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Delivery of effective antidepressant treatment has been hampered by a lack of objective tools for predicting or monitoring treatment response. This study aimed to address this gap by testing novel dynamic resting-state functional network markers of antidepressant response.The Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study randomized adults with major depressive disorder to 8 weeks of either sertraline or placebo, and depression severity was evaluated longitudinally. Participants completed resting-state neuroimaging pretreatment and again after 1 week of treatment (n = 259 eligible for analyses). Coactivation pattern analyses identified recurrent whole-brain states of spatial coactivation, and computed time spent in each state for each participant was the main dynamic measure. Multilevel modeling estimated the associations between pretreatment network dynamics and sertraline response and between early (pretreatment to 1 week) changes in network dynamics and sertraline response.Dynamic network markers of early sertraline response included increased time in network states consistent with canonical default and salience networks, together with decreased time in network states characterized by coactivation of cingulate and ventral limbic or temporal regions. The effect of sertraline on depression recovery was mediated by these dynamic network changes. In contrast, early changes in dynamic functioning of corticolimbic and frontoinsular-default networks were related to patterns of symptom recovery common across treatment groups.Dynamic resting-state markers of early antidepressant response or general recovery may assist development of clinical tools for monitoring and predicting effective intervention.

Background Baseline rostral anterior cingulate cortex (rACC) activity is a well-replicated nonspecific predictor of depression improvement. The rACC is a key hub of the default mode network, which prior studies indicate is hyperactive in major depressive disorder. Because default mode network downregulation is reliant on input from the salience network and frontoparietal network, an important question is whether rACC connectivity with these systems contributes to depression improvement. Methods Our study evaluated this hypothesis in outpatients (N = 238; 151 female) enrolled in the Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) 8-week randomized clinical trial of sertraline versus placebo for major depressive disorder. Depression severity was measured using the Hamilton Rating Scale for Depression, and electroencephalography was recorded at baseline and week 1. Exact low-resolution electromagnetic tomography was used to compute activity from the rACC, and key regions within the default mode network (posterior cingulate cortex), frontoparietal network (left dorsolateral prefrontal cortex), and salience network (right anterior insula [rAI]). Connectivity in the theta band (4.5–7 Hz) and beta band (12.5–21 Hz) was computed using lagged phase synchronization. Results Stronger baseline theta-band rACC–rAI (salience network hub) connectivity predicted greater depression improvement across 8 weeks of treatment for both treatment arms (B = −0.57, 95% confidence interval = −1.07, −0.08, p = .03). Early increases in theta-band rACC–rAI connectivity predicted greater likelihood of achieving remission at week 8 (odds ratio = 2.90, p = .03). Conclusions Among patients undergoing treatment, theta-band rACC–rAI connectivity is a prognostic, albeit treatment-nonspecific, indicator of depression improvement, and early connectivity changes may predict clinically meaningful outcomes.

Background We previously reported higher serotonin 1A receptor (5-HT1A) binding in subjects with major depressive disorder (MDD) during a major depressive episode using positron emission tomography imaging with [ 11 C]WAY-100635. 5-HT1A receptor binding is also associated with treatment outcome after nonstandardized antidepressant treatment. We examined whether pretreatment 5-HT1A binding is associated with treatment outcome following standardized escitalopram treatment in MDD. We also compared 5-HT1A binding between all MDD subjects in this cohort and a sample of healthy control subjects. Methods Twenty-four MDD subjects in a current major depressive episode and 51 previously studied healthy control subjects underwent positron emission tomography scanning with [ 11 C]WAY-100635, acquiring a metabolite-corrected arterial input function and free-fraction measurement to estimate 5-HT1A binding potential (BP F = B max /K D , where B max = available receptors and K D = dissociation constant). Major depressive disorder subjects then received 8 weeks of treatment with escitalopram; remission was defined as a posttreatment 24-item Hamilton Depression Rating Scale Results Remitters to escitalopram had 33% higher baseline 5-HT1A binding in the raphe nuclei than nonremitters ( p = .047). Across 12 cortical and subcortical regions, 5-HT1A binding did not differ between remitters and nonremitters ( p = .86). Serotonin 1A receptor binding was higher in MDD than control subjects across all regions ( p = .0003). Remitters did not differ from nonremitters in several relevant clinical measures. Conclusions Elevated 5-HT1A binding in raphe nuclei is associated with subsequent remission with the selective serotonin reuptake inhibitor escitalopram; this is consistent with data from a separate cohort receiving naturalistic antidepressant treatment. We confirmed our previous findings of higher 5-HT1A binding in current MDD compared with control subjects.

Background Several lines of evidence implicate abnormal serotonergic function in suicidal behavior and completed suicide, including low serotonin transporter binding in postmortem studies of completed suicide. We have also reported low in vivo serotonin transporter binding in major depressive disorder (MDD) during a major depressive episode using positron emission tomography (PET) with [ 11 C]McN5652. We quantified regional brain serotonin transporter binding in vivo in depressed suicide attempters, depressed nonattempters, and healthy controls using PET and a superior radiotracer, [ 11 C]DASB. Methods Fifty-one subjects with DSM-IV current MDD, 15 of whom were past suicide attempters, and 32 healthy control subjects underwent PET scanning with [ 11 C]DASB to quantify in vivo regional brain serotonin transporter binding. Metabolite-corrected arterial input functions and plasma free-fraction were acquired to improve quantification. Results Depressed suicide attempters had lower serotonin transporter binding in midbrain compared with depressed nonattempters ( p = .031) and control subjects ( p = .0093). There was no difference in serotonin transporter binding comparing all depressed subjects with healthy control subjects considering six a priori regions of interest simultaneously ( p = .41). Conclusions Low midbrain serotonin transporter binding appears to be related to the pathophysiology of suicidal behavior rather than of major depressive disorder. This is consistent with postmortem work showing low midbrain serotonin transporter binding capacity in depressed suicides and may partially explain discrepant in vivo findings quantifying serotonin transporter in depression. Future studies should investigate midbrain serotonin transporter binding as a predictor of suicidal behavior in MDD and determine the cause of low binding.

Transthyretin (TTR) is a thyroid hormone binding protein synthesized by choroid plexus and secreted into cerebrospinal fluid (CSF). We sought to replicate and extend our previous findings of lower CSF TTR in depression.Cerebrospinal fluid TTR concentrations of 17 medication-free patients with major depressive disorder (MDD) and 15 healthy individuals were determined by a sensitive, specific radioimmunoassay newly developed in our laboratory (ESL, TBC).Cerebrospinal fluid TTR was lower in the MDD patients compared with healthy volunteers (mean +/- SD, 19.7 +/- 1.6 vs. 21.8 +/- 2.2 mg/L, p = .005). Age correlated positively with CSF TTR (r = .38, p.05). The group difference remained significant (p.005) after covariance for age. Within the MDD group, Scale for Suicide Ideation total score correlated inversely with CSF TTR (beta = -.58, p.05). In the entire sample of depressed and healthy individuals, CSF 5-hydroxyindoleacetic acid (5-HIAA) correlated positively (beta = .34, p.05) with CSF TTR.We replicated our finding of low CSF TTR levels in depression and newly identified two relationships that may explain reports linking thyroid axis dysfunction and suicidal behaviors. Serotonergic hypofunction in depression, reflected by low CSF 5-HIAA, may result in decreased choroid plexus TTR production, alterations in central thyroid hormone kinetics, and increased vulnerability to suicidal ideation and perhaps suicide.

Background In vivo determination of serotonin transporter (5-HTT) occupancy by selective serotonin reuptake inhibitors (SSRI) using positron emission tomography (PET) can aid in determination of dosing. Previous studies used chronic SSRI administration that may down-regulate 5-HTT and used the cerebellum as reference region despite measurable 5-HTT. We examine the reference region and occupancy after acute sertraline dosing. Methods We conducted autoradiography of human postmortem cerebellum to determine an optimal reference region. We quantified 5-HTT binding using [11C]DASB and arterial input functions in 17 healthy volunteers. Baseline PET scans were followed by a scan 4–6 days after 25 mg to 100mg of daily sertraline. Several modeling methods and outcome measures were assessed. Results Cerebellar gray matter is the optimal reference region. Occupation of 5-HTT sites saturates at low plasma sertraline levels (KD = 1.9 ng/ml) with maximal occupancies of 106.8 ± 8.3% across all brain regions. There is a weak correlation between oral sertraline and plasma sertraline. Occupancy measures vary based on the reference region and outcome measure used. Conclusions Occupancy studies and postmortem autoradiography can help define the optimal reference region. Reference tissue modeling using the optimal reference region returns the same occupancy measures as those determined using an arterial input function.

Background In vivo studies find altered serotonin function associated with aggressive and suicidal behaviors. Postmortem studies also reveal serotonergic alterations in suicide subjects but have not reported on the relationship between aggression and the serotonin system. We measured 5-hydroxytryptamine 2A (5-HT 2A ) receptor binding in prefrontal cortex of suicide and nonsuicide subjects and explored the relationship between 5-HT 2A receptor binding, lifetime aggression, and suicide. Methods The 5-HT 2A receptor binding in coronal sections of prefrontal cortex was quantified by autoradiography with [ 3 H] ketanserin in 37 suicide subjects and 73 nonsuicide subjects. The relationship between [ 3 H] ketanserin binding and lifetime aggression, rated on the Brown-Goodwin Aggression History Scale, was assessed controlling for age and sex. Results In suicide subjects, lifetime aggression scores correlated positively with [ 3 H] ketanserin binding in all prefrontal Brodmann areas examined, after adjusting for age and sex. This was not the case in nonsuicide subjects. We found no significant differences in aggression scores or [ 3 H] ketanserin binding between the suicide subjects and nonsuicide subjects. Conclusions The relationship between aggression and 5-HT 2A receptor binding in suicide subjects, but not in nonsuicide subjects, may reflect differences in the regulation of the 5-HT 2A receptor related to suicidal behavior and perhaps other proaggressive changes in brains of suicide subjects.

Background The anxious phenotype of the 5-HT 1A receptor knockout mouse and the anxiolytic properties of 5-HT 1A agonists suggest that the 5-HT 1A receptor modulates anxiety. We investigated the relationship of anxiety expressed in major depressive disorder (MDD) to regional 5-HT 1A binding. Methods Positron emission tomography with [carbonyl- 11 C]WAY-100635 was used to estimate regional 5-HT 1A binding potential (BP) in 28 medication-free MDD subjects. Stepwise linear regression assessed the predictive capacity of three anxiety components, derived from a larger MDD sample and termed psychic, somatic, and motoric anxiety, on regional 5-HT 1A BP. Results Higher psychic (β ≥ .63) and lower somatic (β ≤ –.70) anxiety predicted over 50% of the variance in 5-HT 1A BP in multiple cortical regions, but not in amygdala, hippocampus, or autoreceptors of the raphe nuclei. The psychic and somatic anxiety components were not related to depression severity. Comorbid panic disorder was associated with lower cortical and subcortical 5-HT 1A BP. Conclusions The 5-HT 1A receptor in the same brain regions has different relationships to psychic anxiety versus somatic anxiety. Lower 5-HT 1A BP in panic disorder may be accounted for by higher somatic and lower psychic anxiety. Further study of the pathobiology of these anxiety components may identify distinct therapeutic targets or mechanisms.

Background:We have proposed a stress-diathesis model for suicidal behavior, in which major depression is a stressor and the diathesis is shared with aggression. Neurotransmitter correlates of the stress or diathesis have not been adequately evaluated by previous studies, because they did not simultaneously examine the relationship of multiple neurotransmitters to all three psychopathologies in the same population. In the present study we investigated the relationship of monoamine metabolites to aggressivity, suicidal behavior, and depression in patients with mood disorders. Methods: Ninety-three drug-free subjects with a major depressive episode underwent lumbar puncture and psychiatric evaluation. Cerebrospinal fluid CSF levels of 5hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA) and methoxy-hydroxy-phenylglycol (MHPG) were assayed. The relationships between monoamine metabolites and clinical variables were statistically evaluated. Results: Higher lifetime aggressivity correlated significantly with lower CSF 5-HIAA. Lower CSF 5-HIAA and greater suicidal intent were found in high-lethality suicide attempters compared with low-lethality suicide attempters. Low-lethality attempters did not differ biologically from nonattempters. No correlation between CSF HVA and any of the psychopathological variables was found. Only aggression showed a trend statistically in correlating positively with CSF MHPG levels. Conclusions: Lower CSF 5-HIAA concentration was independently associated with severity of lifetime aggressivity and a history of a higher lethality suicide attempt and may be part of the diathesis for these behaviors. The dopamine and norepinephrine systems do not appear to be as significantly involved in suicidal acts, aggression, or depression. The biological correlates of suicide intent warrant further study.

Background: Reduced dopaminergic transmission has been implicated in the pathophysiology of major depression. The aim of the present study was to measure striatal D 2 receptor availability and amphetamineinduced dopamine release in nonpsychotic, unmedicated, unipolar patients during an episode of major depression. Methods: The striatal equilibrium specific to nonspecific partition coefficient (V 3 ″) of the D 2 receptor antagonist [ 123 I]IBZM was measured with single photon emission computerized tomography before and after amphetamine administration in 9 depressed subjects and 10 matched healthy control subjects. Results: No significant differences were observed in preamphetamine D 2 receptor availability between depressed patients (0.73 ± 0.08) and control subjects (0.78 ± 0.10, p = .23). Amphetamine-induced reduction in [ 123 I]IBZM V 3 ″ (ΔV 3 ″) was similar in depressed patients (−9.8 ± 5.5%) and control subjects (−7.8 ± 2.5%, p = .32). Amphetamine induced a transient improvement in symptomatology in depressed patients, but this improvement did not correlate with [ 123 I]IBZM ΔV 3 ″. Conclusions: This study did not replicate previously reported alterations in striatal D 2 receptor density in depressed patients and suggests that stimulant-induced dopamine release is not altered in major depression.

Background Serotonin 1A receptors (5-HT1A) are implicated in the pathophysiology of major depressive disorder (MDD) and in the action of selective serotonin reuptake inhibitors (SSRI). SSRI desensitize 5-HT1A and down-regulate 5-HT transporters (5-HTT) with the latter persisting for weeks after discontinuation of SSRI. MDD subjects are more likely to be homozygous for the functional 5-HT1A G(-1019) allele of the promoter polymorphism and are postulated to have higher 5-HT1A than healthy volunteers (controls). We measure 5-HT1A in MDD, assess the effects of antidepressant exposure (AE), and examine the role of the C(-1019)G polymorphism. Methods Genotyped and determined 5-HT1A binding potential (BP) by positron emission tomography (PET) using [carbonyl-C-11]-WAY-100635 in 28 medication-free MDD subjects during a current major depressive episode and 43 controls. Results No difference in BP between controls and MDD subjects (p = .235). There was a difference in BP comparing the controls, antidepressant naive (AN) MDD subjects, and subjects with AE across all regions (p = .013). Post hoc testing reveals higher BP in AN compared to controls (p = .008) and to AE (p = .007). The GG genotype is overrepresented in MDD subjects (p = .059), and BP appears higher with the G allele. Conclusions AN have higher 5-HT1A than controls and AE suggesting a model of depression characterized by an over expression of autoinhibitory somatodendritic 5-HT1A receptors, perhaps due to the higher expressing G allele, that may result in reduced terminal field 5-HT release. AE appears to have long-term effects on 5-HT1A.

Background Structural magnetic resonance imaging (MRI) studies of regions of interest in brain have been inconsistent in demonstrating volumetric differences in subjects with bipolar disorder (BD). Voxel-based morphometry (VBM) provides an unbiased survey of the brain, can identify novel brain areas, and validates previously hypothesized regions. We conducted both optimized VBM, comparing MRI gray matter volume, and traditional VBM, comparing MRI gray matter density, in 11 BD subjects and 31 healthy volunteers. To our knowledge, these are the first VBM analyses of BD. Methods Segmented MRI gray matter images were normalized into standardized stereotactic space, modulated to allow volumetric analysis (optimized only), smoothed, and compared at the voxel level with statistical parametric mapping. Results Optimized VBM showed that BD subjects had smaller volume in left ventromedial temporal cortex and bilateral cingulate cortex and larger volume in left insular/frontoparietal operculum cortex and left ventral occipitotemporal cortex. Traditional VBM showed that BD subjects had less gray matter density in left ventromedial temporal cortex and greater gray matter density in left insular/frontoparietal operculum cortex and bilateral thalamic cortex. Exploratory analyses suggest that these abnormalities might differ according to gender. Conclusions Bipolar disorder is associated with volumetric and gray matter density changes that involve brain regions hypothesized to influence mood.