9.1. OVERVIEW OF NEUROIMAGING STRATEGIES

Neuroimaging methods provide a great opportunity to improve our understanding of the pathway between adverse environmental conditions and suicide (see Figure 9.1). Since neuroimaging is completed in vivo, it is tailored to investigate the intermediary links between neuropathology and the symptoms or traits associated with suicide since such symptoms and traits may be measured at the time of brain scanning. As well, links between environmental conditions and neuropathology associated with suicide may be investigated since neuroimaging may be conducted during different environmental conditions.

FIGURE 9.1

The strength of neuroimaging methods is to elucidate steps as outlined in the above diagram. In vivo imaging offers the opportunity to link environmental conditions with biomarker changes and in turn link these biomarkers with symptoms or traits implicated (more...)

In this chapter, the neurobiological targets related to suicide presented include serotonin 5-HT_2A receptors, serotonin transporters (5-HTT), monoamine oxidase A, D₂ receptor binding, and μ-opioid receptors. Recent discoveries in the area of 5-HT_2A receptor, serotonin transporter, and MAO-A imaging have led to a pathophysiological understanding for the mechanism of pessimism in major depressive disorder (MDD). Neuroimaging of MAO-A, D₂ and μ-opioid imaging are leading toward better understanding of mechanisms of impulsivity. An important ongoing direction is determining how environmental conditions lead to alterations in brain neurochemistry that can increase the risk for suicide and this will be illustrated in an example of neuroimaging MAO-A in early postpartum.

9.2. 5-HT_2ARECEPTORS AND SUICIDE

9.2.2. Greater Prefrontal Cortex 5-HT_2a Binding: A Diagnostic and Symptom-Specific Finding

If one examines the list of neuroimaging studies of 5-HT_2A receptors that purely compare depressed and healthy samples as found in Table 9.1, they appear to contradict postmortem findings as many of these between-group comparisons reported a regional decrease in 5-HT_2A binding. The discrepancy can be resolved substantially through the observation that studies in which subjects recently received selective serotonin reuptake inhibitor (SSRI) treatment usually report decreased regional 5-HT_2A receptor binding.^{18–20,23,26,29,30} Since the initial studies in the field sampled people with recent antidepressant treatment, the initial impression derived from this work was that regional 5-HT_2A binding tended to be reduced in MDD.

TABLE 9.1

Imaging Studies of 5-HT_2A Receptors in Major Depressive Disorder.

However, the first two studies not sampling subjects who recently had antidepressant treatment found no difference between depressed and healthy subjects.^21,22 The first study of medication-free subjects by Meyer et al. applied [¹⁸F]setoperone. [¹⁸F] Setoperone is a very good radioligand for imaging 5-HT_2A receptors owing to its specific binding in cortex, reversibility, and favorable ratio of specific binding to free and nonspecific binding^31–35 (see Meyer for a review of neuroimaging radioligands that bind to 5-HT_2A receptor²⁸). The study by Meyer et al. sampled medication-free (>6 months) subjects in the midst of a major depressive episode (MDE) from early onset MDD. Subjects also had no comorbid psychiatric illnesses. No difference in prefrontal cortex 5-HT_2A binding was found as compared to healthy controls.²¹ The second study of medication-free subjects applied [¹⁸F]altanserin positron emission tomography (PET) in older depressed subjects and found no difference in 5-HT_2A binding between patients and healthy controls.²² [¹⁸F]Altanserin is a reasonable technique as it has high specific binding ratio but there are radioactive metabolites that cross the blood–brain barrier, so groups that use this technique currently apply it with a bolus plus infusion approach.³⁶ After considering medication-free status, there still was a discrepancy, but a lesser one, between studies of suicide victims and neuroimaging studies of MDEs: 5-HT_2A density was often elevated in prefrontal cortex in postmortem studies of suicide victims yet 5-HT_2A binding in prefrontal cortex was unchanged in medication-free depressed subjects.

One interpretation of the lack of difference in prefrontal cortex 5-HT_2A binding between medication-free depressed and control subjects is that there is no relationship of this analysis to the investigations of suicide victims. This seems unlikely given that half of suicide victims have a diagnosis of MDD^37,38 and that some of the postmortem studies that reported elevated 5-HT_2A density in prefrontal cortex sampled subjects with MDD.^37,38

An alternative perspective is that a subgroup of MDE subjects have the biological abnormality reported in suicide victims. To investigate this question, one could take advantage of the issue that 5-HT_2A receptor density has an inverse relationship with extracellular serotonin levels such that the density of 5-HT_2A receptors in cortex increases after chronic serotonin depletion and decreases after chronically raising extracellular serotonin.^39–42 Based upon this relationship, the candidate subgroup are depressed subjects suspected of having low extracellular serotonin in prefrontal cortex.

The symptom used to identify this subgroup was the elevated pessimism (dysfunctional attitudes) observed during MDEs. There is a modest level of dysfunctional attitudes in health, which increase to a variable extent during depressive episodes.^43–45 Greater pessimism during MDEs is an important symptom that contributes to the generation of sad mood and is targeted by cognitive therapy.^43–45 This symptom also abates when SSRI treatment is successful.^44,45 The rationale for choosing this symptom of elevated dysfunctional attitudes is that raising extracellular serotonin after administration of intravenous d-fenfluramine is associated with a strong shift in dysfunctional attitudes toward optimism 1 h later in healthy individuals.²⁵ This argues that among the many roles of serotonin, one of them is to modulate dysfunctional attitudes in humans. Both the anterior cingulate cortex and subregions of prefrontal cortex (dorsolateral and medial prefrontal cortex) participate in functions related to optimism and pessimism.^46–49 It is convenient that dysfunctional attitudes can be measured with the dysfunctional attitudes scale (DAS), a measure sensitive for detecting negativistic thinking in the midst of depressive episodes,^50,51 with very good internal consistency (Cronbach’s α = 0.85–0.87)^52,53 and high test–retest reliability.^43,53

A strong correlation was observed between severity of dysfunctional attitudes (pessimism) and the elevation in cortex 5-HT_2A binding potential reflecting specific binding relative to free and nonspecific binding (BP_ND) was discovered. Moreover, cortex 5-HT_2A BP_ND was significantly elevated in subjects with MDE and severe pessimism.²⁵ For example, in the prefrontal cortex region centered on Brodmann area 9, 5-HT_2A BP_ND was elevated 29% in depression subjects with dysfunctional attitude scores higher (more pessimistic) than the median for the group. There was a strong, significant correlation between severity of pessimism and prefrontal cortex 5-HT_2A BP_ND (see Figure 9.2). A recent study by Bhagwagar et al. replicated this relationship between dysfunctional attitudes severity and prefrontal cortex 5-HT_2A BP_ND in recovered depressed subjects.²⁷ In a separate study of a large sample of healthy subjects, two personality facets related to pessimism, vulnerability, and anxiety were also positively correlated with prefrontal cortex, temporal cortex, and left insula 5-HT_2A BP_ND.⁵⁴

FIGURE 9.2

5-HT_2A Binding potential in prefrontal cortex is associated with dysfunctional attitudes in depressed subjects. Age corrected 5-HT_2A receptor binding potential (5-HT_2A BP_ND) within bilateral prefrontal cortex (Brodmann area 9) in depressed subjects is (more...)

The investigations correlating severity of dysfunctional attitudes with greater 5-HT_2A BP_ND ^25,27 are highly consistent with postmortem investigations reporting greater 5-HT_2A receptor density in the prefrontal cortex of suicide victims. Fifty percent of suicide victims have MDD.^37,38 The DAS is highly correlated with hopelessness measured with the Beck Hopelessness Scale.^55–58 Given that hopelessness is a risk factor for suicide,^59,60 it is plausible that investigations of suicide victims reporting increased 5-HT_2A BP_ND sampled depressed subjects with greater severity of pessimism. See Figure 9.3 that represents the relationship of sampling studies for MDD, dysfunctional attitudes, and suicide.

FIGURE 9.3

Elevated prefrontal cortex 5-HT_2A density in suicide reflects sampling from major depressive disorder with pessimism and from aggressive behavior but not from borderline personality disorder.

Two other conditions that may be sampled in the studies of suicide victims are borderline personality and antisocial personality disorder.^37,38,61 In two investigations of 5-HT_2A binding in medication-free borderline personality disorder, no difference was found in the prefrontal cortex, although the second study reported an increase in 5-HT_2A binding in hippocampus in a post hoc analysis.^25,62 Meyer et al. investigated that 5-HT_2A binding in aggressive individuals found no group difference in any region, but did report an age interaction such that 5-HT_2A binding tended to increase considerably more with age in individuals with aggression.⁶³ Some theories of aggression and impulsivity consider the mechanisms of inadequate pruning and it is possible that this age-related effect might represent an index of differential change in pyramidal cell loss, since most 5-HT_2A receptors are found in apical dendrites of pyramidal cell neurons and the pattern of loss of pyramidal cells matches the loss in 5-HT_2A receptors with age.^64–67 A recent study of 5-HT_2A receptors by Rosell et al. reported greater binding in orbitofrontal cortex in a group of aggressive individuals who met current criteria for intermittent explosive personality disorder, some of whom had personality disorders.⁶⁸ A limitation of the latter study is that study subjects did not receive urine screening for substance abuse, a condition commonly comorbid with aggression, and such substances may bias 5-HT_2A receptor binding.^69,70 Hence, among the investigations of 5-HT_2A binding there is support for increased binding in older individuals with aggression throughout cortex and in orbitofrontal cortex in people with aggression.

The findings of greater 5-HT_2A density in the prefrontal cortex of suicide victims in postmortem study can be reinterpreted in light of diagnostic and symptom-specific findings from neuroimaging studies of 5-HT_2A binding. MDD with high levels of pessimism is associated with greater prefrontal cortex 5-HT_2A binding, is sampled heavily in studies of suicide victims because half of the suicide victims have MDD and hopelessness (a strong correlate of pessimism), which is associated with the risk of suicide.^{37,38,55–60} The diagnosis of borderline personality disorder does not contribute to the finding of greater prefrontal cortex 5-HT_2A density in suicide victims since no change in prefrontal 5-HT_2A BP_ND was found in this group.^25,62 In those with aggressive behavior, at least a subgroup of subjects older than age 34 show a similar neurobiological finding and would be expected to also contribute to the original findings of greater prefrontal 5-HT_2A density in suicide victims.^63,68 See Figure 9.3 for a Venn diagram that represents the sampling contributions of the various diagnoses and symptoms to the finding of greater 5-HT_2A density in suicide victims.

9.3. SEROTONIN TRANSPORTER BINDING AND SUICIDE

9.3.3. Relationship of Serotonin Transporter Imaging to Dysfunctional Attitudes and Major Depressive Disorder

Dysfunctional attitude is an important symptom of MDD, particularly because it is strongly related to suicide. Hopelessness^59,60 (and difficulty seeing positive reasons for living¹¹⁶) is an important risk factor for suicide and it has been clearly established in four separate samples of depressed subjects that greater hopelessness is associated with greater severity of dysfunctional attitudes as measured with the DAS.^55–58 The DAS⁴³ is a sensitive measure for detecting pessimistic thinking in the midst of MDE^50,51 that has very good internal consistency (Cronbach’s α = 0.85–0.87)^52,53 and high test–retest reliability.^43,53

Low extracellular serotonin in prefrontal and anterior cingulate cortex during MDD is a highly plausible explanation for the strong correlation between prefrontal and anterior cingulate cortex 5-HT_2A receptor binding and dysfunctional attitudes. Key subregions of prefrontal cortex (particularly the medial prefrontal cortex and dorsolateral prefrontal cortex) as well as the anterior cingulate cortex participate in cognitive functions related to optimism/pessimism.^46–49

Modulation of extracellular serotonin can shift dysfunctional attitudes: Elevating extracellular serotonin abruptly in healthy humans via intravenous d-fenfluramine administration (in contrast to control condition) shifted perspective toward optimism as measured by the DAS.²⁵ The interpretation of this shift toward optimism after d-fenfluramine was that one of the functions of extracellular serotonin in humans is to reduce pessimism.²⁵ A property of 5-HT_2A receptors is that 5-HT_2A receptor density has an inverse relationship with extracellular serotonin levels such that the density of 5-HT_2A receptors in cortex increases after chronic serotonin depletion and decreases after chronically raising extracellular serotonin.^39–42 Therefore, an interpretation of the finding that prefrontal and anterior cingulate cortex 5-HT_2A BP_ND was significantly elevated in subjects with MDE and severe pessimism,²⁵ and that 5-HT_2A BP_ND in these regions is positively associated with severity of dysfunctional attitudes,^25,27 is that extracellular serotonin is low in MDD with severe pessimism.

There are only two postmortem investigations of 5-HTT density in subjects with recent symptoms of depressive episodes.^117,118 In these investigations, one of which concurrently sampled suicide victims reported no changes in 5-HTT density in the dorsal raphe or the locus coeruleus. Other postmortem investigations of 5-HTT density sampled subjects with a history of a depressive episode and these investigations usually studied the prefrontal cortex and/or dorsal raphe nucleus. Findings ranged from decreased 5-HTT density^119–123 to no difference in 5-HTT density.^124–128 In several of these studies, subjects were medication free,^121,124,125 and for many of these investigations, average postmortem delay was less than a day.^{117–119,121,123,127} For greater detail, the reader is referred to the review of Stockmeier.¹¹ Other sampling issues that may influence postmortem investigations are effects of additionally sampling patients with bipolar disorder and possible differences between early versus late onset MDD. None of the postmortem studies investigated the relationship between 5-HTT binding to indices of hopelessness and pessimism.

The first application of [¹¹C]DASB PET imaging to investigate MDD investigated the relationship of 5-HTT BP_ND to severity of dysfunctional attitudes and presence of a MDE. In this study, Meyer et al. sampled 20 subjects with MDEs (from early onset MDD) and 20 healthy controls.⁸⁴ Subjects were medication free for at least 3 months, had no other comorbid axis I illnesses, were nonsmoking, and had early onset depression. There was no evidence for a difference in regional 5-HTT BP_ND in the group with MDEs and those in the midst of health. However, subjects with MDEs and severely pessimistic dysfunctional attitudes had significantly higher 5-HTT BP_ND, compared to healthy in brain regions sampling serotonin nerve terminals (dorsolateral and medial prefrontal cortex, anterior cingulated cortex, thalamus, bilateral caudate, and bilateral putamen). On average, 5-HTT BP_ND was 21% greater in these regions in depressed subjects with severely pessimistic dysfunctional attitudes. Moreover, within the MDE group, greater 5-HTT BP_ND was strongly associated with more negativistic dysfunctional attitudes in the same brain regions (see Figure 9.4). The interpretation was that serotonin transporters have an important role in influencing extracellular serotonin during MDEs: Greater regional 5-HTT levels can provide greater vulnerability to low extracellular 5-HT and symptoms of extremely negativistic dysfunctional attitudes. This interpretation, in subjects with high levels of pessimism during MDE, corresponds to model number three (see earlier under Section 9.3.2).

FIGURE 9.4

Correlations between dysfunctional attitudes scale (DAS) and serotonin transporter binding potential (5-HTT BP) in some of the larger regions in depressed subjects. Highly significant correlations were found: (a) dorsolateral prefrontal cortex (p = 0.0004), (more...)

In general, neuroimaging studies that sample subjects who have early onset MDD, are medication free for greater than 2 months, are nonsmoking, and do not have comorbid axis I disorders and apply better quality radiotracer technology tend to find either no change in regional 5-HTT binding or an increase in regional 5-HTT binding.^84,129–131 Investigations that include sampling of subjects with late onset MDD, comorbid axis I psychiatric disorders, recent antidepressant use, and current cigarette smoking and do not apply a selective radiotracer are more likely to report a reduction in regional 5-HTT binding.^132–136 Only the first study of [¹¹C]DASB PET concurrently investigated a measure of pessimism or hopelessness.

9.4. MONOAMINE OXIDASE A AND SUICIDALITY

Monoamine oxidase A (MAO-A) is a target of interest in research of suicidality given its role in metabolizing monoamines and its widespread distribution throughout the brain. In the brain, the predominant location for this enzyme is on the outer mitochondria membranes in neurons,¹⁵² and monoamine oxidase A density is highest in brain stem (locus coeruleus), lower in the hippocampus, cortex, striatum, and minimal in white matter tissue.^152,153 Monoamine oxidase A metabolizes serotonin given that serotonin is a high affinity substrate for MAO-A,^154–157 MAO-A is detectable in serotonin-releasing neurons,^158,159 and that MAO-A clearly influences extracellular serotonin as administration of MAO-A inhibitors increase extracellular serotonin from 20% to 200%, depending upon drug, dose, and region.^{110,160–165} Norepinephrine^157,166 and dopamine^154–156 are also high affinity substrates for MAO-A,^157,166 and there is evidence that under MAO-A inhibition, extracellular concentrations of these monoamines^{160,167–171} are raised. MAO-A is easily detectable in cells that synthesize norepinephrine^{152,158,159,172} but more difficult to detect in dopamine-synthesizing neurons.^159,173 In knockout models of MAO-A, extracellular serotonin, norepinephrine, and dopamine are also raised substantively (100%–200%) in prefrontal cortex, hippocampus, and superior raphe nuclei.¹⁷⁴

As of 2005, based upon postmortem study, it was unknown as to whether brain MAO-A binding or activity is abnormal during at risk states for suicide such as MDEs because each previous investigation of brain MAO-A had at least two important limitations that created significant heterogeneity in the samples^175–180 such as nonspecificity of technique for MAO-A versus monoamine oxidase B, enrollment of subjects who recently took medication, unclear diagnosis of suicide victims, small sample size, and lack of categorizing between early onset depression and late onset depression. In contrast to the common, early onset depression prior to age 40, late onset depression likely has a different pathophysiology attributable to lesions and/or degenerative disease.¹⁸¹

Neuroimaging radioligands to measure an index of MAO-A levels in humans include [¹¹C]clorgyline, deuterium-labeled [¹¹C]clorgyline, [¹¹C]harmine, and [¹¹C] befloxatone.^182–187 The latter two have an useful advantage in terms of having more rapid kinetics and greater reversibility. [¹¹C]Harmine was also modeled in humans and it possesses high affinity for the MAO-A site, as well as high selectivity, excellent specific binding relative to free and nonspecific binding ratios, and high brain uptake.^{184,186,188–190} Given these properties and validation, it is the lead radiotracer for quantitating brain MAO-A binding in humans at this time.

9.4.1. Monoamine Oxidase A and Major Depressive Disorder

Prior to 2006, there were no studies of MAO-A density, activity, or mRNA in early onset MDD. In 2006, MAO-A V_S, an index of MAO-A density, was measured in 17 MDE and 17 healthy subjects with [¹¹C]harmine PET.¹⁹⁰ All subjects were otherwise healthy. Depressed subjects had early onset depression (before age 40) and were drug free for at least 5 months although most were antidepressant naïve. Depressed subjects were aged 18–50, met DSM-IV diagnosis of current MDE and MDD verified by SCID for DSM IV,¹⁹¹ were nonsmoking and had a reasonable severity of depression with a score greater than 17 on the 17-item HDRS. The MAO-A V_S was highly significantly elevated (p < 0.001 each region, average magnitude 34% [or two standard deviations]) in the depressed subjects (see Figure 9.5). The study was considered definitive for showing that MAO-A binding is elevated in early onset depression because the magnitude was large, the sample was carefully defined, and the method is selective for MAO-A.

FIGURE 9.5

Comparison of MAO-A DVs between depressed and healthy subjects. On average MAO-A DVs was elevated by 34%, or two standard deviations, in depressed individuals. Differences between groups were highly significant in each region: *p = 0.001, **p < (more...)

This finding was subsequently replicated by the same group and the relationship between MAO-A binding and state of MDD was also investigated.¹⁹² During remission from MDD, MAO-A binding was elevated in most brain regions such as prefrontal cortex, anterior cingulate cortex, striatum, hippocampus, thalamus, and midbrain. Elevated MAO-A binding may be viewed as an index of a monoamine-lowering process and a historical set of observations were known that had linked chronic monoamine-lowering processes with subsequent MDEs: During the development of reserpine-based antihypertensives in the 1950s, subsequent onset of MDE occurred typically 2 weeks to 4 months later.¹⁹³ Consistent with this line of observation, those recovered MDD subjects who had recurrence of their MDEs in the subsequent 6 months had the highest levels MAO-A binding in the prefrontal cortex and anterior cingulate cortex at the time of scanning.¹⁹²

The raised MAO-A binding during MDEs adds to a pathophysiological model of extracellular serotonin loss contributing to pessimism during MDEs. Greater MAO-A binding can be viewed as an index of greater MAO-A levels. When MAO-A levels are greater in cell lines or in brain homogenates, MAO-A activity shows a positively correlated parallel, and typically linear relationship.^{153,194–196} Hence, the index of greater MAO-A binding may be viewed as a mechanism of excessive serotonin removal. The inverse relationship between extracellular serotonin levels and dysfunctional attitudes as demonstrated by the shift in dysfunctional attitudes after intravenous d-fenfluramine and the reduction in dysfunctional attitudes after SSRI treatment suggests a role for extracellular serotonin in modulating optimism/pessimism.²⁵ Brain regions most strongly associated for a role in optimism/pessimism include the anterior cingulate cortex, and the medial and dorsolateral subdivisions of the prefrontal cortex.^46,197 5-HT_2A receptor density has an inverse relationship to extracellular serotonin levels,^39–42 and greater 5-HT_2A receptor binding was observed in these regions during MDD with higher levels of pessimism.^25,27 5-HTT has a role in clearing extracellular serotonin, and a positive correlation between total 5-HTT binding and severity of dysfunctional attitudes was found in the medial prefrontal cortex, the dorsolateral prefrontal cortex, and the anterior cingulate cortex.⁸⁴ Collectively, the findings suggest that pessimism in the anterior cingulate cortex and prefrontal cortex is associated with greater 5-HT_2A binding, which may reflect ongoing loss of extracellular serotonin in these regions, and potential sources of loss are excessive 5-HTT binding, and elevated MAO-A levels (see Figure 9.6).

FIGURE 9.6

(See color insert.) Modern model of excessive extracellular serotonin loss during major depressive disorder (A) serotonin release in a synapse in health. (B) During a major depressive episode, monoamine oxidase A (MAO-A) density is elevated resulting (more...)

9.4.2. Postpartum, Suicide, and Monoamine Oxidase A

On average, during pregnancy, the risk of suicide is lower and it elevates during postpartum, yet is still less than other times in life.¹⁹⁸ However, when psychiatric illness such as postpartum depression (PPD) occurs, the risk of suicide elevates >10-fold.^199,200 This issue, coupled with the fact that the general risk of a MDE during the postpartum period is 13%,^201–205 illustrates the importance of investigating the neurobiology of early postpartum related to the risk for MDE and suicide.

The most likely psychiatric disturbances in the postnatal period affect mood and there are three types. One is the “baby blues” or maternity blues, which is common (occurring up to 75% of the time) and transient, usually finishing within the first week postpartum.^206,207 The second is MDE with postpartum onset (“postpartum depression”), which is defined as a MDE that occurs within the first 4 weeks after delivery.²⁰⁸ Twenty percent of women with maternity blues will go on to have a MDE with postpartum onset.^207,209 The third is postpartum psychosis (which may be accompanied by depressive symptoms). The third condition is rare occurring in 0.1%–0.2% of deliveries and is strongly associated with the presence of bipolar disorder.^210,211

A profound change that occurs during the first week postpartum, when “postpartum blues” are common, is the enormous reduction in 17β-estradiol and estriol levels. It is well known that estradiol and estriol are produced by the placenta during pregnancy and that plasma levels raise 100-fold and 1000-fold, respectively.²¹² It is also well known that estradiol and estriol levels decrease abruptly during postpartum with loss of the placenta. Most of the decline is in the first 4 days with a modest decline thereafter.^207,213,214 It is also a time of reduction in progesterone levels.

Declines in estrogen and progesterone have been implicated in generating sad mood. In an experimental paradigm involving a reduction in estrogen and progesterone, Bloch et al.²¹⁵ found that women with a history of PPD had lowering of mood. In this paradigm, eight women with a history of PPD and eight women without a history of PPD were given a gonadotrophin-releasing agonist for 8 weeks and then the agonist was withdrawn (to simulate delivery and loss of placenta). Five of the eight women who had a history of PPD had sustained lowered mood, whereas none of the women who had no history of PPD had sustained lowered mood. Additional support for an inverse relationship between estrogen and mood was supported by the fact that estrogen (17β-estradiol) administration has reduced mood symptoms in some preliminary clinical trials as a treatment for MDE with postpartum onset and MDE in postmenopausal women.^216–223 These findings implicate an inverse relationship between estrogen change and mood; however, it was unclear how this might link to the pathophysiology of MDD.

A candidate link between estrogen loss and the pathophysiology of MDD was the relationship between changes in estrogen levels and changes in MAO-A density. Within regions of high MAO-A density, repeated (increased) estrogen administration is associated with reductions in MAO-A density, mRNA, and/or activity in contrast to estrogen depletion, which is associated with increases in MAO-A density, mRNA, and/or activity: Estradiol administration for 1–3 weeks consistently lowers MAO-A activity in high density areas (amygdala and hypothalamus) in ovariectomized rats.^224–226 In ovariectomized macaque monkeys, 1 month of estradiol administration reduced MAO-A mRNA in the dorsal raphe nucleus.²²⁷ In a separate study of ovariectomized macaque monkeys, 1 month of estradiol administration reduced MAO-A protein in the dorsal raphe region by ∼50%.²²⁸ Repeated estradiol administration is associated with a reduction in MAO-A activity in neuroblastoma cell lines. In a neuroblastoma cell line that expresses the human estrogen receptor, exposure to 17β-estradiol for 12 days lowers MAO-A activity.²²⁹ This finding was replicated with exposure to physiological levels of 17β-estradiol for 10 days.²³⁰ Although changes in several indices of MAO-A levels had been reported in relation to estrogen loss, MAO-A binding, mRNA, or activity had never been studied in any species in early postpartum.

Given the 100- to 1000-fold decline in estrogen over the first 4 days postpartum,^201,213,214 the relationship between estrogen decline and elevation in MAO-A synthesis, and the link between greater MAO-A levels and lower mood, there was a strong rationale to neuroimage MAO-A binding in brain regions involved in affect regulation during early postpartum (during days 4–6). Applying [¹¹C]harmine PET neuroimaging, we completed the first investigation of MAO-A binding in any species during the immediate postpartum period. The main finding is a significant elevation of MAO-A binding postpartum (magnitude of 43%) throughout all brain regions assayed (prefrontal cortex, anterior cingulate cortex, hippocampus, striatum, and thalamus) in the immediate postpartum period in healthy women (see Figure 9.7). A voxel-based analysis confirmed that the elevation in MAO-A binding was present throughout the gray matter of the brain (MAO-A density is minimal in white matter^152,153).

FIGURE 9.7

Monoamine oxidase A binding in the immediate postpartum period. MAO-A V_T is an index of harmine binding to tissue at equilibrium and is an index of MAO-A level. On average regional MAO-A, V_T was elevated by 43% during the early postpartum period. Differences (more...)

This discovery provides a neurobiological model of postpartum blues in humans, involving a rapid decline in estrogen, followed by a rapid rise in MAO-A levels in affect-modulating structures in the brain, with subsequent sad mood and symptoms of postpartum blues. As mentioned earlier, estrogen removal has been associated with a rise in indexes of MAO-A levels,^{224,227,228,230,231} and the findings shown in Figure 9.8 argue that this relationship applies strongly during the immediate postpartum period in humans. Consistent with this neurobiological model, MAO-A binding was highest on day 5 postpartum, the day most strongly associated with the lowest mood in most investigations of postpartum blues.²³³ MAO-A V_T measured in early postpartum can be viewed as an index for MAO-A levels. Changes in levels of MAO-A density parallel changes in MAO-A activity during paradigms of hormone administration.¹⁹⁶ The acute rise in MAO-A levels in the early postpartum period can be interpreted as an important monoamine-lowering process and monoamine-lowering is associated with sad mood.^{91,92,95,233–237}

FIGURE 9.8

Association between impulsiveness (IMP) and deliberation (DLB) scores and baseline μ-opioid receptor availability. Areas in which significant differences in μ-receptor availability in vivo were observed between individuals with high and (more...)

A therapeutic implication of this neurobiological model is that one may target the proposed pathway of estrogen decline, rise in MAO-A levels, excessive metabolism of monoamines, and subsequent sad mood/distress. In order to prevent PPD, it may be useful to attenuate the severity of postpartum blues because greater severity of postpartum blues is associated with greater risk for PPD.^207,238 Given the need to develop treatments that are compatible with breast-feeding and widespread use, dietary supplements of monoamine precursors in early postpartum may be a promising strategy to maintain a sufficient balance of monoamines during this time. For example, the administration of precursor supplements, such as the amino acids tryptophan for serotonin and tyrosine for norepinephrine and dopamine, could be investigated for the prevention of severe postpartum blues and PPD. Other strategies for prophylaxis in high risk groups could include inhibiting MAO-A, or raising multiple monoamines (that are metabolized by MAO-A with antidepressants). Less invasive strategies such as administration of amino acid precursors have potential for women at low risk of developing PPD, whereas interventions such as MAO-A inhibitors could be considered for those at high risk for PPD.

9.5. NEUROCHEMICAL ABNORMALITIES ASSOCIATED WITH PERSONALITY TRAITS OF IMPULSIVITY

Since the etiology of suicidal behavioral is multifactorial, one useful contribution from neuroimaging is the ability to quantitate the neurochemistry associated with specific risk factors for suicide. Earlier in this chapter, the neurochemistry of dysfunctional attitudes, a construct related closely to hopelessness, was presented. Similarly, greater impulsivity represents another factor associated with greater risk for death by suicide. Personality assessment instruments have been applied in combination with brain imaging and to date have identified strong relationships between impulsivity and MAO-A binding (in all brain regions assessed), striatal dopamine release, and ventral striatal μ-opioid binding.

9.6. CONCLUSIONS

While neuroimaging is limited by the range in biomarkers available, its ability for in vivo measurement enables discoveries bridging neurochemistry to specific clinic states. For example, the finding of greater 5-HT_2A binding in the dorsolateral prefrontal cortex of suicide victims can be translated into diagnostic and symptom specificity: 5-HT_2A binding is greater throughout the prefrontal cortex in MDD with high levels of pessimism (a symptom that creates risk for suicide).^25,27 The mechanism for this finding is best explained by excessive serotonin loss consequent to greater levels of functional serotonin transporter and high levels of monoamine oxidase A (leading to greater metabolism).^190,84 Greater monoamine oxidase A binding occurs throughout the brain in early postpartum and may explain the vulnerability to psychiatric illness, in particular MDD, which occurs in postpartum.²⁷¹ Since MDD during early postpartum is associated with more than a 10-fold greater risk of suicide, preventing PPD is important.^199,200 Potential biological strategies for prevention of PPD may involve suppressing the pathway between estrogen decline and MAO-A rise or dietary compensations for high MAO-A.

The findings of reduced ventral prefrontal 5-HTT binding in suicide victims are also present with similar regional specificity in a neuroimaging study of obsessive–compulsive disorder,^144,145 but reduced 5-HTT binding may also be present in this region in ecstasy abuse within the previous 4 months, and in the winter relative to summer.^139–143 Neuroimaging of impulsive macaque monkeys shows a pattern of brain 5-HTT loss that spares the ventral prefrontal region.¹⁴⁶ Further neuroimaging studies are needed to understand the diagnostic and symptom specificity of 5-HTT change related to suicide.

Another advantage of in vivo imaging measurement is that it can be related to clinical measures associated with suicide, that are also sampled in vivo, proximal to the time of brain scanning. For example, impulsivity is associated with particular neurochemical findings: The association of greater impulsivity with reduced regional brain MAO-A binding in humans^256,257 is implicated in altered neurodevelopment leading to altered neural architecture and organization of sensory input. Impulsivity in humans is also associated with neurochemical markers implicated in greater responsivity to reward such as enhanced ventral striatal dopamine release, reduced D₂/D₃ autoreceptor binding,²⁶³ and greater ventral striatal μ-opioid receptor binding.²⁶⁹ In the future, it is possible that these findings will represent new therapeutic targets for impulsivity-reducing treatments so as to reduce the risk of suicide.

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