Antidepressant medication exposure and 5-HT1A autoreceptor binding in major depressive disorder.

OBJECTIVE: We have previously reported higher brain serotonin 1A (5-HT1A ) autoreceptor binding in antidepressant-naïve patients with Major Depressive Disorder (MDD) compared with healthy volunteers, and a decrease in binding in MDD after selective serotonin reuptake inhibitor (SSRI) treatment. This SSRI effect is also present in rodents administered SSRIs chronically. We therefore sought to determine the duration of antidepressant medication effects on 5-HT1A receptor binding after medication discontinuation. METHODS: Positron emission tomography (PET) imaging with the 5-HT1A receptor radioligand [11 C]WAY-100635 was performed in 66 individuals with current DSM-IV MDD to examine relationships between 5-HT1A binding and time since most recent antidepressant treatment. All subjects were medication-free for at least 2 weeks prior to scanning. Thirty-two additional MDD comparison subjects were antidepressant naïve. RESULTS: No differences in [11 C]WAY-100635 binding were observed between antidepressant naïve and antidepressant exposed MDD groups in 13 a priori cortical and subcortical regions of interest, including raphe autoreceptors, assessed simultaneously in linear mixed effects models. Furthermore, [11 C]WAY-100635 binding did not correlate with time off antidepressants in the antidepressant exposed patients considering these ROIs. The same results were observed when effects of treatment discontinuation of any psychotropic medication used to treat their depression was examined. CONCLUSION: These results indicate that any antidepressant-associated downregulation of 5-HT1A autoreceptor binding reverses within 2 weeks of medication discontinuation. Since this effect is hypothesized to mediate the antidepressant action of SSRIs, and perhaps other antidepressants, it suggests that patients who need ongoing treatment may relapse rapidly when medication is discontinued. Moreover, 2 weeks appears to be a sufficiently long washout of antidepressant medications for a reliable measure of illness-related binding levels.

Whole-transcriptome brain expression and exon-usage profiling in major depression and suicide: evidence for altered glial, endothelial and ATPase activity.

Brain gene expression profiling studies of suicide and depression using oligonucleotide microarrays have often failed to distinguish these two phenotypes. Moreover, next generation sequencing approaches are more accurate in quantifying gene expression and can detect alternative splicing. Using RNA-seq, we examined whole-exome gene and exon expression in non-psychiatric controls (CON, N=29), DSM-IV major depressive disorder suicides (MDD-S, N=21) and MDD non-suicides (MDD, N=9) in the dorsal lateral prefrontal cortex (Brodmann Area 9) of sudden death medication-free individuals post mortem. Using small RNA-seq, we also examined miRNA expression (nine samples per group). DeSeq2 identified 35 genes differentially expressed between groups and surviving adjustment for false discovery rate (adjusted P<0.1). In depression, altered genes include humanin-like-8 (MTRNRL8), interleukin-8 (IL8), and serpin peptidase inhibitor, clade H (SERPINH1) and chemokine ligand 4 (CCL4), while exploratory gene ontology (GO) analyses revealed lower expression of immune-related pathways such as chemokine receptor activity, chemotaxis and cytokine biosynthesis, and angiogenesis and vascular development in (adjusted P<0.1). Hypothesis-driven GO analysis suggests lower expression of genes involved in oligodendrocyte differentiation, regulation of glutamatergic neurotransmission, and oxytocin receptor expression in both suicide and depression, and provisional evidence for altered DNA-dependent ATPase expression in suicide only. DEXSEq analysis identified differential exon usage in ATPase, class II, type 9B (adjusted P<0.1) in depression. Differences in miRNA expression or structural gene variants were not detected. Results lend further support for models in which deficits in microglial, endothelial (blood-brain barrier), ATPase activity and astrocytic cell functions contribute to MDD and suicide, and identify putative pathways and mechanisms for further study in these disorders.

A pilot in vivo proton magnetic resonance spectroscopy study of amino acid neurotransmitter response to ketamine treatment of major depressive disorder.

The N-methyl-D-aspartate receptor antagonist ketamine can improve major depressive disorder (MDD) within hours. To evaluate the putative role of glutamatergic and GABAergic systems in ketamine's antidepressant action, medial prefrontal cortical (mPFC) levels of glutamate+glutamine (Glx) and γ-aminobutyric acid (GABA) were measured before, during, and after ketamine administration using proton magnetic resonance spectroscopy. Ketamine (0.5 mg kg(-1) intravenously) was administered to 11 depressed patients with MDD. Glx and GABA mPFC responses were measured as ratios relative to unsuppressed voxel tissue water (W) successfully in 8/11 patients. Ten of 11 patients remitted (50% reduction in 24-item Hamilton Depression Rating Scale and total score ⩽10) within 230 min of commencing ketamine. mPFC Glx/W and GABA/W peaked at 37.8%±7.5% and 38.0%±9.1% above baseline in ~26 min. Mean areas under the curve for Glx/W (P=0.025) and GABA/W (P=0.005) increased and correlated (r=0.796; P=0.018). Clinical improvement correlated with 90-min norketamine concentration (df=6, r=-0.78, P=0.023), but no other measures.

Risperidone-induced topological alterations of anatomical brain network in first-episode drug-naive schizophrenia patients: a longitudinal diffusion tensor imaging study.

BACKGROUND: It remains unclear whether the topological deficits of the white matter network documented in cross-sectional studies of chronic schizophrenia patients are due to chronic illness or to other factors such as antipsychotic treatment effects. To answer this question, we evaluated the white matter network in medication-naive first-episode schizophrenia patients (FESP) before and after a course of treatment. METHOD: We performed a longitudinal diffusion tensor imaging study in 42 drug-naive FESP at baseline and then after 8 weeks of risperidone monotherapy, and compared them with 38 healthy volunteers. Graph theory was utilized to calculate the topological characteristics of brain anatomical network. Patients' clinical state was evaluated using the Positive and Negative Syndrome Scale (PANSS) before and after treatment. RESULTS: Pretreatment, patients had relatively intact overall topological organizations, and deficient nodal topological properties primarily in prefrontal gyrus and limbic system components such as the bilateral anterior and posterior cingulate. Treatment with risperidone normalized topological parameters in the limbic system, and the enhancement positively correlated with the reduction in PANSS-positive symptoms. Prefrontal topological impairments persisted following treatment and negative symptoms did not improve. CONCLUSIONS: During the early phase of antipsychotic medication treatment there are region-specific alterations in white matter topological measures. Limbic white matter topological dysfunction improves with positive symptom reduction. Prefrontal deficits and negative symptoms are unresponsive to medication intervention, and prefrontal deficits are potential trait biomarkers and targets for negative symptom treatment development.

Dopamine and serotonin signaling during two sensitive developmental periods differentially impact adult aggressive and affective behaviors in mice.

Pharmacologic blockade of monoamine oxidase A (MAOA) or serotonin transporter (5-HTT) has antidepressant and anxiolytic efficacy in adulthood. Yet, genetically conferred MAOA or 5-HTT hypoactivity is associated with altered aggression and increased anxiety/depression. Here we test the hypothesis that increased monoamine signaling during development causes these paradoxical aggressive and affective phenotypes. We find that pharmacologic MAOA blockade during early postnatal development (P2-P21) but not during peri-adolescence (P22-41) increases anxiety- and depression-like behavior in adult (>P90) mice, mimicking the effect of P2-21 5-HTT inhibition. Moreover, MAOA blockade during peri-adolescence, but not P2-21 or P182-201, increases adult aggressive behavior, and 5-HTT blockade from P22-P41 reduced adult aggression. Blockade of the dopamine transporter, but not the norepinephrine transporter, during P22-41 also increases adult aggressive behavior. Thus, P2-21 is a sensitive period during which 5-HT modulates adult anxiety/depression-like behavior, and P22-41 is a sensitive period during which DA and 5-HT bi-directionally modulate adult aggression. Permanently altered DAergic function as a consequence of increased P22-P41 monoamine signaling might underlie altered aggression. In support of this hypothesis, we find altered aggression correlating positively with locomotor response to amphetamine challenge in adulthood. Proving that altered DA function and aggression are causally linked, we demonstrate that optogenetic activation of VTA DAergic neurons increases aggression. It therefore appears that genetic and pharmacologic factors impacting dopamine and serotonin signaling during sensitive developmental periods can modulate adult monoaminergic function and thereby alter risk for aggressive and emotional dysfunction.

Life events: a complex role in the timing of suicidal behavior among depressed patients.

Suicidal behavior is often conceptualized as a response to overwhelming stress. Our model posits that given a propensity for acting on suicidal urges, stressors such as life events or major depressive episodes (MDEs) determine the timing of suicidal acts. Depressed patients (n=415) were assessed prospectively for suicide attempts and suicide, life events and MDE over 2 years. Longitudinal data were divided into 1-month intervals characterized by MDE (yes/no), suicidal behavior (yes/no) and life event scores. Marginal logistic regression models were fit, with suicidal behavior as the response variable and MDE and life event score in either the same or previous month, respectively, as time-varying covariates. Among 7843 person-months, 33% had MDE and 73% had life events. MDE increased the risk for suicidal behavior (odds ratio (OR)=4.83, P⩽0.0001). Life event scores were unrelated to the timing of suicidal behavior (OR=1.06 per 100 point increase, P=0.32), even during a MDE (OR=1.12, P=0.15). However, among those without borderline personality disorder (BPD), both health- and work-related life events were key precipitants, as was recurrent MDE, with a 13-fold effect. The relationship of life events to suicidal behavior among those with BPD was more complex. Recurrent MDE was a robust precipitant for suicidal behavior, regardless of BPD comorbidity. The specific nature of life events is key to understanding the timing of suicidal behavior. Given unanticipated results regarding the role of BPD and study limitations, these findings require replication. Of note, that MDE, a treatable risk factor, strongly predicts suicidal behaviors is cause for hope.

Neuropsychological deficits in past suicide attempters with varying levels of depression severity.

BACKGROUND: Our previous work identified deficits in interference processing and learning/memory in past suicide attempters who were currently depressed and medication-free. In this study, we extend this work to an independent sample studied at various stages of illness and treatment (mild symptoms, on average) to determine if these deficits in past suicide attempters are evident during a less severe clinical state. METHOD: A total of 80 individuals with a past history of major depression and suicide attempt were compared with 81 individuals with a history of major depression and no lifetime suicide attempts on a battery of neurocognitive measures assessing attention, memory, abstract/contingent learning, working memory, language fluency and impulse control. RESULTS: Past attempters performed more poorly in attention, memory and working memory domains, but also in an estimate of pre-morbid intelligence. After correction for this estimate, tests that had previously distinguished past attempters - a computerized Stroop task and the Buschke Selective Reminding Test - remained significantly worse in attempters. In a secondary analysis, similar differences were found among those with the lowest levels of depression (Hamilton Depression Rating Scale score <10), suggesting that these deficits may be trait markers independent of current symptomatology. CONCLUSIONS: Deficits in interference processing and learning/memory constitute an enduring defect in information processing that may contribute to poor adaptation, other higher-order cognitive impairments and risk for suicidal behavior.

Neuropsychological function and suicidal behavior: attention control, memory and executive dysfunction in suicide attempt.

BACKGROUND: Executive dysfunction, distinct from other cognitive deficits in depression, has been associated with suicidal behavior. However, this dysfunction is not found consistently across samples. METHOD: Medication-free subjects with DSM-IV major depressive episode (major depressive disorder and bipolar type I disorder) and a past history of suicidal behavior (n = 72) were compared to medication-free depressed subjects with no history of suicidal behavior (n = 80) and healthy volunteers (n = 56) on a battery of tests assessing neuropsychological functions typically affected by depression (motor and psychomotor speed, attention, memory) and executive functions reportedly impaired in suicide attempters (abstract/contingent learning, working memory, language fluency, impulse control). RESULTS: All of the depressed subjects performed worse than healthy volunteers on motor, psychomotor and language fluency tasks. Past suicide attempters, in turn, performed worse than depressed non-attempters on attention and memory/working memory tasks [a computerized Stroop task, the Buschke Selective Reminding Task (SRT), the Benton Visual Retention Test (VRT) and an N-back task] but not on other executive function measures, including a task associated with ventral prefrontal function (Object Alternation). Deficits were not accounted for by current suicidal ideation or the lethality of past attempts. A small subsample of those using a violent method in their most lethal attempt showed a pattern of poor executive performance. CONCLUSIONS: Deficits in specific components of attention control, memory and working memory were associated with suicidal behavior in a sample where non-violent attempt predominated. Broader executive dysfunction in depression may be associated with specific forms of suicidal behavior, rather than suicidal behavior per se.

Pollen counts and suicide rates. Association not replicated.

OBJECTIVE: To replicate a previously reported association between pollen counts and county suicide rates in the continental United States, across space and time. METHOD: The authors evaluated the relationship between airborne pollen counts and suicide rates in 42 counties of the continental United States, containing a pollen-counting station participating in the Aeroallergen Monitoring Network in the United States (N = 120,076 suicides), considering years' quarter, age group, sex, race, rural/urban location, number of local psychiatrists, and median household income, from 1999 to 2002. The county-level effects were broken into between-county and within-county. RESULTS: No within-county effects were found. Between-county effects for grass and ragweed pollen on suicide rates lost statistical significance after adjustment for median income, number of psychiatrists, and urban vs. rural location. CONCLUSION: Future research is necessary to reappraise the previously reported relationship between pollen levels and suicide rates that may have been driven by socioeconomic confounders.

The effect of social adjustment and attachment style on suicidal behaviour.

OBJECTIVE: Prior studies examining the relationship between social adjustment and suicidal ideation or behaviour have not examined attachment. This study examines the effect of attachment on the association between current social adjustment and suicide attempt risk. METHOD: Attachment, social adjustment, and history of suicide attempt were assessed in patients participating in research on major depressive disorder (N = 524). Suicide attempters and non-attempters were compared with attachment style and social adjustment using hierarchical logistic regression models. The two factor scoring method of the Adult Attachment Scale (secure vs. avoidant) was utilized as each measures unique aspects of attachment. RESULTS: Anxious attachment (OR = 1.33; 95% CI = 1.016-1.728; P = 0.038) but not overall social adjustment (P = 0.14) was associated with a history of a past suicide attempt when both attachment and social adjustment were assessed in the same model. Among subtypes of social adjustment, work adjustment was associated with past history of suicide attempt (OR = 1.25; 95%CI = 1.019-1.540; P = 0.033). As impairment in work adjustment increased by 1 unit, the likelihood of reporting a suicide attempt increased by approximately 25%. There was no interaction between anxious attachment and work adjustment (P = 0.81). CONCLUSION: Anxious attachment and work adjustment warrant further study as potential treatment targets in depressed suicidal patients.

Biodistribution, toxicology, and radiation dosimetry of 5-HT1A-receptor agonist positron emission tomography ligand [11C]CUMI-101.

Sprague Dawley rats (10/sex/group) were given a single intravenous (iv) dose of CUMI-101 to determine acute toxicity of CUMI-101 and radiation dosimetry estimations were conducted in baboons with [(11)C]CUMI-101. Intravenous administration of CUMI-101 did not produce overt biologically or toxicologically significant adverse effects except transient hypoactivity immediately after dose in the mid- and high-dose groups, which is not considered to be a dose-limiting toxic effect. No adverse effects were observed in the low-dose group. The no observed adverse effect level (NOAEL) is considered to be 44.05 µg/kg for a single iv dose administration in rats. The maximum tolerated dose (MTD) was estimated to be 881 µg/kg for a single iv dose administration. The Medical Internal Radiation Dose (MIRDOSE) estimates indicate the maximum permissible single-study dosage of [(11)C]CUMI-101 in humans is 52 mCi with testes and urinary bladder as the critical organ for males and females, respectively.

Evaluation of volume-based and surface-based brain image registration methods.

Establishing correspondences across brains for the purposes of comparison and group analysis is almost universally done by registering images to one another either directly or via a template. However, there are many registration algorithms to choose from. A recent evaluation of fully automated nonlinear deformation methods applied to brain image registration was restricted to volume-based methods. The present study is the first that directly compares some of the most accurate of these volume registration methods with surface registration methods, as well as the first study to compare registrations of whole-head and brain-only (de-skulled) images. We used permutation tests to compare the overlap or Hausdorff distance performance for more than 16,000 registrations between 80 manually labeled brain images. We compared every combination of volume-based and surface-based labels, registration, and evaluation. Our primary findings are the following: 1. de-skulling aids volume registration methods; 2. custom-made optimal average templates improve registration over direct pairwise registration; and 3. resampling volume labels on surfaces or converting surface labels to volumes introduces distortions that preclude a fair comparison between the highest ranking volume and surface registration methods using present resampling methods. From the results of this study, we recommend constructing a custom template from a limited sample drawn from the same or a similar representative population, using the same algorithm used for registering brains to the template.

Elevated expression of tryptophan hydroxylase-2 mRNA at the neuronal level in the dorsal and median raphe nuclei of depressed suicides.

Deficient levels of serotonin are associated with suicide and depression. Paradoxically, in the dorsal raphe nucleus (DRN) there are more serotonin neurons and more neuronal tryptophan hydroxylase-2 (TPH2) expression postmortem in depressed suicides. In this study, we sought to determine whether greater TPH2 expression in depressed suicides was the result of more TPH2 expression per neuron. In situ hybridization and computer-assisted image analysis were performed on tissue sections throughout the extent of the raphe nuclei at the level of silver grains per neuron to systematically quantify TPH2 neuronal expression. Depressed suicides have 26.5% more TPH2 grain density per neuron in the DRN compared with matched controls (P=0.04). The difference in grain density is greater at mid- and caudal anatomical levels across the rostrocaudal axis of the DRN. Densitometric analysis of TPH2 expression in the DRN subnuclei showed that higher expression levels were observed at posterior anatomical levels of depressed suicides (121% of control in the caudal subnucleus). Higher TPH2 expression in depressed suicides may explain more TPH2 protein and reflect a homeostatic response to deficient serotonin levels in the brains of depressed suicides. Localized changes in TPH2 expression in specific subnuclei of the DRN suggest that the serotonergic compensatory mechanism in depression and suicide is specifically regulated within the DRN and has implications for regions innervated by this subnucleus.

Genetic architecture of the human tryptophan hydroxylase 2 Gene: existence of neural isoforms and relevance for major depression.

Impaired brain serotonin neurotransmission is a potential component of the diathesis of major depression. Tryptophan hydroxylase-2 (TPH2), is the rate limiting biosynthetic isoenzyme for serotonin that is preferentially expressed in the brain and a cause of impaired serotonin transmission. Here, we identify a novel TPH2 short isoform with truncated catalytic domain expressed in human brainstem, prefrontal cortex, hippocampus and amygdala. An exploratory study of 166 Caucasian subjects revealed association with major depression or suicide of a novel single nucleotide polymorphism (SNP) g.22879A>G located in exon 6 of this short isoform. This SNP and additional SNPs were discovered through a systematic characterization of the genetic architecture of the TPH2 gene for further genetic and functional investigations of its relationship to major depression and other psychopathology.

Mental symptoms in Huntington's disease and a possible primary aminergic neuron lesion.

Monoamine oxidase activity was higher in the cerebral cortex and basal ganglia of patients dying from Huntington's disease than in controls. Enzyme kinetics and multiple substrate studies indicated that the increased activity was due to elevated concentrations of monoamine oxidase type B. Concentrations of homovanillic acid were increased in the cerebral cortex but not in the basal ganglia of brains of patients with Huntington's disease. These changes may represent a primary aminergic lesion that could underlie some of the mental symptoms of this disease.

Multivariate meta-analyses of mitochondrial complex I and IV in major depressive disorder, bipolar disorder, schizophrenia, Alzheimer disease, and Parkinson disease.

Complex I (NADH dehydrogenase, NDU) and complex IV (cytochrome-c-oxidase, COX) of the mitochondrial electron transport chain have been implicated in the pathophysiology of major psychiatric disorders, such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ), as well as in neurodegenerative disorders, such as Alzheimer disease (AD) and Parkinson disease (PD). We conducted meta-analyses comparing complex I and IV in each disorder MDD, BD, SZ, AD, and PD, as well as in normal aging. The electronic databases Pubmed, EMBASE, CENTRAL, and Google Scholar, were searched for studies published between 1980 and 2018. Of 2049 screened studies, 125 articles were eligible for the meta-analyses. Complex I and IV were assessed in peripheral blood, muscle biopsy, or postmortem brain at the level of enzyme activity or subunits. Separate meta-analyses of mood disorder studies, MDD and BD, revealed moderate effect sizes for similar abnormality patterns in the expression of complex I with SZ in frontal cortex, cerebellum and striatum, whereas evidence for complex IV alterations was low. By contrast, the neurodegenerative disorders, AD and PD, showed strong effect sizes for shared deficits in complex I and IV, such as in peripheral blood, frontal cortex, cerebellum, and substantia nigra. Beyond the diseased state, there was an age-related robust decline in both complexes I and IV. In summary, the strongest support for a role for complex I and/or IV deficits, is in the pathophysiology of PD and AD, and evidence is less robust for MDD, BD, or SZ.

Psychotropic and neurological medication effects on mitochondrial complex I and IV in rodent models.

Mitochondrial complex I (NADH-dehydrogenase) and complex IV (cytochrome-c-oxidase) are reported to be affected by drugs used to treat psychiatric or neurodegenerative diseases, including antidepressants, antipsychotics, anxiolytics, mood stabilizers, stimulants, antidementia, and antiparkinsonian drugs. We conducted meta-analyses examining the effects of each drug category on complex I and IV. The electronic databases Pubmed, EMBASE, CENTRAL, and Google Scholar were searched for studies published between 1970 and 2018. Of 3105 screened studies, 68 articles covering 53 drugs were included in the meta-analyses. All studies assessed complex I and IV in rodent brain at the level of enzyme activity. Results revealed that selected antidepressants increase or decrease complex I and IV, antipsychotics and stimulants decrease complex I but increase complex IV, whereas anxiolytics, mood stabilizers, antidementia, and antiparkinsonian drugs preserve or even enhance both complex I and IV. Potential contributions to the drug effects were found to be related to the drugs' neurotransmitter receptor profiles with adrenergic (α1B), dopaminergic (D1/2), glutaminergic (NMDA1,3), histaminergic (H1), muscarinic (M1,3), opioid (OP1-3), serotonergic (5-HT2A, 5-HT2C, 5-HT3A) and sigma (σ1) receptors having the greatest effects. The findings are discussed in relation to pharmacological mechanisms of action that might have relevance for clinical and research applications.

Effect of BDNF val66met polymorphism on age-related amygdala volume changes in healthy subjects.

Brain-derived neurotrophic factor (BDNF) has been implicated in the mechanism of age-related regional brain volumetric changes. Healthy volunteers with the valine to methionine polymorphism at codon 66 of the BDNF gene (val66met) exhibit decreased volume of a number of brain structures, including hippocampus, temporal and occipital lobar gray matter volumes, and a negative correlation between age and the volume of bilateral dorsolateral prefrontal cortices. We sought to characterize the relationship between age, BDNF and amygdala volumes among healthy volunteers. We measured amygdala volumes in 55 healthy, right-handed volunteers who underwent structural magnetic resonance imaging (MRI) and were also characterized demographically and genotyped with respect to BDNF. Using an ANCOVA model, we found that amygdala volumes were inversely correlated with age in BDNF val66met carriers but not in non-carriers. This is the first report of age-related BDNF val66met polymorphism effects on amygdala volume.

Evaluation of clinical prognostic models for suicide attempts after a major depressive episode.

OBJECTIVE: In this study, we compare the performance of prognostic models of increasing complexity for prediction of future suicide attempt. METHOD: Using data from a 2-year prospective study of 304 depressed subjects, a series of Cox proportional hazard regression models were developed to predict future suicide attempt. The models were evaluated in terms of discrimination (the ability to rank subjects in order of risk), calibration (accuracy of predicted probabilities of attempt), and sensitivity and specificity of risk group stratification based on cross-validated predicted probabilities. RESULTS: Although an additive model with past attempt, smoking status, and suicidal ideation achieved 75% (cross-validated) sensitivity and specificity, models that performed best in terms of discrimination included interactions between predictor variables. CONCLUSION: As several models had similar predictive power, clinical considerations and ease of interpretation may have a significant role in the final stage of model selection for assessing future suicide attempt risk.