3 months before the study. The simplified reference tissue method was used to estimate the binding potential of [11C]RTI-32 in eleven brain regions. Depressed Parkinson patients had lower binding potentials than non-depressed Parkinson patients in four of the regions, namely thalamus, anterior cingulate, amygdala and locus coeruleus. Further data analysis revealed a negative correlation between the patients' score on the Beck self-rating depression inventory and the binding potential of [11C]RTI-32 in the patients' left ventral striatum. In summary, [11C]RTI-32 binding was lower in brain regions of depressed Parkinson patients than in non-depressed Parkinson patients.

5. Histaminergic neurotransmission 5.1. Histamine H1 receptor [11C]Doxepin Kano et al. used [11C]doxepin to test the notion that the histaminergic neuron system could be involved in human depression (Kano et al., 2004). They carried out PET scanning with [11C]doxepin in ten male patients with major depressive disorder and 10 healthy, age-matched males. The patients were

624 allowed to take benzodiapines for insomnia and/or fluvoxamine for treatment of depression. PET data analysis used region-ofinterest time–activity curves and an average arterial plasma concentration as input function. The volume-of-distribution of [11C]doxepin was estimated in brain regions by graphical analysis (Logan et al., 1990) and the values obtained were used to calculate the binding potential with cerebellum as reference region. A reliable reduction in the binding potential of [11C] doxepin was found in anterior cingulate cortex as well as middle and interior frontal gyri of depressed patients, with a reliable negative correlation between binding potential and self-rated depression in patients and healthy subjects. In summary, depression was related to reduced binding by histamine H1 receptors in a relatively small group of males.

6. Monoamine oxidase MAO 6.1. MAO type A [11C]Harmine 6.1.1. Medication-free patients Meyer et al. used [11C]harmine, a reversible inhibitor of type A MAO, to see whether the activity of that enzyme differs between depressed patients and age-matched healthy subjects (Meyer et al., 2006a). A minimum score of 17 on the Hamilton Depression Scale was used for inclusion of patients. All participants were non-smokers so as to rule out effects that tobacco smoking might have on MAO activity, and none of the patients had received antidepressant medication for at least 5 months before the study. Arterial blood samples were obtained and used in the kinetic analysis of PET data, using a 2-tissue compartment model. The volume-of-distribution of [11C]harmine turned out to be higher in brain regions of depressed patients than in healthy subjects, but no correlation was found between clinical variables and PET findings in the patients. In summary, [11C]harmine accumulation in brain regions was higher in depressed patients than in healthy subjects, but failed to correlate with the patients' clinical condition.

7. Cholinergic neurotransmission 7.1. Muscarinic type 2 receptor [18F]FP-TZTP 7.1.1. Medication-free patients Cannon et al. examined the role of the central muscarinic– cholinergic system in major depressive disorder by PETscanning with [18F]FP-TZTP (Cannon et al., 2006a). They studied depressed patients with a diagnosis of either recurrent major depressive disorder or bipolar disorder, and compared them with healthy subjects. None of the participants had received psychotropic drugs including nicotine for at least 3 weeks prior to PETscanning. Arterial blood samples were obtained and used for quantifying the plasma concentration of [18F]FP-TZTP for the kinetic data analysis. Distribution volumes of [18F]FP-TZTP in brain regions were estimated by a 1-tissue compartment model. Regions-of-interest were established in each subject by a rater who was blind to the PET data. [18F]FP-TZTP binding in cortical

D.F. Smith, S. Jakobsen brain regions and white matter was lower in bipolar depressed patients than in healthy subjects, but failed to differ between healthy subjects and depressed patients with recurrent major depressive disorder. The severity of depression in bipolar patients correlated negatively with the volume-of-distribution of [18F]FP-TZTP in several brain regions. In summary, [18F]FP-TZTP binding was reduced in patients with bipolar depressive disorder, and negatively correlated with depression severity.

8. Discussion The complexity of both depression and PET provide a series of challenges for studying molecular mechanisms of depressive disorders in the living brain. Depression continues to plague populations allover the world, causing major suffering and economic burden. Depression consists of a variety of symptoms including hopelessness, sleep disturbance, altered appetite, lack of energy, concentration difficulties, low self-esteem, selfdestructive behavior, painful bodily sensations, and suicidal ideation, with symptoms and severity differing from person-toperson. The complexity of depression warns against viewing it as a single disease with a single neuromolecular cause that can be identified by a single PET scan with a single radioligand that is highly selective for a single synaptic transporter or receptor. PET neuroimaging is a challenging technology. It requires rapid synthesis of highly-purified positron-emitting radioligands of high specific activity, intravenous injection of radioactive compound often with arterial blood sampling in partially immobilized subjects, 3-dimensional registration of photon emissions from the target organ over time, and computerized computations of kinetic parameters. The kinetic parameter used most often to describe the outcome of PET neuroimaging, namely the binding potential, is a complex entity composed of three factors: the number of receptors that are available for binding by the PET radioligand, the affinity of the available receptors toward the PET radioligand, and the concentration of molecules other than the PETradioligand that bind to those receptors (Dunlop and Nemeroff, 2007; Laruelle, 2000; Lammertsma, 2002). The binding potential is an estimate that reflects a series of molecular events, and its value depends on the kinetic model selected for the data analysis. The contribution of individual factors to the binding potential cannot be determined by the single-scan design used in most PETstudies of depression. Thus, the complexity of both depression and PETsets limits on the interpretation of findings. Serotonergic neurotransmission has received most attention in PET studies of depression. We find, however, that PET studies of depression have not provided consistent findings of a central defect of serotonergic neurotransmission. Ten PET studies published since the beginning of 2003 have used [11C]McNeil 5652 or [11C]DASB to assess the serotonin transporter in 181 medication-free depressed subjects and 266 healthy controls. Four of those studies noted less binding by the serotonin transporter in brain regions of depressed subjects (Miller et al., 2008; Oquendo et al., 2007; Parsey et al., 2006a; Reimold et al., 2008), four studies found more binding by the serotonin transporter in depressed subjects (Reivich et al., 2004; Cannon et al., 2006b; Cannon et al., 2007; Boileau et al., 2008), and two studies found no difference between depressed subjects and healthy controls in binding by serotonin transporters in brain

Molecular tools for assessing human depression by positron emission tomography regions (Meyer et al., 2004a; Bhagwagar et al., 2007). Similar inconsistencies derive from PET studies carried out since the beginning of 2003 using [11C]WAY-100635 or [18F]FCWAY to assess serotonin type 1A receptors in 197 medication-free depressed subjects and 173 healthy controls. Here, five studies noted less binding by serotonin type 1A receptors in brain regions of depressed subjects (Bhagwagar et al., 2004; Meltzer et al., 2004; Hirvonen et al., 2008; Drevets et al., 2007; Theodore et al., 2007), one study reported no difference between depressed subjects and healthy controls in binding by serotonin type 1A receptors (Mickey et al., 2008), while the largest study found more binding by serotonin type 1A receptors in brain regions of depressed subjects than of healthy controls (Parsey et al., 2006b). In addition, neither antidepressant treatment nor induction of depression by depletion of tryptophan affected binding by serotonin type 1A receptors in brain regions (MosesKolko et al., 2007; Praschak-Rieder et al., 2004). Such findings clearly challenge the notion that causal defects of either serotonin transporters or serotonin type 1A receptors can be detected reliably in depressed subjects by PET with available molecular tools (Drevets et al., 2007; Meyer, 2007). Serotonin type 2 receptors have also been studied by PET in recent years in relation to depressive disorders. Two closely-related studies used [18F]altanserin for PETand noted less hippocampal binding in medication-free depressed subjects than in healthy controls (Mintun et al., 2004; Sheline et al., 2004). In contrast, two other PET studies used either [11C]MDL 100,907 or [18F]setoperone to assess serotonin type 2 receptors and noted more binding in medicationfree depressive subjects than in healthy controls (Bhagwagar et al., 2006; Meyer et al., 2003). In our view, PET studies with the radioligands that are currently available for assessing serotonergic functions in the living human brain have failed to provide conclusive evidence for aberrant serotonergic mechanisms in depressive disorders. We have noted, however, that receptor occupancy of serotonin transporters can be assessed reliably by PETwith [11C]DASB or [11C]McNeil 5652 (Voineskos et al., 2007; Miller et al., 2008). Perhaps such studies can provide a means of determining whether treatment-resistance to certain antidepressant drugs stems from an inadequate blockade of central serotonin transporters. Dopaminergic neurotransmission is thought to play a role in depression, perhaps via defects in central reward systems (Randrup and Braestrup, 1977; Spanagel and Weiss, 1999). Several PET radioligands have been used in recent years for probing dopaminergic mechanisms in depressed humans. [18F] Fluoro-L-dopa is used routinely for assessing dopamine synthesis by PET in Parkinson's disease (Takikawa et al., 1994), and it showed reduced striatal uptake in depressed subjects with retarded movement (Bragulat et al., 2007). Certain dopamine receptors have also been examined by PET in recent years in depressed subjects. Dopamine D1 receptors were assessed by [11C]SCH 23,390 or [11C]NNC-112 in two PET studies of depression (Dougherty et al., 2006; Cannon et al., 2008), and both reports found less binding in striatal regions of depressed subjects than of healthy controls. Dopamine D2/3 receptors have been assessed in four PET studies using either [11C]raclopride or [11C]FLB 457 in 44 depressed subjects and 52 healthy controls; one study noted more striatal binding by dopamine D2/3 receptors in depressed subjects (Meyer et al., 2006b), another study found less dopamine D2/3 receptor binding in depression (Montgomery et al., 2007), and two other studies showed no

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difference between depressed and healthy subjects in dopamine D2/3 receptor binding in brain regions (Kuroda et al., 2006; Montgomery et al., 2007). The transport of dopamine as well as noradrenaline from the synaptic cleft into presynaptic terminals was assessed by PET using [11C]RTI-32 in 20 Parkinson patients, some of which were depressed (Remy et al., 2005). Less transporter binding was noted in brain regions of depressed Parkinson patients than of non-depressed patients with Parkinson's disease. In our view, a consistent picture of causal relationships between dopaminergic disturbances and depression has failed to appear from PET studies carried out with the positron-emitting radioligands that are currently available for use in humans, except perhaps for movement disorders of depressed subjects. Too few PET studies of histamine H1 receptors, MAO type A, and the muscarinic type 2 receptors have been done to determine whether [11C]doxepin, [11C] harmine and [18F]FP-TZTP can disclose causal relationships between aberrant neuronal functions and depressive disorders. In our view, PET studies with available molecular tools have neither proved nor refuted conclusively any aspect of the monoamine hypothesis of depression. Molecular tools currently available for PET neuroimaging in humans assess primarily the binding capacity of monoamine receptors and transporters located on the surface of membranes in the synaptic cleft. As a result, the focus of PETstudies of depression has been almost exclusively on various aspects of the monoamine hypothesis. Current notions on molecular mechanism in depression have, however, advanced far beyond postulates of the classical monoamine hypotheses (Schildkraut and Kety, 1967; Asberg et al., 1976; Meltzer and Lowy, 1987). Today, depression is viewed as the result of multiple neurobiologic processes including disturbances of gene expression, intracellular signaling, cytokines and neurotropic agents (Tanis and Duman, 2007; Berton and Nestler, 2006; Krishnan and Nestler, 2008; Maes, 2008). In our view, the future success of PET scanning in determining the role of neurobiological processes in depression will depend heavily on the invention of appropriate molecular tools, in the form of positron-emitting radioligands, for testing directly, in the living human brain, ever-changing hypotheses on causal connections between neuromolecular processes and the symptoms and severity of depressive disorders.

Role of the funding source The authors are employed by the regional government of Middle Jutland that provides the finances required by the hospital-health system. The authors declare that, except for income received from our primary employer, no financial support has been received for preparing this review.

Contributors Donald F. Smith and Steen Jakobsen

Conflict of interest The authors declare that, except for income received from our primary employer, no financial support has been received for the writing of this review.

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Acknowledgments We thank everybody at the Center for Psychiatric Research and the PET Center of Aarhus University for providing a positive atmosphere in which to work.

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