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1.  The serotonergic system in mood disorders and suicidal behaviour 
A stress-diathesis explanatory model of suicidal behaviour has proved to be of heuristic value, and both clinical and neurobiological components can be integrated into such a model. A trait deficiency in serotonin input to the anterior cingulate and ventromedial prefrontal cortex is found in association with suicide, and more recently non-fatal suicidal behaviour, and is linked to decision-making and suicide intent by imaging and related studies in vivo. The same neural circuitry and serotonin deficiency may contribute to impulsive aggressive traits that are part of the diathesis for suicidal behaviour and are associated with early onset mood disorders and greater risk for suicidal behaviour. Other brain areas manifest deficient serotonin input, that is, a trait related to recurrent major depressive disorder and bipolar disorder. Thus the serotonin system is involved in both the diathesis for suicidal behaviour in terms of decision-making, and to a major stressor, namely episodes of major depression.
PMCID: PMC3638390  PMID: 23440471
serotonin; suicide; mood disorders
2.  Teaching Evidence-Based Approaches to Suicide Risk Assessment and Prevention that Enhance Psychiatric Training 
Comprehensive psychiatry  2012;54(3):201-208.
This report describes one in a series of National Institute of Health (NIH) supported conferences aimed at enhancing the ability of leaders of psychiatry residency training to teach research literacy and produce both clinician-scholars and physician-scientists in their home programs. Most psychiatry training directors would not consider themselves research scholars or even well-schooled in evidence based practice. Yet they are the front line educators to prepare tomorrow’s psychiatrists to keep up with, critically evaluate, and in some cases actually participate in the discovery of new and emerging psychiatric knowledge. This annual conference is meant to help psychiatry training directors become more enthusiastic, knowledgeable and pedagogically prepared to create research-friendly environments at their home institutions, so that more trainees will, in turn, become research literate, practice evidence-based psychiatry, and enter research fellowships and careers. The overall design of each year’s meeting is a series of plenary sessions introducing participants to new information pertaining to the core theme of that year’s meeting, integrated with highly interactive small group teaching sessions designed to consolidate knowledge and provide pragmatic teaching tools appropriate for residents at various levels of training. The theme of each meeting, selected to be a compelling and contemporary clinical problem, serves as a vehicle to capture training directors’ attention while teaching relevant brain science, research literacy and effective pedagogy. This report describes the content and assessment of the 2011 annual pre-meeting, “Evidence-based Approaches to Suicide Risk Assessment and Prevention: Insights from the Neurosciences and Behavioral Sciences for use in Psychiatry Residency Training.”
PMCID: PMC3529811  PMID: 22995449
Depression and anxiety  2013;30(3):10.1002/da.22019.
Brain serotonin-1A receptors (5-HT1A) are implicated in anxiety. We compared regional brain 5-HT1A binding in medication-free participants with posttraumatic stress disorder (PTSD) and healthy volunteers using fully quantitative positron emission tomography (PET) methods.
Twenty patients with DSM-IV PTSD (13 with comorbid major depressive disorder, [MDD]) and 49 healthy volunteers underwent PET imaging with 5-HT1A antagonist radioligand [C-11]WAY100635. Arterial blood sampling provided a metabolite-corrected input function and the concentration of free ligand in plasma (fP) for estimation of regional binding potential, BPF ( = Bavailable /KD). Linear mixed modeling compared BPF between groups across regions of interest (ROIs).
The PTSD group had higher 5-HT1A BPF across brain ROIs (P = .0006). Post hoc comparisons showed higher 5-HT1A BPF in PTSD in all cortical ROIs (26–33%), amygdala (34%), and brainstem raphe nuclei (43%), but not hippocampus. The subgroup of seven PTSD patients without comorbid MDD had higher 5-HT1A BPF compared with healthy volunteers (P = .03).
This is the first report of higher brainstem and forebrain 5-HT1A binding in vivo in PTSD. The finding is independent of MDD. PTSD and MDD have in common an upregulation of 5-HT1A binding including midbrain autoreceptors that would favor less firing and serotonin release. This abnormality may represent a common biomarker of these stress-associated brain disorders.
PMCID: PMC3785097  PMID: 23408467
posttraumatic stress disorder (PTSD); serotonin-1A (5-HT1A); positron emission tomography; WAY100635; major depressive disorder
5.  Relationship Between Antiepileptic Drugs and Suicide Attempts in Patients With Bipolar Disorder 
Archives of general psychiatry  2009;66(12):1354-1360.
On January 31, 2008, the Food and Drug Administration issued an alert regarding increased risk of suicidal thoughts and behavior related to use of antiepileptic drugs (AEDs). On July 10, 2008, a Food and Drug Administration scientific advisory committee voted that, yes, there was a significant positive association between AEDs and suicidality but voted against placing a black box warning on AEDs for suicidality.
To determine if AEDs increase the risk of suicide attempt in patients with bipolar disorder.
A pharmacoepidemiologic study in which suicide attempt rates were compared before and after treatment and with a medication-free control group. Analyses were restricted to AED and lithium monotherapy.
We used the PharMetrics medical claims database to study the relationship between the 11 AEDs identified in the FDA alert, and lithium, to suicide attempts.
Main Outcome Measure
Suicide attempts.
A cohort of 47 918 patients with bipolar disorder with a minimum 1-year window of information before and after the index date of their illness.
Overall, there was no significant difference in suicide attempt rates for patients treated with an AED (13 per 1000 person-years [PY]) vs patients not treated with an AED or lithium (13 per 1000 PY). In AED-treated subjects, the rate of suicide attempts was significantly higher before treatment (72 per 1000 PY) than after (13 per 1000 PY). In patients receiving no concomitant treatment with an antidepressant, other AED, or antipsychotic, AEDs were significantly protective relative to no pharmacologic treatment (3 per 1000 vs 15 per 1000 PY).
Despite Food and Drug Administration reports regarding increased risk of suicidality associated with AED treatment, the current study reveals that, as a class, AEDs do not increase risk of suicide attempts in patients with bipolar disorder relative to patients not treated with an AED or lithium. Use of AEDs reduces suicide attempt rates both relative to patients not receiving any psychotropic medication and relative to their pretreatment levels.
PMCID: PMC3926811  PMID: 19996040
6.  The Columbia–Suicide Severity Rating Scale: Initial Validity and Internal Consistency Findings From Three Multisite Studies With Adolescents and Adults 
The American journal of psychiatry  2011;168(12):1266-1277.
Research on suicide prevention and interventions requires a standard method for assessing both suicidal ideation and behavior to identify those at risk and to track treatment response. The Columbia–Suicide Severity Rating Scale (C-SSRS) was designed to quantify the severity of suicidal ideation and behavior. The authors examined the psychometric properties of the scale.
The C-SSRS’s validity relative to other measures of suicidal ideation and behavior and the internal consistency of its intensity of ideation subscale were analyzed in three multisite studies: a treatment study of adolescent suicide attempters (N=124); a medication efficacy trial with depressed adolescents (N=312); and a study of adults presenting to an emergency department for psychiatric reasons (N=237).
The C-SSRS demonstrated good convergent and divergent validity with other multi-informant suicidal ideation and behavior scales and had high sensitivity and specificity for suicidal behavior classifications compared with another behavior scale and an independent suicide evaluation board. Both the ideation and behavior subscales were sensitive to change over time. The intensity of ideation subscale demonstrated moderate to strong internal consistency. In the adolescent suicide attempters study, worst-point lifetime suicidal ideation on the C-SSRS predicted suicide attempts during the study, whereas the Scale for Suicide Ideation did not. Participants with the two highest levels of ideation severity (intent or intent with plan) at baseline had higher odds for attempting suicide during the study.
These findings suggest that the C-SSRS is suitable for assessment of suicidal ideation and behavior in clinical and research settings.
PMCID: PMC3893686  PMID: 22193671
7.  Therapeutic mechanisms of a mindfulness-based treatment for IBS: Effects on visceral sensitivity, catastrophizing, and affective processing of pain sensations 
Journal of behavioral medicine  2011;10.1007/s10865-011-9391-z.
Irritable bowel syndrome (IBS) is a prevalent functional disorder characterized by abdominal pain and hypervigilance to gastrointestinal sensations. We hypothesized that mindfulness training (MT), which promotes nonreactive awareness of emotional and sensory experience, may target underlying mechanisms of IBS including affective pain processing and catastrophic appraisals of gastrointestinal sensations. Seventy five female IBS patients were randomly assigned to participate in either 8 weeks of MT or a social support group. A theoretically grounded, multivariate path model tested therapeutic mediators of the effect of MT on IBS severity and quality of life. Results suggest that MT exerts significant therapeutic effects on IBS symptoms by promoting nonreactivity to gut-focused anxiety and catastrophic appraisals of the significance of abdominal sensations coupled with a refocusing of attention onto interoceptive data with less emotional interference. Hence, MT appears to target and ameliorate the underlying pathogenic mechanisms of IBS.
PMCID: PMC3883954  PMID: 22161025
Mindfulness; irritable bowel syndrome; pain; therapeutic mechanisms; path analysis; interoception
8.  Regional Brain Glucose Uptake Distinguishes Suicide Attempters from Non-Attempters in Major Depression 
This study compared regional cerebral metabolic rates of glucose (rCMRglu) determined by [18F]-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) in suicide attempters and non-attempters.
Medication-free patients with major depression (n=29) had FDG-PET after single-blind administration of placebo (day 1) and fenfluramine (day 2). Suicide attempt history was obtained before scanning and at assessments over two subsequent years. Statistical parametric mapping evaluated associations between attempt status and rCMRglu, controlling for age.
The study included 13 patients with and 16 without a history of suicide attempt within 2 years before or after scanning. After placebo, rCMRglu in attempters was lower in right dorsolateral prefrontal regions and higher in ventromedial regions than in non-attempters. After fenfluramine, relatively hypometabolic areas enlarged, and no hypermetabolic areas were detected.
Distinct rCMRglu patterns may be serotonin-sensitive biomarkers of suicide risk.
PMCID: PMC3831169  PMID: 24224676
Suicide; Major Depressive Disorder; Bipolar Disorder; positron emission tomography; FDG
9.  Neural responses to incongruency in a blocked-trial Stroop fMRI task in major depressive disorder 
Journal of affective disorders  2012;143(1-3):241-247.
Patients with major depressive disorder (MDD) perform poorly on the Stroop task, which is a measure of the executive control of attention, with impaired interference resolution. The neural correlates of this deficit are not well described. To examine how this deficit relates to pathophysiological abnormalities in MDD, we conducted an fMRI Stroop study comparing MDD subjects to controls.
Forty-two unmedicated patients with current MDD and 17 control subjects underwent fMRI scanning with a color-word Stroop task. Subjects assessed font color during alternating color identification (ex. ‘XXXX’ in blue) and incongruent color/word blocks (ex. the word ‘red’ in blue). We examined neural activation that was greater in incongruent than color identification blocks (Z>2.3 and corrected p<0.05), controlling for trial-by-trial reaction time.
Compared to controls, MDD subjects exhibited lower activation during incongruent blocks across multiple brain regions, including middle frontal gyrus, paracingulate and posterior cingulate, precuneus, occipital regions, and brain stem. No brain regions were identified in which MDD subjects were more active than controls during incongruent blocks.
Not all MDD subjects were antidepressant-naïve.
Brain regions related to executive function, visual processing, and semantic processing are less active during processing of incongruent stimuli in MDD subjects as compared to controls. Deficits of attention in MDD may be the product of a failure to maintain activity across a distributed network in a sustained manner, as is required over the sequential trials in this block design. Further studies may clarify whether the abnormalities represent a trait or state deficit.
PMCID: PMC3501555  PMID: 22995943
Stroop task; functional magnetic resonance imaging; depression; executive function; incongruency; attention
10.  A large-scale candidate gene analysis of mood disorders: evidence of neurotrophic tyrosine kinase receptor and opioid receptor signaling dysfunction 
Psychiatric genetics  2013;23(2):10.1097/YPG.0b013e32835d7028.
Despite proven heritability, little is known about the genetic architecture of mood disorders. Although a number of family and case–control studies have examined the genetics of mood disorders, none have carried out joint linkage-association studies and sought to validate the results with gene expression analyses in an independent cohort.
We present findings from a large candidate gene study that combines linkage and association analyses using families and singletons, providing a systematic candidate gene investigation of mood disorder. For this study, 876 individuals were recruited, including 83 families with 313 individuals and 563 singletons. This large-scale candidate gene analysis included 130 candidate genes implicated in addictive and other psychiatric disorders. These data showed significant genetic associations for 28 of these candidate genes, although none remained significant after correction for multiple testing. To evaluate the functional significance of these 28 candidate genes in mood disorders, we examined the transcriptional profiles of these genes within the dorsolateral prefrontal cortex and anterior cingulate for 21 cases with mood disorders and 25 nonpsychiatric controls, and carried out a pathway analysis to identify points of high connectivity suggestive of particular molecular pathways that may be dysregulated.
Two primary gene candidates were supported by the linkage-association, gene expression profiling, and network analysis: neurotrophic tyrosine kinase receptor, type 2 (NTRK2), and the opioid receptor, κ1 (OPRK1).
This study supports a role for NTRK2 and OPRK1 signaling in the pathophysiology of mood disorder. The unique approach incorporating evidence from multiple experimental and computational modalities enhances confidence in these findings.
PMCID: PMC3869619  PMID: 23277131
linkage and association; mood disorders; neurotrophic tyrosine kinase receptor; opioid receptor; type 2; κ1
11.  CSF monoamine metabolites and lethality of suicide attempts in depressed patients with alcohol dependence 
Alcohol dependence (alcoholism) and major depressive disorder are frequently comorbid and are risk factors for suicidal behavior. Monoaminergic abnormalities have been implicated in the pathophysiology of depression, alcohol dependence, and suicidal behavior. Lower cerebrospinal fluid (CSF) 5-hydroxyindolacetic acid (5-HIAA) levels are associated with higher lethality of suicide attempts in major depression and predict a higher rate of future suicide. We sought to study the relationship of CSF monoamine metabolites to lethality of suicidal acts in depressed subjects with comorbid alcoholism.
We compared 16 high-and 16 low-lethality drug-free depressed suicide attempters with comorbid alcoholism. Subjects were free from any substance use disorder for at least two months. Demographic and clinical parameters, and CSF 5-HIAA, homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels were examined.
The two groups did not differ with regard to the demographic characteristics. CSF 5-HIAA levels were lower in high-lethality attempters compared to low-lethality attempters. There were no group difference in CSF HVA or MHPG levels.
Higher lethality of suicidal behavior in depressed patients with alcoholism is related to lower serotonergic activity.
PMCID: PMC3869621  PMID: 16762535
CSF monoamine metabolites; Suicide attempts; Alcohol dependence; Major depressive disorder; Low serotonergic activity
12.  SEP-225289 Serotonin and Dopamine Transporter Occupancy: A PET Study 
SEP-225289 is a novel compound that, based on in vitro potencies for transporter function, potentially inhibits reuptake at dopamine, norepinephrine, and serotonin transporters. An open-label PET study was conducted during the development of SEP-225289 to investigate its dopamine and serotonin transporter occupancy.
Different single doses of SEP-225289 were administered to healthy volunteers in 3 cohorts: 8 mg (n = 7), 12 mg (n = 5), and 16 mg (n = 7). PET was performed before and approximately 24 h after oral administration of SEP-225289, to assess occupancy at trough levels. Dopamine and serotonin transporter occupancies were estimated from PET using 11C-N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl) nortropane (11C-PE2I) and 11C-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine (11C-DASB), respectively. Plasma concentration of SEP-225289 was assessed before ligand injection, and subjects were monitored for adverse events.
Average dopamine and serotonin transporter occupancies increased with increasing doses of SEP-225289. Mean dopamine and serotonin transporter occupancies were 33% ± 11% and 2% ± 13%, respectively, for 8 mg; 44% ± 4% and 9% ± 10%, respectively, for 12 mg; and 49% ± 7% and 14% ± 15%, respectively, for 16 mg. On the basis of the relationship between occupancy and plasma concentration, dopamine transporter IC50 (the plasma concentration of drug at 50% occupancy) was determined (4.5 ng/mL) and maximum dopamine transporter occupancy was extrapolated (85%); however, low serotonin transporter occupancy prevented similar serotonin transporter calculations. No serious adverse events were reported.
At the doses evaluated, occupancy of the dopamine transporter was significantly higher than that of the serotonin transporter, despite similar in vitro potencies, confirming that, in addition to in vitro assays, PET occupancy studies can be instrumental to the drug development process by informing early decisions about indication, dose, and therapeutic potential.
PMCID: PMC3856248  PMID: 21680689
dopamine; serotonin; occupancy; positron emission tomography; SEP-225289
13.  In Vivo Quantification of Human Serotonin 1A Receptor Using 11C-CUMI-101, an Agonist PET Radiotracer 
The serotonin (5-hydroxytryptamine, or 5-HT) type 1A receptor (5-HT1AR) is implicated in the pathophysiology of numerous neuropsychiatric disorders. We have published the initial evaluation and reproducibility in vivo of [O-methyl-11C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5 (2H,4H)dione (11C-CUMI-101), a novel 5-HT1A agonist radiotracer, in Papio anubis. Here, we report the optimal modeling parameters of 11C-CUMI-101 for human PET studies.
PET scans were obtained for 7 adult human volunteers. 11C-CUMI-101 was injected as an intravenous bolus, and emission data were collected for 120 min in 3-dimensional mode. We evaluated 10 different models using metabolite-corrected arterial input functions or reference region approaches and several outcome measures.
When using binding potential (BPF = Bavail/KD [total available receptor concentration divided by the equilibrium dissociation constant]) as the outcome measure, the likelihood estimation in the graphical analysis (LEGA) model performed slightly better than the other methods evaluated at full scan duration. The average test–retest percentage difference was 9.90% ± 5.60%. When using BPND (BPND = fnd × Bavail/KD; BPND equals the product of BPF and fnd [free fraction in the nondisplaceable compartment]), the simplified reference tissue method (SRTM) achieved the lowest percentage difference and smallest bias when compared with nondisplaceable binding potential obtained from LEGA using the metabolite-corrected plasma input function (r2 = 0.99; slope = 0.92). The time–stability analysis indicates that a 120-min scan is sufficient for the stable estimation of outcome measures. Voxel results were comparable to region-of-interest–based analysis, with higher spatial resolution.
On the basis of its measurable and stable free fraction, high affinity and selectivity, good blood–brain barrier permeability, and plasma and brain kinetics, 11C-CUMI-101 is suitable for the imaging of high-affinity 5-HT1A binding in humans.
PMCID: PMC3856257  PMID: 21098796
test–retest reproducibility; kinetic; compartment; voxel; bootstrap
14.  A pilot genome wide association and gene expression array study of suicide with and without major depression 
Suicide is partly heritable but the responsible genes have not been identified. We conducted a gene-centric, low coverage single nucleotide polymorphism (SNP) pilot genome-wide association study (GWAS) seeking new candidate regions in suicides with and without depression, combined with gene expression assay of brain tissue.
Ninety-nine Caucasian subjects, including 68 who completed suicide and 31 who died suddenly from other causes, were genotyped postmortem using GeneChip® Mapping 50K Xba. Clinical data were obtained from relatives. SNPs with Hardy – Weinberg equilibrium P values below 0.001 were excluded from analysis. Illumina chip expression arrays assayed the transcriptome in prefrontal cortex in a drug-free subgroup.
GWAS analysis (cutoff P < 0.001) yielded 58 SNPs, 22 of them in or near 19 known genes, with risk allele-associated odds ratios between 2.7 and 6.9. Diagnosis of mood disorder did not explain the associations. Some of the SNPs matched into four functional groups in gene ontology. Gene expression in the prefrontal and the anterior cingulate cortex for these 19 genes was measured on a separate, though overlapping, sample of suicides and seven of 19 genes showed altered expression in suicides as compared with controls, especially in immune system related genes.
Matching GWAS findings with expression data assesses functional effect of new candidate genes in suicide, and is an alternative form of confirmation or replication study. Results highlight a role for neuroimmunological effects in suicidal behaviour.
PMCID: PMC3493880  PMID: 22059935
Suicide; genetics; mood disorders; single nucleotide polymorphism; psychological autopsy
15.  Testosterone levels in suicide attempters with bipolar disorder 
Journal of psychiatric research  2012;46(10):10.1016/j.jpsychires.2012.06.016.
The best known neurobehavioral effects of testosterone are on sexual function and aggression. However, testosterone and other androgens may be involved in the pathophysiology of mood disorders and suicidal behavior. This is the first study to examine whether there is a relation between testosterone levels and clinical parameters in bipolar suicide attempters.
Patients with a DSM-IV diagnosis of a bipolar disorder (16 males and 51 females), in a depressive or mixed episode with at least one past suicide attempt were enrolled. Demographic and clinical parameters, including lifetime suicidal behavior, were assessed and recorded. Plasma testosterone was assayed using a double antibody radioimmunoassay procedure.
The number of major depressive episodes, the maximum lethality of suicide attempts, and the testosterone levels were higher in men compared to women. Current suicidal ideation scores were higher in women compared to men. Controlling for sex, we found that testosterone levels positively correlated with the number of manic episodes and the number of suicide attempts.
Our findings are consistent with previous observations of the association between testosterone levels and parameters of mood and behavior. This study suggests that testosterone levels may be related to the course of bipolar disorder and suicidal behavior. Further studies of the role of testosterone in the neurobiology of mood disorders and suicidal behavior are merited.
PMCID: PMC3810946  PMID: 22858352
testosterone; bipolar disorder; depression; suicide; smoking
16.  Sleep, psychiatric disorders and suicide 
Journal of psychiatric research  2013;47(1):10.1016/j.jpsychires.2012.09.011.
PMCID: PMC3810958  PMID: 23157799
17.  The potential contribution of tumour-related factors to the development of FOLFOX-induced sinusoidal obstruction syndrome 
British Journal of Cancer  2013;109(9):2396-2403.
Chemotherapy-associated liver injury (CALI) has been linked to increased morbidity and poorer disease-specific outcomes in patients undergoing resection of colorectal liver metastases (CRLM). The aim of this study was to assess the contribution of tumour-related factors to the development of FOLFOX-induced liver injury.
We assessed the effect of FOLFOX treatment on the murine liver either in the presence or absence of CRLM to evaluate the contribution of both chemotherapy and tumour death to the development of CALI.
In the presence of liver metastases, there was increased hepatic expression of plasminogen activator inhibitor-1 (146-fold; P<0.01) and vWF (2.4-fold; P<0.01) transcript as compared with sham-operated controls. In addition, we detected large clusters of megakaryocytes in the spleen of FOLFOX-treated tumour-bearing animals. The livers of FOLFOX-treated animals also showed changes in matrix remodelling genes such as TGFβ (P<0.01), MMP2 (P<0.001), TIMP1 (P<0.001) and Pro-Collagen I (P<0.05) which was exacerbated in the presence of tumour. These genes have previously been demonstrated to have a key role in FOLFOX-induced liver injury.
It appears that the toxicity of FOLFOX chemotherapy is enhanced by tumour-related factors.
PMCID: PMC3817338  PMID: 24113143
sinusoidal obstruction syndrome; colorectal liver metastases; Oxaliplatin; 5-FU
18.  Wolframin gene H611R polymorphism: No direct association with suicidal behavior but possible link to mood disorders☆ 
Wolframin gene polymorphisms, including the H611R polymorphism, are reportedly associated with mood disorders and psychiatric hospitalization, but there is disagreement about the association of this specific variant with suicidality and impulsive traits. This study tested the association of the H611R polymorphism with mood disorders, suicidal behavior, and aggressive–impulsive traits. Two hundred and one subjects with mood disorders and 113 healthy volunteers were genotyped for the H611R polymorphism and underwent structured interviews for diagnosis and clinical ratings. All were Caucasians. The H611R polymorphism was associated with mood disorders but not suicidal behavior, aggressive/impulsive traits or suicidality in first-degree relatives. The HR heterozygote genotype was more frequent in mood disorder (χ2=7.505; df=2; p=.023). If this finding will be replicated, the H611R polymorphism may be a possible marker for mood disorders in a psychiatric population, and not just in relatives of Wolfram syndrome probands.
PMCID: PMC3804895  PMID: 19328217
Depression; Genetics; Mood disorders; Polymorphism; Suicide; Wolfram syndrome
19.  Association of Suicide and Antidepressant Prescription Rates in Japan, 1999–2003 
We examined the relationship of increasing prescription volume of newer antidepressants, introduced in Japan in 1999, to national rates of suicide.
The relationship between annual changes in rates of suicide (obtained from the Japanese Ministry of Health, Labor, and Welfare Vital Statistics Database) and prescription volume of the newer antidepressants paroxetine, fluvoxamine, and milnacipran (obtained from the database of IMS Japan K.K.), stratified by gender and age groups, was modeled statistically for the years 1999 through 2003. Effects of unemployment and alcohol consumption and the interaction of gender and age with antidepressant prescribing were assessed.
From 1999 through 2003 in Japan, total antidepressant prescriptions increased 57% among males and 50% among females. Approximately 80% of this increase involved the selective serotonin reuptake inhibitors (SSRIs). To reduce a limitation of ecological analysis, we compared annual change in prescription and suicide rates, which eliminates the effect of long-term (secular) linear trends. We found an inverse association between year-to-year changes in the suicide rate and prescription volume of newer antidepressants (fluvoxamine, paroxetine, and milnacipran) (β = −1.34, p = .008) and SSRIs specifically (fluvoxamine, paroxetine) (β = −1.41, p = .019). An increase of 1 defined daily dose of SSRI use/1000 population/day was associated with a 6% decrease in suicide rate. Exploratory analysis suggested a stronger association in males, who experienced a greater increase in antidepressant use. Changes in unemployment and alcohol consumption rates did not explain the association.
In Japan during 1999 through 2003, absent long-term linear trend effects, annual increases in prescribing of newer antidepressant medications, mainly SSRIs, were associated with annual decreases in suicide rates, particularly among males.
PMCID: PMC3804897  PMID: 17592916
20.  Early visual information processing deficit in depression with and without Borderline Personality Disorder 
Psychiatry research  2006;149(0):139-145.
Backward masking is a measure of early visual information processing usually abnormal in psychotic disorders. Previous studies of subjects with Borderline Personality Disorder have been inconsistent regarding their impairment or lack of impairment on backward masking. We examined visual backward masking performance in samples of unmedicated depressed patients with (n=12) and without (n=16) Borderline Personality Disorder, and healthy volunteers (n=18). Accuracy was poorer in depressed BPD patients, relative to both non-BPD depressed and healthy comparison subjects. As in previous studies, no differences in accuracy were found between non-BPD depressed patients and healthy comparison subjects. Differences in BPD subjects’ accuracy were most evident at the fastest ISI and were not attributable to intercurrent psychotic symptoms. Beyond these group differences, accuracy at faster ISI’s correlated with self-ratings of impulsiveness in all patients, and may be a general correlate of this trait. Poor early information processing appears to be a feature of Borderline Personality Disorder, and may play a role in the impulsive behavior that is characteristic of the disorder.
PMCID: PMC3804900  PMID: 17097149
Backward masking; Borderline Personality Disorder; Depression; Information processing; Impulsiveness; Impulsiveness assessment
21.  Pretreatment regional brain glucose uptake in the midbrain on PET may predict remission from a major depressive episode after three months of treatment 
Psychiatry research  2009;173(1):63-70.
In order to test the hypotheses that pretreatment metabolic activity in the midbrain and the rostral anterior cingulate may predict remission in response to medications enhancing monoaminergic transmission, we compared relative regional cerebral metabolic rate of glucose (rCMRglu) using positron emission tomography (PET) in medication-free patients with major depression who remitted after 3 months of monoaminergic medication, with non-remitters on the same treatment. [18F]-FDG PET was conducted in a group of 33 drug-free DSM-IV major depression subjects prior to antidepressant treatment. Patients were prescribed paroxetine initially (61%) unless they had failed paroxetine previously. Treatment was then managed by the subjects’ own physician with 91% receiving a selective serotonin reuptake inhibitor and 78% another non-selective monoamine reuptake inhibitor during the 3 months of treatment. Voxel-based parametric brain maps of remitters were compared with maps of non-remitters using SPM2. Remission was defined as a N50% decrease in and a final score of ≤10 on the 24-item Hamilton Depression Rating Scale. We found that treatment remitters have lower activity in a single contiguous brain region (with global maxima in the midbrain, cluster level P=0.013, corrected for multiple comparison (CMC)), prior to treatment, compared with non-remitters to 3 months of community-based monoaminergic antidepressant treatment. Degree of improvement correlated with pretreatment midbrain activity. Pretreatment clinical picture and intensity of treatment did not distinguish remitters. No other area of the brain showed a significant difference between remitters and non-remitters even with CMC completely disabled. Lower relative regional brain activity in the region of monoaminergic nuclei prior to treatment predicts remission in response to 3 months of antidepressant treatment, despite no clinical differences at baseline and no difference in treatment intensity. Brain imaging is a potential objective laboratory technique that may guide treatment selection where clinical methods have not shown promise. Prospective studies are needed to replicate these findings and determine whether outcome prediction is limited to a specific class of antidepressants.
PMCID: PMC3804908  PMID: 19446443
Depression; PET; FDG; Brain regions; Remission; Antidepressant treatment; Outcome; Positron emission tomography
22.  Familial Pathways to Early-Onset Suicidal Behavior: Familial and Individual Antecedents of Suicidal Behavior 
The American journal of psychiatry  2007;164(9):1364-1370.
The authors sought to identify clinical predictors of new-onset suicidal behavior in children of parents with a history of mood disorder and suicidal behavior.
In a prospective study of offspring of parents with mood disorders, 365 offspring (average age, 20 years) of 203 parents were followed for up to 6 years. Offspring with incident suicide attempts or emergency referrals for suicidal ideation or behavior (“incident events”) were compared with offspring without such events on demographic and clinical characteristics. Multivariate analyses were conducted to examine predictors of incident events and predictors of time to incident event.
Offspring of probands who had made suicide attempts, compared with offspring of parents with mood disorders who had not made attempts, had a higher rate of incident suicide attempts (4.1% versus 0.6%, relative risk=6.5) as well as overall suicidal events (8.3% versus 1.9%, relative risk=4.4). Mood disorder and self-reported impulsive aggression in offspring and a history of sexual abuse and self-reported depression in parents predicted earlier time to, and greater hazard of, an incident suicidal event.
In offspring of parents with mood disorders, precursors of early-onset suicidal behavior include mood disorder and impulsive aggression as well as parental history of suicide attempt, sexual abuse, and self-reported depression. These results suggest that efforts to prevent the familial transmission of early-onset suicidal behavior by targeting these domains could reduce the morbidity of suicidal behavior in high-risk youths.
PMCID: PMC3804909  PMID: 17728421
23.  Brain penetration effects of microelectrodes and DBS leads in STN or GPi 
To determine how intraoperative microelectrode recordings (MER) and intraoperative lead placement acutely influence tremor, rigidity, and bradykinesia. Secondarily, to evaluate whether the longevity of the MER and lead placement effects were influenced by target location (subthalamic nucleus (STN) or globus pallidus interna (GPi)).
Currently most groups who perform deep brain stimulation (DBS) for Parkinson disease (PD) use MER, as well as macrostimulation (test stimulation), to refine DBS lead position. Following MER and/or test stimulation, however, there may be a resultant “collision/implantation” or “microlesion” effect, thought to result from disruption of cells and/or fibres within the penetrated region. These effects have not been carefully quantified.
47 consecutive patients with PD undergoing unilateral DBS for PD (STN or GPi DBS) were evaluated. Motor function was measured at six time points with a modified motor Unified Parkinson Disease Rating Scale (UPDRS): (1) preoperatively, (2) immediately after MER, (3) immediately after lead implantation/collision, (4) 4 months following surgery—off medications, on DBS (12 h medication washout), (5) 6 months postoperatively—off medication and off DBS (12 h washout) and (6) 6 months—on medication and off DBS (12 h washout).
Significant improvements in motor scores (p<0.05) (tremor, rigidity, bradykinesia) were observed as a result of MER and lead placement. The improvements were similar in magnitude to what was observed at 4 and 6 months post-DBS following programming and medication optimisation. When washed out (medications and DBS) for 12 h, UPDRS motor scores were still improved compared with preoperative testing. There was a larger improvement in STN compared with GPi following MER (p<0.05) and a trend for significance following lead placement (p<0.08) but long term outcome was similar.
This study demonstrated significant acute intraoperative penetration effects resulting from MER and lead placement/collision in PD. Clinicians rating patients in the operating suite should be aware of these effects, and should consider pre- and post-lead placement rating scales prior to activating DBS. The collision/implantation effects were greater intraoperatively with STN compared with GPi, and with greater disease duration there was a larger effect.
PMCID: PMC3791596  PMID: 19237386
Biological psychiatry  2012;72(7):562-571.
Adult neurogenesis is coupled to angiogenesis in neurogenic niches in the dentate gyrus (DG) and increased by antidepressants in rodents. We hypothesized that, in major depressive disorder (MDD), antidepressants increase neural progenitor cells (NPCs) and capillaries in the human DG.
NPCs and capillaries, detected on hippocampal sections by immunohistochemistry for nestin, were quantified by stereology in matched MDDs (untreated, n=12), MDD treated with selective serotonin reuptake inhibitors (MDD*SSRI, n=6) or tricyclic antidepressants (MDD*TCA, n=6) and nonpsychiatric controls (n=12), all confirmed by psychological autopsy.
MDD*SSRI had a larger capillary area and more NPCs versus MDDs (p=.034 and p=.008, respectively) and controls (p=.010 and p=.002, respectively) in the whole DG, more NPCs in the anterior (pes, p=.042) and central (mid-body, p=.004) DG, and greater capillary area in the pes (p=.002) and mid-body (p=.021). NPC number and capillary area correlated positively in the whole sample (R2=.454, p<.001) and in treated subjects (R2=.749, p=.001). We found no NPCs or antidepressant-related angiogenesis in CA1 and parahippocampal gyrus. DG volume correlated positively with NPC number (p=.004) and capillary area (p<.001), and differed between groups in whole hippocampus (p=.013) and mid-body (p=.036). Age negatively correlated with NPC number (p=.042), capillary area (p=.037) and bifurcations (p=.030). No sex effect was detected.
Antidepressants increase human hippocampal NPCs and angiogenesis selectively in the anterior and mid DG. These results raise the possibility of a causal relationship between angiogenesis and neurogenesis, as seen in other proliferating tissues, and support their possible role in the mechanism of action of antidepressants.
PMCID: PMC3438317  PMID: 22652019
neural progenitor cells; nestin; dentate gyrus; postmortem; stereology; immunohistochemistry
25.  Lowering dietary linoleic acid reduces bioactive oxidized linoleic acid metabolites in humans 
Linoleic acid (LA) is the most abundant polyunsaturated fatty acid in human diets, a major component of human tissues, and the direct precursor to the bioactive oxidized LA metabolites (OXLAMs), 9- and 13 hydroxy-octadecadienoic acid (9- and 13-HODE) and 9- and 13-oxo-octadecadienoic acid (9- and 13-oxoODE). These four OXLAMs have been mechanistically linked to pathological conditions ranging from cardiovascular disease to chronic pain. Plasma OXLAMs, which are elevated in Alzheimer’s dementia and non-alcoholic steatohepatitis, have been proposed as biomarkers useful for indicating the presence and severity of both conditions. Because mammals lack the enzymatic machinery needed for de novo LA synthesis, the abundance of LA and OXLAMs in mammalian tissues may be modifiable via diet. To examine this issue in humans, we measured circulating LA and OXLAMs before and after a 12-week LA lowering dietary intervention in chronic headache patients. Lowering dietary LA significantly reduced the abundance of plasma OXLAMs, and reduced the LA content of multiple circulating lipid fractions that may serve as precursor pools for endogenous OXLAM synthesis. These results show that lowering dietary LA can reduce the synthesis and/or accumulation of oxidized LA derivatives that have been implicated in a variety of pathological conditions. Future studies evaluating the clinical implications of diet-induced OXLAM reductions are warranted.
PMCID: PMC3467319  PMID: 22959954
Linoleic acid; HODE; hydroxy-octadecadienoic acid; oxoODE; oxo-octadecadienoic acid; oxidation; OXLAM; PUFA; polyunsaturated fatty acid

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