In Review

PET And SPECT Imaging in Psychiatric Disorders

Robert B Zipursky, MD, FRCPC1, Jeffrey H Meyer, MD, PhD, FRCPC2, N Paul Verhoeff, MD, PhD, FRCPC3
Objectives: To review recent findings from positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies that investigate the pathophysiology and treatment of schizophrenia, depression, and dementia. Methods: We carried out a review of the literature. Results: PET and SPECT studies have provided evidence of dopamine system dysregulation in patients with schizophrenia and variable loss of monoamines in patients with depression. Antipsychotic response has been demonstrated to be associated with blockade of dopamine D2 receptors, and antidepressant response has now been linked to blockade of serotonin transporter receptors. PET and SPECT have been extensively evaluated as diagnostic procedures for dementia. Substantial progress has been made in developing radioligands that bind to amyloid deposits in the brain, which should provide new opportunities for early diagnosis and treatment monitoring in Alzheimers disease. Conclusion: Advances in PET and SPECT imaging have provided new insights into the biology of major psychiatric disorders and their treatment. In the future, we can expect that these imaging techniques will become more central to the management of psychiatric disorders. (Can J Psychiatry 2007;52:146157) Information on funding and support and author affiliations appears at the end of the article.

Clinical Implications Antipsychotic dosing for most patients with schizophrenia can be expected to occur within a narrow range of D2 receptor blockade. Antidepressant response for most patients can be expected to occur with blockade of 80% or more of the serotonin transporter receptors. Imaging of cerebral glucose metabolism and perfusion has become an important tool in the diagnosis of AD. Future advances in the imaging of brain amyloid deposits will likely be of great clinical importance in the diagnosis and management of AD. Limitations It is not known why some patients with schizophrenia fail to respond to treatment, despite substantial D2 receptor blockade. Many cases of depression will not resolve, despite high levels of serotonin transporter receptor blockade. Larger-scale studies are required to establish whether new ligands for labelling amyloid deposits will have clinical utility in the early diagnosis of AD.

Key Words: positron emission tomography, single photon emission computed tomography, schizophrenia, depression, dementia, dopamine, serotonin, amyloid, antipsychotics, antidepressants

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he central focus of brain imaging research in psychiatry has been the elucidation of the brain mechanisms that underlie major psychiatric illness. With the advent of computer-based imaging modalities in the 1970s, it became possible to apply quantitative methods to investigate whether patients with different psychiatric disorders could be shown to differ in brain tissue and fluid volumes, as revealed by CT and MRI, or to differ in neuroreceptor density, as revealed by PET and SPECT. The clinical applications of brain imaging in psychiatry have for the most part been limited to the use of CT and MRI to rule out neurologic disorders in the differential diagnosis of major mental illnesses. Recent advances in neuroreceptor imaging have revealed new clues about the pathophysiology of psychiatric disease and have led to the development of research paradigms that warrant consideration as clinical tools in the future. This paper reviews progress in PET and SPECT imaging as it relates to 3 major psychiatric disorders: schizophrenia, depression, and dementia.

Schizophrenia
It is hoped that advances in understanding the neurobiological basis of schizophrenia will lead to improvements in treatment and, ultimately, in clinical outcomes. The advent of neuroreceptor imaging with PET and SPECT has provided a new opportunity to systematically investigate the biology of schizophrenia. New findings have influenced our understanding of schizophrenia and also our understanding of how treatments affect the illness. Investigating the Biology of Schizophrenia The dopamine hypothesis of schizophrenia has been the most influential theory advanced to explain the biology of schizophrenia. Until recently, the evidence supporting the dopamine hypothesis has been indirect: medications that share the ability to improve the psychotic symptoms of schizophrenia share the property of blocking dopamine D2 receptors, and drugs that increase dopamine levels (such as amphetamine and cocaine) can both provoke psychotic symptoms in otherwise healthy individuals and worsen psychotic symptoms in patients with schizophrenia. Postmortem studies have not consistently reported differences in dopamine levels or in dopamine receptor density. These studies are very much limited by postmortem methods and by the effects of chronic treatment. Neuroreceptor imaging with PET and SPECT has offered an important opportunity both to investigate the biology of schizophrenia unencumbered by medication effects and to understand the mechanism of action of antipsychotic medications. The most fundamental test of the dopamine hypothesis would involve determining whether schizophrenia patients with active psychosis have elevated levels of dopamine. It is now possible to address this question directly. Initial PET ligand studies of schizophrenia focused on determining whether patients with schizophrenia had increased numbers of dopamine receptors, which might then explain why their dopamine systems appeared to be overactive. Studies of nevermedicated schizophrenia patients, using the PET D2 ligand [11C]raclopride and N-[11C]methylspiperone and the SPECT ligand [123I]IBZM, have not yielded consistent results.1 Seeman et al proposed that the discrepant results could be explained by differences in the sensitivities of different ligands to the effects of endogenous dopamine.2,3 If endogenous dopamine competes with the radioligand for binding at the D2 receptors, then higher levels of dopamine will reduce the availability of binding sites for the ligand, especially for ligands that are more readily displaced by dopamine (such as [11C]raclopride), thereby reducing the estimate of total D2 receptor numbers. In this scenario, it may not be possible, with some radioligands, to identify whether patients with
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Abbreviations used in this article

[11C]DASB [11C]PIB [11C]N, N-dimethyl-2-(2-amino-4-cyanophenylthi) benzylamine [11C]2-(4-(methylaminophenyl)-6hydroxybenzothiazole. Also referred to as [11C]6-OH-BTA-1 [11C]4-N-methylamino-4-hydroxystilbene [123I]iodobenzamide [18F]2-(1-(6-[(2-fluoroethyl)methyl-amino]-2naphthyl)ethylidend)malononitrile [18F]fluorodeoxyglucose

[11C]SB-13 [123I]IBZM [18F]FDDNP [18F]FDG

[99mTc]HMPAO [99mTc]hexamethylpropyleneamine oxime 5-HT AD AMPT Ab CT FGA FLD GABA MCI MRI NFT PET SGA SPECT SSRI serotonin Alzheimers disease alpha-methyl-para-tyrosine b-amyloid computed tomography first-generation antipsychotic frontotemporal lobar degeneration gamma-aminobutyric acid mild cognitive impairment magnetic resonance imaging neurofibrillary tangle positron emission tomography second-generation antipsychotic single photon emission computed tomography selective serotonin reuptake inhibitor

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In Review

schizophrenia do have higher levels of dopamine receptors because higher levels of endogenous dopamine leave lower numbers of receptors available for the radioligand to bind. If this is the case, it should follow that: Administering drugs that increase levels of endogenous dopamine should result in a reduction in the number of receptors bound to the radiotracer ligand.
Removing endogenous dopamine is necessary to

accurately estimate total D2 receptor numbers in patients with schizophrenia.

Determining whether endogenous dopamine levels are

elevated in schizophrenia should be possible because measurements of D2 receptor density should be proportional to the concentration of endogenous dopamine.46 Using this displacement principle, studies by Laruelle et al4 and Breier et al5 demonstrated that, when unmedicated schizophrenia patients were given amphetamine, which is known to cause release of dopamine presynaptically, they were observed to have greater average decreases in D2specific ligand binding, compared with control subjects. These findings suggest that patients with schizophrenia may be on average more sensitive to the dopamine-releasing effects of amphetamine. Abi-Dargham et al6 extended this finding by administering the tyrosine hydroxylase inhibitor AMPT to deplete dopamine prior to estimating D2 receptor density in schizophrenia patients and control subjects with the SPECT tracer [123I]IBZM. Abi-Dargham et al reported that D2 receptor availability increased after AMPT administration and was greater in patients than in control subjects after dopamine was depleted, but not before. That is, following dopamine depletion, the number of receptors available to be quantified with the radioligand was greater in patients with schizophrenia, consistent with the hypothesis that these patients have higher levels of dopamine. AMPT administration led to a reduction in positive symptoms, with higher levels of synaptic dopamine prior to treatment predicting symptom improvement with AMPT. Further, higher levels of intrasynaptic dopamine at baseline predicted that positive symptoms would respond to 6 weeks of treatment with risperidone. Taken together, these studies suggest that patients with schizophrenia have higher levels of intrasynaptic dopamine, that they are more sensitive to the dopamine-releasing properties of drugs such as amphetamine, and that higher levels of dopamine are associated with more severe psychotic symptoms and with greater positive s ymp to m imp r o v e men t w ith d o p a min e - b lo c k in g medications. Laruelle has demonstrated that both drug-free and drug-naive patients show greater dopamine release than control subjects in response to an amphetamine challenge.7 However, patients
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who were scanned while in remission did not have increased sensitivity to amphetamine, whereas those who were relapsed and were acutely ill did. These findings suggest that the increased sensitivity of the dopamine system in schizophrenia patients is malleable and may reflect either the relapsed state or, perhaps, risk for relapse. PET studies have also revealed that cocaine, cannabis, and stress can increase dopamine levels.810 Older literature has demonstrated that patients whose s ymp to ms w o r s e n e d f o llo w in g a mp h e tamin e o r methylphenidate administration were more likely to relapse over time, compared with patients whose symptoms did not worsen.11,12 Taken together, evidence to date suggests that patients suffering from psychosis or at high risk for relapse have hypersensitive dopamine systems that may be particularly vulnerable to the dopamine-releasing effects of illicit drugs and stress. The Mechanism of Action of Antipsychotic Medications If psychosis is associated with an overactive and oversensitive dopamine system, how then do antipsychotic medications act to resolve psychotic symptoms? Early PET studies clearly demonstrated that clinical dosages of antipsychotic medications block D2 receptors.13 A question of immediate clinical relevance is whether poor response to treatment can be explained by inadequate blockade of D2 receptors. Wolkin et al14 clearly demonstrated that patients with chronic schizophrenia who failed to respond to treatment with very substantial dosages of haloperidol had high levels of D2 receptor occupancies that were comparable to those observed in treatment responders. This work clearly demonstrated that poor response in patients receiving high dosages of antipsychotic medication could not be explained by failure of the medication to bind brain dopamine receptors at adequate levels. The demonstration of poor response with high levels of D2 occupancy does not preclude the possibility that, in those patients who do respond well, there might be an important relation between the degree of occupancy and the degree of improvement. Farde demonstrated that treatment of schizophrenia patients with a range of antipsychotic medications resulted in blockade of 65% to 90% of striatal D2 receptors13,15 and that patients with acute extrapyramidal symptoms had higher levels of D2 receptor occupancy.15 Although it was clear that clinical dosages of all FGAs resulted in blockade of a substantial percentage of D2 receptors, it was not known whether a threshold level of blockade would be sufficient for antipsychotic action. In our studies at the University of Toronto of patients with a first episode of psychosis, we were struck by the marked response of many patients to low dosages of haloperidol that generally resulted in plasma haloperidol levels below the accepted therapeutic range.16 This finding was consistent with
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earlier clinical work by McEvoy et al17 but could not be directly related to the emerging PET literature on antipsychotics. Using PET with [11C]raclopride, we were able to demonstrate that haloperidol dosages of 2 mg daily led to D2 occupancy of 53% to 74% as well as to clinical response in some patients.18 We subsequently carried out a study in which we randomized first-episode psychosis patients to either 1 mg or 2.5 mg daily of haloperidol and calculated D2 occupancy.19 At these dosages, D2 occupancy varied from 38% to 87%, as measured after 2 weeks of treatment. Clinical response was more likely to be observed with D2 occupancies of 65% or greater, whereas hyperprolactinemia and exprapyramidal symptoms were more likely to occur with occupancies greater than 72% and 78%, respectively. These findings established that low dosages of the FGA haloperidol not only led to clinical response but also did so by achieving very substantial levels of D2 occupancy despite the low dosages. These studies also clearly demonstrated that levels of D2 receptor occupancy associated with clinical response can be achieved with dosages of FGAs that are in some cases only 5% to 10% of those used in common clinical practice. These clinical PET studies have also helped us to appreciate that small increases in the dosage of these medications have the potential to move patients into a D2 occupancy range associated with both hyperprolactinemia and extrapyramidal symptoms. As it was becoming clear that haloperidol and other FGAs were being dosed at levels that result in much higher levels of D2 occupancy than is necessary to achieve a therapeutic response, new SGAs were being introduced with the promise of greater tolerability and efficacy. In particular, clozapine emerged as a treatment with increased efficacy for those who respond poorly to other medications. A central motivating question for a great deal of PET research in schizophrenia has involved investigating the mechanisms that underlie clozapines superior efficacy. Three main hypotheses have been proposed to account for the superiority of clozapine, each of which is predicated on a body of clinical PET and SPECT research: 5-HT2D2, loose binding, and regional specificity.20 When the SGAs were introduced in the 1990s, it was thought that they were distinguishable from FGAs by a higher ratio of 5-HT2 receptor binding affinity, relative to their D2 binding affinity. While debate on this issue continues, it would seem unlikely that this feature alone explains the superiority of clozapine because other SGAs such as olanzapine would provide a similar ratio of 5-HT2 and D2 receptor occupancy at dosages below the accepted clinical dosage range for olanzapine.20,21 If SGAs are not distinguished by their 5-HT2D2 binding profile, then the question arises of whether it might be the quality of the D 2 binding itself that is different. Farde et al 15 had
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demonstrated that therapeutic dosages of clozapine resulted in lower levels of D2 occupancy, in the range of 38% to 63%. PET studies, however, revealed that both risperidone and olanzapine in clinical dosages lead to levels of D2 occupancy that are comparable to those observed with low dosages of FGAs.22 More recently, ziprasidone has been demonstrated to result in similar levels of D2 occupancy.23 The long-acting injectable form of risperidone has also recently been demonstrated to result in pre- and postinjection levels of D2 occupancy in the range of 50% to 80%.24 Notably, when the SGAs were initially introduced, the evidence for their superiority was established by comparing them with dosages of haloperidol (10 to 20 mg daily) that were considered standard at the time but clearly led to much higher levels of D2 occupancy. Recent studies have confirmed that, at least in the domain of symptom improvement, risperidone and olanzapine are not more effective than FGAs if the comparisons are carried out at dosages that lead to comparable levels of D2 occupancy.2527 Although olanzapine, risperidone, and ziprasidone occupy D2 receptors to the same degree as FGAs in clinically prescribed dosages, this does not appear to be the case for clozapine or quetiapine. Both of these drugs have been reported to result in much lower levels of D2 occupancy,15,22 again raising the question of whether their mechanisms of action differ. Quetiapine has been shown to occupy less than 30% of D2 receptors, as assessed 12 hours postdose; however, occupancy seems to peak in the 60% range in the first few hours following the dose.28 This PET observation has led Kapur and Seeman29 to suggest that SGAs may be characterized by a faster dissociation from the D2 receptor, referred to as loose binding. Whether this underlies the greater tolerability of some SGAs or, in the case of clozapine, its superiority for treatment-resistant cases remains a matter of debate. What does seem clear from these PET studies is that continuous high levels of binding of the antipsychotic at the D2 receptor are not required for ongoing antipsychotic efficacy. This is in keeping with the PET observation that D2 receptor occupancies may dip very low (20%) over the course of the month-long injection cycle in patients stabilized on haloperidol decanoate, the long-acting injectable formulation of haloperidol.30 This is also consistent with the observation that remitted patients who discontinue their medications are not expected to relapse once there is no further binding of the drug left at the D2 receptors; rather, it may take 8 months on average for symptoms to recur.31 Taken together, findings from PET research suggest that D2 occupancy levels of 50% to 70% may be required to bring about an antipsychotic response but that this occupancy level may not need to be sustained throughout the day. Rather, this occupancy level may only need to be reached intermittently (as in the case of clozapine
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In Review

and quetiapine). Now that standard clinical practice involves the use of much lower dosages of antipsychotics than were in common practice even a decade ago, it is questionable whether there is any role for dosage reduction in the maintenance phase. It may be more important to dose antipsychotics during the maintenance phase in a way that ensures that D2 occupancies reach over 50% intermittently. What remains to be precisely determined is how much occupancy is required, for how long, or over what intervals. Optimizing Dopamine Activity It would of course be most conservative to ensure that patients with schizophrenia be maintained on dosages of antipsychotic medications that continuously bind to D2 receptors at moderately high levels. However, it is also possible that the superiority of medications such as clozapine may in part be related to their more intermittent occupancy. Laruelle et al32 have estimated, from the observed degree of elevation of synaptic dopamine levels in neuroleptic-naive patients, that antipsychotic medications would need to occupy 48% of the D2 receptors to normalize dopamine transmission.32 That patients are generally treated with dosages of medication that result in 60% to 80% D2 receptor blockade (and higher with standard dosing of FGAs) means that their dopamine tone is being maintained at lower levels than would be seen in healthy individuals. It has been suggested that ongoing dopamine receptor blockade and reduced dopamine tone may contribute to the dysphoria, secondary negative symptoms, and depression experienced by some patients even in the absence of extrapyramidal symptoms.33,34 DeHaan et al35 have also suggested that higher levels of D2 receptor occupancy are associated with increased cigarette consumption in patients with schizophreniathe implication being that those treated with higher dosages are using nicotine to overcome the reduced dopamine tone. One possible implication of this work might be that using medications that result in lower D2 receptor blockade or more intermittent blockade may help efforts to reduce smoking in patients with schizophrenia. The clinical relevance remains to be established. However, it does seem to be that in clinical practice there may well be a trade-off between blocking enough D 2 receptors to ensure an antipsychotic response and blocking so many that subjective experience and functioning may be negatively affected. It is possible that the advent of new antipsychotics that act as partial agonists may offer a better approach to achieving substantial D2 receptor occupancy with a lesser impact on subjective well-being.36 The application of PET and SPECT to the study of schizophrenia has provided new opportunities to explore how symptoms, clinical response, and medication side effects may be related to different neurotransmitter systems. In addition, it is possible that different antipsychotic medications exert their
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effects in different brain areas, which could potentially explain any differences in efficacy for different symptom clusters. There has been much interest in the possibility that SGAs may bind preferentially in limbic regions of the brain. Although several SPECT studies have suggested that this is the case,37,38 recent PET findings have failed to replicate this.39 PET and SPECT radioligand research to date has provided evidence that patients with schizophrenia have a modest increase in D2 receptor numbers and a substantial increase in endogenous dopamine and that intermittent blockade of D2 receptors is necessary to bring about antipsychotic response. Further work is required to determine what levels of occupancy are required and for what amount of time, why a minority of patients fail to respond well despite substantial D2 occupancy, and how other domains of symptomatology may relate to medication binding at dopamine and nondopamine neuroreceptors.

Depression
New ligand technology is rapidly having an impact on our understanding of major depressive disorder and antidepressant effects.4047 This information can influence how one views treatment targets and how antidepressants are prescribed in clinical practice. Investigating the Biology of Depression Evidence is accumulating that there is a variable loss of monoamines in major depressive disorder across different subjects and that those patients with more severe depressive symptoms have a greater degree of monoamine loss.44 This differs from the original monoamine theory proposing that all 3 monoamines (serotonin, norepinephrine, and dopamine) are similarly low across individuals with major depressive disorder.48 Were the original monoamine theory true, one would expect increased 5-HT2 receptor density in untreated subjects with depression because 5-HT 2 density increases when extracellular 5-HT is low. There are 2 PET studies of 5-HT2A receptors in untreated subjects suffering from depression.49,50 Both have substantial sample sizes, and both find no difference during depressive episodes. However, it is of interest that in depression patients with more severe pessimism, higher 5-HT2A binding potential (an index of 5-HT2A density) has been found.51 This relation between 5-HT2A binding potential and pessimism (dysfunctional attitudes) has also been replicated.51,52 A plausible explanation for this finding is that low extracellular 5-HT contributes to the intensity of pessimism, which is consistent with the evidence that serotonin has a role in modulating pessimism in humans. Fenfluramine, a serotonin-raising medication, is reported to abruptly lower
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pessimism.51 These findings suggest that particular symptoms of depression, rather than the diagnosis of depression per se, reflect lowered levels of different mononamines in the brain. As described for the study of schizophrenia above, [11C]raclopride PET measures the D2 receptor binding potential in the striatum, and this measure increases when extracellular dopamine is low.53 D2 receptor binding potential in unmedicated depression patients47 has been found to be elevated during major depressive episodes, most prominently when motor slowing was present.47 This finding may be interpreted as providing support for the view that dopamine levels may be lowered during depressive episodes, which may account for the intensity of motor slowing.47 Such an interpretation is consistent with the known role of dopamine in modulating motor speed in Parkinsons disease and with previous findings of lower dopamine metabolites in depression patients with more severe motor retardation.5456 Evidence from PET studies also provides support for the notion that the 5-HT transporter and the dopamine transporter may have a role in contributing to monoamine removal during untreated major depressive episodes, thereby contributing to symptoms. For example, regional 5-HT transporter binding potentials are higher during depressive episodes with more severe pessimism, and regional dopamine transporter binding potential is higher when motor retardation is more severe.57,58 It is well known that these transport sites remove their respective monoamines from functionally relevant extracellular locations,59,60 so these results may be interpreted to argue that greater monoamine transporter density facilitates monoamine loss, which in turn contributes to greater severity of depressive symptoms. The Mechanism of Action of Antidepressant Medications Advances in receptor ligand technology, particularly for the 5-HT transporter with [11C]DASB PET, have made it possible to quantify more precisely the degree to which commonly prescribed antidepressant medications bind to the transporter at different dosages.45,46 A comparison of 5-HT transporter methods has been reviewed previously.61 The 5-HT transporter is a 630 amino acid long receptor.62,63 Most 5-HT transporters are located at outer cell membranes, either perisynaptically or along axons.64 In humans, the density of 5-HT transporter varies by region: Superior and inferior raphe nuclei > hypothalamus > thalamus (depending on nucleus) . amygdala > putamen > caudate . hippocampus > insular cortex > prefrontal cortex > white matter > cerebellar cortex (except vermis).6567 The pertinent physiological role of the 5-HT transporter in major depressive disorder and antidepressant treatment is its removal of extracellular 5-HT. Antidepressants which bind to the 5-HT transporter raise extracellular 5-HT.59,68,69
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The first SSRI occupancy study with [11C]DASB PET reported an 80% occupancy in multiple regions after 4 weeks of paroxetine at 20 mg daily and citalopram at 20 mg daily.45 Subsequently, this occupancy level has been replicated with fluvoxamine, 70 as well as fluoxetine, sertraline, and venlafaxine,46 at SSRI dosages known to have clinical effects that distinguish them from placebo (see Figure 1). This 80% striatal 5-HT transporter occupancy occurs at minimum clinical dosages despite the hundredfold range in affinity of the 5 SSRIs for the 5-HT transporter.46 These results demonstrate that, although affinity is an important property of a drug, it cannot predict occupancy, even when plasma levels are known.46 The ability of antidepressant medications to cross the bloodbrain barrier and be absorbed in the brain must also be considered in antidepressant development. Given the association between the clinically relevant dosage and 5-HT transporter occupancy for all SSRIs, it is now generally believed that an 80% 5-HT transporter occupancy with an SSRI is the therapeutically useful threshold. Consequently, for development of antidepressants with 5-HT transporter binding, an 80% 5-HT transporter occupancy is viewed as optimal for first-line treatment. The second [11C]DASB PET occupancy study46 also studied the relation between 5-HT transporter occupancy and plasma level for 5 commonly prescribed SSRIs. Occupancy increased with increasing plasma levels, and occupancy plateaued at the higher doses and higher plasma levels. An important result of this study was that dosage and, especially, plasma level were very strongly associated with 5-HT transporter occupancy. Therefore, if one wishes to estimate 5-HT transporter occupancy during clinical treatment, one need not complete a 5-HT transporter imaging study; rather, one can use the plasma level and the published table to estimate whether the 5-HT transporter occupancy of any SSRI46 is at a level associated with clinical response. Another important result of the [11C]DASB PET studies46 is that the 5-HT transporter occupancy did not exceed 90% for any of the SSRIs. This raises the possibility of a gap in current therapeutic development because no available SSRIs result in very high levels of 5-HT transporter occupancy. Conversely, PET has shown that clomipramine leads to close to 100% 5-HT transporter occupancy in the clinical dosing range,70 suggesting that clomipramine may lead to higher 5-HT transporter occupancies than can be achieved with any of the SSRIs. This finding may underlie the clinical preference for clomipramine or high-dosage SSRIs in the treatment of obsessivecompulsive disorder 71 (for which greater 5-HT transporter occupancy is preferred). One available antidepressant medication, bupropion, is known to be a dopamine reuptake inhibitor. However, the
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affinity of bupropion for the dopamine transporter is quite low (0% to 25 % occupancy of the dopamine transporter).7274 As a result, there is a therapeutic gap in available dopamine transporter reuptake inhibitors because buproprion is unlikely to have optimal dopamine transporterblocking properties. Clinical Implications Receptor ligand imaging has not only informed us about mechanisms that may underlie major depression and its symptoms, it has also provided clinically relevant information that bears on how antidepressant medications should be prescribed. Current evidence suggests that SSRIs should be dosed to achieve 5-HT transporter occupancy of at least 80%. For example, our data suggest that sertraline, which is now available in a 25-mg preparation, is unlikely to result in a level of 5-HT transporter occupancy that will be optimally effective.46 If a patient fails to respond to a standard dosage of an SSRI, the next antidepressant options should be a high-dose SSRI rather than another SSRI at minimum clinical dosage, that is, the dosage that distinguishes from placebo. Since all the SSRIs have similar 5-HT transporter blockade at minimum clinical dosage,45,46 simply switching to another SSRI at the same dosage is a fairly similar strategy. If a high-dose SSRI does not achieve response, the next antidepressant option should be a switch to another class of medication (rather than another high-dose SSRI). If there is heterogeneity of monoamine loss 44 and if monoamine loss is one of the targets of treatment, then failure to respond to an SSRI may be due to inadequate targeting of other monoamines that are possibly affected in an individuals depressive episode. Switching classes would be a way to target alternative monoamines. Dopamine transporters are not optimally targeted with bupropion, so it may be better to increase dopamine by inhibiting monoamine oxidase A.75,76 If a 5-HT reuptake inhibitor has been helpful but leads to only a partial response, targeting 5-HT reuptake more aggressively with clomipramine may be of value because it should result in higher 5-HT transporter occupancy. 70

FLD syndromes. Because dementia syndromes have distinctive natural histories, precise diagnosis can lead to a better understanding of prognosis, which is essential for counselling patients, their families, and other caregivers. PET and SPECT imaging will likely have an increasingly important role in the assessment and management of dementia syndromes. Given the increasing number of individuals who suffer from AD, improving early detection of the condition and studying the effects of new treatments for it are of critical importance. Studies examining long-term effects of acetylcholinesterase inhibitors indicate that, on average, medication treatment delays cognitive decline in AD patients by 9 to 12 months and the need for institutionalization by 18 months.8185 Moreover, in trials with rivastigmine,86 galantamine,87 and donepezil,88 better cognitive performance was seen at 1 year in patients who began acetylcholinesterase inhibitor treatment at the start, compared with those who began 6 months after the start of the trial. With the advent of new treatments for AD, early assessment and diagnosis are becoming increasingly important. Functional neuroimaging will very likely be critical to these efforts. Glucose Metabolism PET and Perfusion SPECT The clinical assessment of older patients presenting with cognitive decline includes a comprehensive medical history, physical examination, neurologic examination, neuropsychological testing, laboratory testing, and structural neuroimaging. With this approach, it can be expected that AD can be diagnosed with a sensitivity of 83% to 85%, a specificity of 50% to 55%, and an overall accuracy of 69%. Functional nuclear imaging of cerebral glucose metabolism or blood flow can especially improve the specificity of the clinical assessment for early dementia. Glucose metabolism is measured with [18F]FDG PET. The characteristic pattern for AD includes early uptake deficits in parietal, temporal, and posterior cingulate association cortices, with relative sparing of primary sensorimotor and primary visual cortices and with sparing of subcortical structures such as the striatum, thalamus, and cerebellum.89 Studies comparing [18F]FDG PET with neuropathological examination showed a sensitivity of 88% to 94% and a specificity of 63% to 73% for detecting AD. 8 9 Reviews that included studies lacking neuropathological confirmation reported a sensitivity of 90% to 96%, a specificity of 67% to 97%, and a diagnostic accuracy of 86% to 100% for [18F]FDG PET detection of AD.90,91 A review of pathological verification studies suggests that clinical criteria may be more sensitive in detecting AD than [99mTc]HMPAO brain perfusion SPECT (81%, compared with 74%, respectively) but that [99mTc]HMPAO SPECT was more specific than clinical criteria in discriminating AD from other types of dementia (91%, compared with 70%, respectively).92 The combination of SPECT findings positive for
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Dementia
Dementing illness is common in older adults, affecting 6% to 8% of individuals older than 65 years. Prevalence increases with advancing age, and among individuals older than 85 years the prevalence rate exceeds 30%.77 AD78 is the leading neurodegenerative disorder, accounting for about one-third to two-thirds of dementia cases.77,79 Vascular dementia80 appears to be the second most common syndrome, followed by Lewy Body dementia, Parkinsons disease, and several
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temporoparietal hypoperfusion and a clinical diagnosis of probable or possible AD has been associated with the highest levels of sensitivity (> 95%) and specificity (> 80%).93 In general, the magnitude of hypometabolism seen with [18F]FDG PET in AD is greater than the magnitude of hypoperfusion seen with SPECT.89 Comparative studies suggest an increased accuracy of 15% to 20% for [18F]FDG PET, compared with perfusion SPECT.9497 However, it should be noted that the utility of both PET and SPECT can be influenced by factors such as the spatial resolution and count rate sensitivity of the scanners, as well as by other instrumentation parameters, acquisition and processing techniques (including corrections for attenuation and atrophy), methods and quality of image display, data analysis (including visual, region of interest, or voxel-based methods), the interpretive criteria used, and the experience of the interpreters with each modality.89,98 Specific Ligands for Imaging A Plaques Although the specificity of the clinical evaluation for AD can be improved with glucose metabolism PET or perfusion SPECT, further improvements can be expected from in vivo imaging of the pathological processes considered to be more specific for AD: intraneuronal NFTs,99101 extraneuronal A plaques,102,103 and interneuronal synapse loss.104,105 To our knowledge, no NFT-specific tracers have been developed for in vivo imaging. The first successful in vivo attempt to image A plaques in the brains of AD patients used PET and the malononitrile derivative [18F]FDDNP to specifically label amyloid deposits in 9 AD patients and 7 comparison subjects.106 The area of highest r e t e n t i o n at eq u i l i b r i u m w a s th e h i p p o c a mp u s amygdalaentorhinal cortex region, where NFTs are mainly concentrated postmortem.99 In contrast, autopsy studies107 have shown that dense core (or neuritic) A plaques are more densely concentrated in the lateral temporal and occipital lobes, whereas limbic areas, including the hippocampus amygdalaentorhinal cortex region, contain the fewest dense core A plaques. Therefore, it has been hypothesized that [18F]FDDNP may be an in vivo marker for NFTs as well as for diffuse and dense core A plaques.108 If this hypothesis is correct, it could increase the potential ability of this tracer to detect AD presymptomatically, but it also suggests that [18F]FDDNP is not solely an A-specific radiotracer, complicating its use in monitoring the effectiveness of A-reducing medication. The second successful in vivo attempt to image A plaques in the brain of AD patients used the benzothiazole aniline derivative [11C]PIB, which has been reported to bind specifically to fibrillar A at tracer concentrations in vivo.109 Compared with control subjects, AD patients typically showed marked
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retention of [11C]PIB in areas of association cortex known to contain large amounts of amyloid deposits in AD. In the AD patient group, [11C]PIB retention was increased most prominently in the frontal cortex. Large increases were also observed in the parietal, temporal, and occipital cortices, as well as in the striatum. [11C]PIB retention was equivalent in AD patients and comparison subjects in areas known to be relatively unaffected by amyloid deposition (such as the subcortical white matter, pons, and cerebellum). A significant negative correlation between [18F]FDG and [11C]PIB retention was observed in the parietal but not in the frontal cortex at both the initial and 2-year follow-up evaluations.110 This is interesting because in vitro studies have suggested that the neurotoxicity of fibrillar A is related to impaired glucose transport111 and is enhanced under conditions of reduced glucose metabolism.112 The third successful in vivo attempt to image A plaques in the brains of AD patients compared the novel stilbene derivative [11C]SB-13 with [11C]PIB in 5 female AD patients and 6 matched healthy control subjects.113 The 2 radiotracers demonstrated similar binding properties with respect to regional distribution of retention (increased retention in the frontal and posterior temporalinferior parietal association cortices in the AD patients, but not in the control subjects). The data indicated that [11C]SB-13 may be similar to [11C]PIB in discriminating AD patients from healthy control subjects. Because cerebral fibrillar A deposition may occur decades before the manifestation of the clinical AD syndrome,103,114 imaging of this pathology in vivo may make early detection possible, allowing new medications developed to prevent A accumulation to be used. A syndrome of amnestic MCI has been identified that is associated with an increased risk of progression to AD (subjects with MCI havedepending on the definition and group from which they have been recruitedan annual incidence of about 12% of progressing to AD, in contrast to 1% to 2% for cognitively normal subjects from the same community).115 One [11C]PIB PET follow-up study has shown a relatively stable [11C]PIB uptake over 2 years in patients with mild AD,110 with amnestic MCI subjects as a group having [18F]FDDNP uptake ranging between the groups of cognitively normal subjects and patients with mild AD.116 Some amnestic MCI subjects already had an increased [11C]PIB uptake comparable to that in patients with mild AD,117 suggesting that these A aggregationinhibiting treatments may be the most effective at earlier stages, that is, as preventative rather than curative therapies. For these preventive therapies to be fully effective, therefore, subjects at risk may have to be identified at a stage even prior to amnestic MCI. A marked reduction of synaptic density in AD has been reported to correlate better with the degree of dementia than
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the classic neuropathological features such as brain atrophy, NFTs, A plaques, loss of neurons, and loss of dendritic arborizations.104 It may be that efforts to image synaptic density have greater clinical potential than approaches targeting NFTs and A plaques. In 6 patients with probable AD, SPECT with the benzodiazepine receptor radioligand [123I]iomazenil showed a reduced estimated benzodiazepine receptor distribution volume in all cortical regions except for the occipital cortex, compared with 5 age-matched control subjects.118 Since the GABAergic system is the major inhibitory synaptic system in the brain, [123I]iomazenil SPECT might provide more clinically relevant information that better reflects synaptic loss and, hence, functional loss in AD.118 Thus benzodiazepine receptor imaging may be more sensitive to detect lesions in AD than cerebral blood flow imaging and might reveal pathophysiological aspects directly related to the severity of cognitive impairment. However, the relation between synapse loss and benzodiazepine receptor reductions has not been firmly established, and more research will need to be done in this area to confirm these preliminary findings. In the future, nuclear imaging could play a role in increasing the specificity of the differential diagnosis of dementia by more specifically targeting molecules involved in the underlying neuropathology in vivo of different dementia syndromes. For example, radiotracers specific for NFTs and for different conformations of tau proteins could help differentiate AD from other tauopathies underlying some of the FLD syndromes.101,119 As the number of people who are entering the age of risk for dementia increases, it will become increasingly important to have accurate methods for making diagnoses and for monitoring the effects of therapy. Radioligand imaging is poised to play a critical role in this effort.

Health Foundation. Dr Verhoeffs research was supported by the Alzheimer Society of Canada, the Alzheimer Society of Saskatchewan, the Alzheimers Association, the Canadian Institutes of Health Research, and the Scottish Rite Charitable Foundation of Canada.

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Summary
PET and SPECT imaging have provided us with new approaches for investigating the pathophysiology of major mental disorders, including schizophrenia, depression, and dementia. Over the past decade, new research using these technologies has had a direct clinical impact on the pharmacologic management of both schizophrenia and depression as well as on the diagnosis of AD. We can expect that our understanding of other mental disorders will also be informed by the application of these imaging techniques and that they will one day assume an important role in our care of patients with psychiatric disorders.
Funding and Support Dr Zipurskys work was supported by the Tapscott Chair in Schizophrenia Studies at the University of Toronto, the Canadian Institutes of Health Research, Eli Lilly Canada Inc, and Astra Zeneca Canada. Dr Meyers research was supported by the Canadian Institutes of Health Research and the Ontario Mental
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Manuscript received and accepted November 2006. 1 Professor and Morgan Firestone Chair in Psychiatry, Department of Psychiatry and Behavioural Neurosciences, Michael G DeGroote School of Medicine, McMaster University, Hamilton, Ontario; Chief of Psychiatry, St Josephs Healthcare (Hamilton) and Hamilton Health Sciences, Hamilton, Ontario. 2 Associate Professor, Department of Psychiatry, Faculty of Health Sciences, University of Toronto, Toronto, Ontario; Staff psychiatrist, Mood and Anxiety Program, Centre for Addiction and Mental Health, Toronto, Ontario. 3 Associate Professor, Department of Psychiatry, Faculty of Health Sciences, University of Toronto, Toronto, Ontario; Clinical Research Scientist, Kunin-Lunenfeld Applied Research Unit, Baycrest Centre for Geriatric Care, Toronto, Ontario. Address for correspondence: DR RB Zipursky, Department of Psychiatry, St Josephs Healthcare (Hamilton), 50 Charlton Ave E, Fontbonne Bldg Rm F442, Hamilton, ON L8N 4A6; zipursky@mcmaster.ca

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W La Revue canadienne de psychiatrie, vol 52, no 3, mars 2007

PET And SPECT Imaging in Psychiatric Disorders

Rsum : Limagerie TEP et TMPE des troubles psychiatriques

Objectifs : Examiner les rcents rsultats dtudes de tomographie par mission de positons (TEP) et de tomographie monophotonique dmission (TMPE) qui portent sur la pathophysiologie et le traitement de la schizophrnie, de la dpression et de la dmence. Mthodes : Nous avons men un examen de la documentation. Rsultats : Les tudes de TEP et de TMPE ont fourni des preuves de la drgulation du systme de la dopamine chez les patients souffrant de schizophrnie et dune perte variable de monoamines chez ceux souffrant de dpression. La rponse aux antipsychotiques a t associe au blocage des rcepteurs de la dopamine D2 tandis que la rponse aux antidpresseurs a maintenant t lie au blocage des rcepteurs transporteurs de srotonine. La TEP et la TMPE ont t largement values comme procdures diagnostiques de la dmence. Des progrs substantiels sont survenus dans le dveloppement de ligands radioactifs qui se lient aux dpts amylodes du cerveau, ce qui devrait ouvrir de nouvelles possibilits au diagnostic prcoce et au suivi du traitement de la maladie dAlzheimer. Conclusion : Les progrs de limagerie de TEP et de TMPE ont apport de nouvelles ides de la biologie des principaux troubles psychiatriques et de leur traitement. lavenir, on peut sattendre ce que ces techniques dimagerie occupent le centre de la prise en charge de ces troubles psychiatriques.

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