Association Between Folic Acid Prescription Fills and Suicide Attempts and Intentional Self-harm Among Privately Insured US Adults.

Importance: Suicide is a leading cause of death in the United States, having increased more than 30% from 2000 to 2018. An inexpensive, safe, widely available treatment for preventing suicidal behavior could reverse this trend. Objective: To confirm a previous signal for decreased risk of suicide attempt following prescription fills for folic acid in a national pharmacoepidemiologic study of patients treated with folic acid. Design, Setting, and Participants: A within-person exposure-only cohort design was used to study the dynamic association between folic acid (vitamin B9) prescription fills over a 24-month period and suicide attempts and intentional self-harm. Data were collected from a pharmacoepidemiologic database of US medical claims (MarketScan) for patients with private health insurance who filled a folic acid prescription between 2012 and 2017. The same analysis was repeated with a control supplement (cyanocobalamin, vitamin B12). Data were analyzed from August 2021 to June 2022. Exposure: Folic acid prescription fills. Main Outcome and Measure: Suicide attempt or intentional self-harm resulting in an outpatient visit or inpatient admission as identified by codes from the International Statistical Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification. Results: Data on 866 586 patients were collected; 704 514 (81.30%) were female, and 90 296 (10.42%) were 60 years and older. Overall, there were 261 suicidal events during months covered by a folic acid prescription (5 521 597 person-months) for a rate of 4.73 per 100 000 person-months, compared with 895 suicidal events during months without folic acid (8 432 340) for a rate of 10.61 per 100 000 person-months. Adjusting for age and sex, diagnoses related to suicidal behavior, diagnoses related to folic acid deficiency, folate-reducing medications, history of folate-reducing medications, and history of suicidal events, the hazard ratio (HR) for folic acid for suicide events was 0.56 (95% CI, 0.48-0.65), with similar results for the modal dosage of 1 mg of folic acid per day (HR, 0.57; 95% CI, 0.48-0.69) and women of childbearing age (HR, 0.60; 95% CI, 0.50-0.73). A duration-response analysis (1-mg dosage) revealed a 5% decrease in suicidal events per month of additional treatment (HR, 0.95; 95% CI, 0.93-0.97). The same analysis for the negative control, cyanocobalamin, found no association with suicide attempt (HR, 1.01; 95% CI, 0.80-1.27). Conclusions and Relevance: This large-scale pharmacoepidemiologic study of folic acid found a beneficial association in terms of lower rates of suicide attempts. The results warrant the conduct of a randomized clinical trial with suicidal ideation and behavior as outcomes of interest. If confirmed, folic acid may be a safe, inexpensive, and widely available treatment for suicidal ideation and behavior.

Anterior hippocampal volume predicts affect-focused psychotherapy outcome.

BACKGROUND: The hippocampus plays an important role in psychopathology and treatment outcome. While posterior hippocampus (PH) may be crucial for the learning process that exposure-based treatments require, affect-focused treatments might preferentially engage anterior hippocampus (AH). Previous studies have distinguished the different functions of these hippocampal sub-regions in memory, learning, and emotional processes, but not in treatment outcome. Examining two independent clinical trials, we hypothesized that anterior hippocampal volume would predict outcome of affect-focused treatment outcome [Interpersonal Psychotherapy (IPT); Panic-Focused Psychodynamic Psychotherapy (PFPP)], whereas posterior hippocampal volume would predict exposure-based treatment outcome [Prolonged Exposure (PE); Cognitive Behavioral Therapy (CBT); Applied Relaxation Training (ART)]. METHODS: Thirty-five patients with posttraumatic stress disorder (PTSD) and 24 with panic disorder (PD) underwent structural magnetic resonance imaging (MRI) before randomization to affect-focused (IPT for PTSD; PFPP for PD) or exposure-based treatments (PE for PTSD; CBT or ART for PD). AH and PH volume were regressed with clinical outcome changes. RESULTS: Baseline whole hippocampal volume did not predict post-treatment clinical severity scores in any treatment. For affect-focused treatments, but not exposure-based treatments, anterior hippocampal volume predicted clinical improvement. Smaller AH correlated with greater affect-focused treatment improvement. Posterior hippocampal volume did not predict treatment outcome. CONCLUSIONS: This is the first study to explore associations between hippocampal volume sub-regions and treatment outcome in PTSD and PD. Convergent results suggest that affect-focused treatment may influence the clinical outcome through the 'limbic' AH, whereas exposure-based treatments do not. These preliminary, theory-congruent, therapeutic findings require replication in a larger clinical trial.

Resting-state amplitude of low-frequency fluctuation is associated with suicidal ideation.

BACKGROUND: Identifying brain activity patterns that are associated with suicidal ideation (SI) may help to elucidate its pathogenesis and etiology. Suicide poses a significant public health problem, and SI is a risk factor for suicidal behavior. METHODS: Forty-one unmedicated adult participants in a major depressive episode (MDE), 26 with SI on the Beck Scale for Suicidal Ideation and 15 without SI, underwent resting-state functional magnetic resonance imaging scanning. Twenty-one healthy volunteers (HVs) were scanned for secondary analyses. Whole brain analysis of both amplitude of low-frequency fluctuations (ALFFs) and fractional ALFF was performed in MDE subjects to identify regions where activity was associated with SI. RESULTS: Subjects with SI had greater ALFF than those without SI in two clusters: one in the right hippocampus and one in the thalamus and caudate, bilaterally. Multi-voxel pattern analysis distinguished between those with and without SI. Post hoc analysis of the mean ALFF in the hippocampus cluster found it to be associated with a delayed recall on the Buschke memory task. Mean ALFF from the significant clusters was not associated with depression severity and did not differ between MDE and HV groups. DISCUSSION: These results indicate that SI is associated with altered resting-state brain activity. The pattern of elevated activity in the hippocampus may be related to how memories are processed.

How lipids may affect risk for suicidal behavior.

Suicide and nonfatal suicidal behaviors are major causes of mortality and morbidity worldwide. Variability in rates of suicide and suicidal behaviors within and between countries has been attributed to population and individual risk factors, including economic status and cultural differences, both of which can have suicide risk effects mediated through a variety of factors, of which perhaps the least understood is the role of diet. We therefore review the scientific literature concerning two major dietary lipid classes, cholesterol and polyunsaturated fatty acids (PUFAs), that have been associated with higher risk of suicide attempts and suicide. We consider potential mechanistic intermediates including serotonin transporters and receptors, toll-like receptors (TLRs), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), and peroxisome proliferator activated receptors (PPARs). Based on this review, we describe a theoretical model linking cholesterol and PUFA status to suicide risk, taking into account the effects of cholesterol-lowering interventions on PUFA balance, membrane lipid microdomains (rafts) as a nexus of interaction between cholesterol and omega-3 PUFAs, and downstream effects on serotonergic neurotransmission and specific inflammatory pathways.

Radiosynthesis and in Vivo Evaluation of [11C]A1070722, a High Affinity GSK-3 PET Tracer in Primate Brain.

Dysfunction of glycogen synthase kinase 3 (GSK-3) is implicated in the etiology of Alzheimer's disease, Parkinson's disease, diabetes, pain, and cancer. A radiotracer for functional positron emission tomography (PET) imaging could be used to study the kinase in brain disorders and to facilitate the development of small molecule inhibitors of GSK-3 for treatment. At present, there is no target-specific or validated PET tracer available for the in vivo monitoring of GSK-3. We radiolabeled the small molecule inhibitor [11C]1-(7-methoxy- quinolin-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea ([11C]A1070722) with high affinity to GSK-3 (Ki = 0.6 nM) in excellent radiochemical yield. PET imaging experiments in anesthetized vervet/African green monkey exhibited that [11C]A1070722 penetrated the blood-brain barrier (BBB) and accumulated in brain regions, with highest radioactivity binding in frontal cortex followed by parietal cortex and anterior cingulate, and with the lowest bindings found in caudate, putamen, and thalamus, similarly to the known distribution of GSK-3 in human brain. Our studies suggest that [11C]A1070722 can be a potential PET radiotracer for the in vivo quantification of GSK-3 in brain.

Lipid correlates of antidepressant response to omega-3 polyunsaturated fatty acid supplementation: A pilot study.

Low omega-3 polyunsaturated fatty acid (PUFA) levels are seen in major depression. We examined effects of six weeks of fish oil supplementation on clinical characteristics in 16 patients with symptomatic major depressive disorder, and tested plasma phospholipid levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) as correlates of clinical response. Depression symptoms improved after supplementation (p=0.007). The reduction in depression severity was not predicted by baseline PUFA levels but did exhibit a relationship with endpoint PUFAs, correlating negatively with DHA as a percentage of plasma phospholipids (DHA%; R2=0.60, p=0.004), adjusting for endpoint EPA%; and correlating positively with endpoint EPA% (R2=0.58, p=0.007), adjusting for endpoint DHA%. Thus, the higher the proportion of DHA to EPA, the greater the reduction in depression severity (r=-0.43, p=0.097). Five patients showed a decrease of >50% on the 17-item Hamilton Depression Rating Scale and a final score <7 and were thus not only responders but met standard criteria for remission, and were distinguished from non-responders by higher levels of DHA% (p=0.03). This pilot study suggests that post-supplementation DHA% levels may be a necessary target for antidepressant response to fish oil, and that this may depend to some extent on the efficacy of EPA conversion to DHA.

Radiosynthesis and in Vivo Evaluation of Neuropeptide Y5 Receptor (NPY5R) PET Tracers.

Neuropeptide Y receptor type 5 (NPY5R) is a G-protein coupled receptor (GPCR) that belongs to the subfamily of neuropeptide receptors (NPYR) that mediate the action of endogenous neuropeptide Y (NPY). Animal models and preclinical studies indicate a role for NPY5R in the pathophysiology of depression, anxiety, and obesity and as a target of potential therapeutic drugs. To better understand the pathophysiological involvement of NPY5R, and to measure target occupancy by potential therapeutic drugs, it would be advantageous to measure NPY5R binding in vivo by positron emission tomography (PET). Four potent and selective NPY5R antagonists were radiolabeled via nucleophilic aromatic substitution reactions with [(18)F]fluoride. Of the four radioligands investigated, PET studies in anesthetized baboons showed that [(18)F]LuAE00654 ([(18)F]N-[trans-4-({[4-(2-fluoropyridin-3-yl)thiazol-2-yl]amino}methyl)cyclohexyl]propane-2-sulfonamide) penetrates blood brain barrier (BBB) and a small amount is retained in the brain. Slow metabolism of [(18)F]LuAE00654 was observed in baboon plasma. Blocking studies with a specific NPY5R antagonist demonstrated up to 60% displacement of radioactivity in striatum, the brain region with highest NPY5R binding. Our studies suggest that [(18)F]LuAE00654 can be a potential PET radiotracer for the quantification and occupancy studies of NPY5R drug candidates.

Omega-3 polyunsaturated fatty acid supplementation and white matter changes in major depression.

White matter abnormalities are implicated in major depressive disorder (MDD). As omega-3 polyunsaturated fatty acids (PUFAs) are low in MDD and affect myelination, we hypothesized that PUFA supplementation may alleviate depression through improving white matter integrity. Acutely depressed MDD patients (n = 16) and healthy volunteers (HV, n = 12) had 25-direction diffusion tensor imaging before and after 6 weeks of fish oil supplementation. Plasma phospholipid omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and omega-6 PUFA arachidonic acid (AA) levels were determined before and after supplementation using high-throughput extraction and gas chromatography and expressed as a percentage of total phospholipids (PUFA%). Fractional anisotropy (FA) was computed using a least-squares-fit diffusion tensor with non-linear optimization. Regression analyses were performed with changes in PUFA levels or Hamilton Depression Rating Scale scores as predictors, voxel-wise difference maps of FA as outcome, covariates age and sex, with family-wise correction for multiple comparisons. Increases in plasma phospholipid DHA% (but not EPA% or AA%) after fish oil predicted increases in FA in MDD but not HV, in a cluster including genu and body of the corpus callosum, and anterior corona radiata and cingulum (cluster-level p < 0.001, peak t-score = 8.10, p = 0.002). There was a trend for greater change in FA in MDD responders over nonresponders (t = -1.874, df = 13.56, p = 0.08). Decreased depression severity predicted increased FA in left corticospinal tract and superior longitudinal fasciculus (cluster-level p < 0.001, peak t-score = 5.04, p = 0.0001). Increased FA correlated with increased DHA% and decreased depression severity after fish oil supplementation suggests therapeutic effects of omega-3 PUFAs may be related to improvements in white matter integrity.

Low plasma eicosapentaenoic acid levels are associated with elevated trait aggression and impulsivity in major depressive disorder with a history of comorbid substance use disorder.

Major depressive disorder (MDD) is associated with low levels of omega-3 polyunsaturated fatty acids (PUFAs), holding promise for new perspectives on disease etiology and treatment targets. As aggressive and impulsive behaviors are associated with low omega-3 PUFA levels in some clinical contexts, we investigated plasma PUFA relationships with trait aggression and impulsivity in patients with MDD. Medication-free MDD patients (n = 48) and healthy volunteers (HV, n = 35) were assessed with the Brown-Goodwin Aggression Inventory. A subset (MDD, n = 39; HV, n = 33) completed the Barratt Impulsiveness Scale. Plasma PUFAs eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3), and arachidonic acid (AA, 20:4n-6) were quantified and ln-transformed to mitigate distributional skew. Ln-transformed PUFA (lnPUFA) levels were predictors in regression models, with aggression or impulsivity scores as outcomes, and cofactors of sex and diagnostic status (MDD with or without a history of substance use disorder [SUD], or HV). Interactions were tested between relevant PUFAs and diagnostic status. Additional analyses explored possible confounds of depression severity, self-reported childhood abuse history, and, in MDD patients, suicide attempt history. Among PUFA, lnEPA but not lnDHA predicted aggression (F1,76 = 12.493, p = 0.001), and impulsivity (F1,65 = 5.598, p = 0.021), with interactions between lnEPA and history of SUD for both aggression (F1,76 = 7.941, p = 0.001) and impulsivity (F1,65 = 3.485, p = 0.037). Results remained significant when adjusted for childhood abuse, depression severity, or history of suicide attempt. In conclusion, low EPA levels were associated with aggression and impulsivity only in patients with MDD and comorbid SUD, even though in most cases SUD was in full sustained remission.

Omega-3 polyunsaturated fatty acid (PUFA) status in major depressive disorder with comorbid anxiety disorders.

BACKGROUND: Although lower levels of omega-3 polyunsaturated fatty acids (PUFAs) are found in major depressive disorder, less is known about PUFA status and anxiety disorders. METHOD: Medication-free participants with DSM-IV-defined major depressive disorder (MDD), with (n = 18) and without (n = 41) comorbid DSM-IV anxiety disorders, and healthy volunteers (n = 62) were recruited from October 2006 to May 2010 for mood disorder studies at the New York State Psychiatric Institute. Participants were 18-73 years of age (mean age, 35.8 ± 12.6 years). Depression and anxiety severity was assessed using depression and anxiety subscales from the 17-item Hamilton Depression Rating Scale. Plasma PUFAs eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) and the ratio of arachidonic acid (AA; 22:4n-6) to EPA (AA:EPA) were quantified. This secondary analysis employed analysis of variance with a priori planned contrasts to test for diagnostic group differences in log-transformed PUFA levels (logDHA, logEPA, and logAA:EPA). RESULTS: Plasma levels of logDHA (F(2,118) = 4.923, P = .009), logEPA (F(2,118) = 6.442, P = .002), and logAA:EPA (F(2,118) = 3.806, P = .025) differed across groups. Participants with MDD had lower logDHA (t(118) = 2.324, P = .022) and logEPA (t(118) = 3.175, P = .002) levels and higher logAA:EPA levels (t(118) = -2.099, P = .038) compared with healthy volunteers. Lower logDHA (t(118) = 2.692, P = .008) and logEPA (t(118) = 2.524, P = .013) levels and higher logAA:EPA levels (t(118) = -2.322, P = .022) distinguished anxious from nonanxious MDD. Depression severity was not associated with PUFA plasma levels; however, anxiety severity across the entire sample correlated negatively with logDHA (r(p) = -0.22, P = .015) and logEPA (r(p) = -0.25, P = .005) levels and positively with logAA:EPA levels (r(p) = 0.18, P = .043). CONCLUSIONS: The presence and severity of comorbid anxiety were associated with the lowest EPA and DHA levels. Further studies are needed to elucidate whether omega-3 PUFA supplementation may preferentially alleviate MDD with more severe anxiety.

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.

Synthesis and in vitro evaluation of [18F](R)-FEPAQ: a potential PET ligand for VEGFR2.

Synthesis and in vitro evaluation of [(18)F](R)-N-(4-bromo-2-fluorophenyl)-7-((1-(2-fluoroethyl)piperidin-3-yl)methoxy)-6-methoxyquinazolin-4-amine ((R)-[(18)F]FEPAQ or [(18)F]1), a potential imaging agent for the VEGFR2, using phosphor image autoradiography are described. Synthesis of 2, the desfluoroethyl precursor for (R)-FEPAQ was achieved from t-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (3) in five steps and in 50% yield. [(18)F]1 was synthesized by reaction of sodium salt of compound 2 with [(18)F]fluoroethyl tosylate in DMSO. The yield of [(18)F]1 was 20% (EOS based on [(18)F]F(-)) with >99% radiochemical purity and specific activity of 1-2 Ci/µmol (n=10). The total synthesis time was 75 min. The radiotracer selectively labeled VEGFR2 in slide-mounted sections of human brain and higher binding was found in surgically removed human glioblastoma sections as demonstrated by in vitro phosphor imager studies. These findings suggest [(18)F]1 may be a promising radiotracer for imaging VEGFR2 in brain using PET.

Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression.

OBJECTIVE: Randomized trials of omega-3 polyunsaturated fatty acid (PUFA) treatment for depression have differed in outcome. Recent meta-analyses ascribe discrepancies to differential effects of eicosapentaenoic acid (EPA) versus docosahexaenoic acid (DHA) and to diagnostic heterogeneity. This meta-analysis tests the hypothesis that EPA is the effective component in PUFA treatment of major depressive episodes. DATA SOURCES: PubMed/MeSH was searched for studies published in English from 1960 through June 2010 using the terms fish oils (MeSH) AND (depressive disorder [MeSH] OR bipolar depression) AND randomized controlled trial (publication type). The search was supplemented by manual bibliography review and examination of relevant review articles. STUDY SELECTION: The search yielded 15 trials involving 916 participants. Studies were included if they had a prospective, randomized, double-blinded, placebo-controlled study design; if depressive episode was the primary complaint (with or without comorbid medical conditions); if omega-3 PUFA supplements were administered; and if appropriate outcome measures were used to assess depressed mood. DATA EXTRACTION: Extracted data included study design, sample sizes, doses and percentages of EPA and DHA, mean ages, baseline and endpoint depression ratings and standard deviations for PUFA and placebo groups, and P values. The clinical outcome of interest was the standardized mean difference in the change from baseline to endpoint scores on a depression rating scale in subjects taking PUFA supplements versus subjects taking placebo. DATA SYNTHESIS: In a mixed-effect model, percentage of EPA in the supplements was the fixed-effect predictor, dichotomized into 2 groups: EPA < 60% or EPA ≥ 60% of the total EPA + DHA. Secondary analyses explored the relevance of treatment duration, age, and EPA dose. RESULTS: Supplements with EPA ≥ 60% showed benefit on standardized mean depression scores (effect size = 0.532; 95% CI, 0.277-0.733; t = 4.195; P < .001) versus supplements with EPA < 60% (effect size = -0.026; 95% CI, -0.200 to 0.148; t = -0.316; P = .756), with negligible contribution of random effects or heteroscedasticity and with no effects of treatment duration or age. Supplements with EPA < 60% were ineffective. Exploratory analyses supported a nonlinear model, with improvement determined by the dose of EPA in excess of DHA, within the range of 200 to 2,200 mg/d of EPA. CONCLUSIONS: Supplements containing EPA ≥ 60% of total EPA + DHA, in a dose range of 200 to 2,200 mg/d of EPA in excess of DHA, were effective against primary depression. Translational studies are needed to determine the mechanisms of EPA's therapeutic benefit.

Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder.

BACKGROUND: Inflammation has been linked to depression and suicide risk. One inflammatory process that has been minimally investigated in this regard is cytokine-stimulated production of kynurenine (KYN) from tryptophan (TRP). Recent data suggest that KYN increases in cerebrospinal fluid (CSF) are associated with depressive symptoms secondary to immune activation. KYN may alter dopaminergic and glutamatergic tone, thereby contributing to increased arousal, agitation and impulsivity - important risk factors in suicide. We hypothesized that patients with major depressive disorder (MDD) and a history of suicide attempt would have higher levels of KYN than depressed nonattempters, who in turn would have higher levels than healthy volunteers. METHODS: Plasma KYN, TRP, and neopterin were assayed by high performance liquid chromatography in three groups: healthy volunteers (n=31) and patients with MDD with (n=14) and without (n=16) history of suicide attempt. Analysis of variance tested for group differences in KYN levels. RESULTS: KYN levels differed across groups (F=4.03, df=(2,58), and p=0.023): a priori planned contrasts showed that KYN was higher in the MDD suicide attempter subgroup compared with MDD non-attempters (t=2.105, df=58, and p=0.040), who did not differ from healthy volunteers (t=0.418, df=58, and p=0.677). In post hoc testing, KYN but not TRP was associated with attempt status, and only suicide attempters exhibited a positive correlation of the cytokine activation marker neopterin with the KYN:TRP ratio, suggesting that KYN production may be influenced by inflammatory processes among suicide attempters. CONCLUSION: These preliminary results suggest that KYN and related molecular pathways may be implicated in the pathophysiology of suicidal behavior.

A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure.

Leptin inhibition of bone mass accrual requires the integrity of specific hypothalamic neurons but not expression of its receptor on these neurons. The same is true for its regulation of appetite and energy expenditure. This suggests that leptin acts elsewhere in the brain to achieve these three functions. We show here that brainstem-derived serotonin (BDS) favors bone mass accrual following its binding to Htr2c receptors on ventromedial hypothalamic neurons and appetite via Htr1a and 2b receptors on arcuate neurons. Leptin inhibits these functions and increases energy expenditure because it reduces serotonin synthesis and firing of serotonergic neurons. Accordingly, while abrogating BDS synthesis corrects the bone, appetite and energy expenditure phenotypes caused by leptin deficiency, inactivation of the leptin receptor in serotonergic neurons recapitulates them fully. This study modifies the map of leptin signaling in the brain and identifies a molecular basis for the common regulation of bone and energy metabolisms. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.

Metabolic abnormalities in fronto-striatal-thalamic white matter tracts in schizophrenia.

The anterior limb of the internal capsule (ALIC) is the major white matter tract providing reciprocal connections between the frontal cortex, striatum and thalamus. Mounting evidence suggests that this tract may be affected in schizophrenia, with brain imaging studies reporting reductions in white matter volume and density, changes in fractional anisotropy and reduced asymmetry. However, the molecular correlates of these deficits are currently unknown. The aim of this study was to identify alterations in protein and metabolite levels in the ALIC in schizophrenia. Samples were obtained post-mortem from individuals with schizophrenia (n=15) and non-psychiatric controls (n=13). Immunoreactivity for the myelin-associated protein myelin basic protein (MBP), and the axonal-associated proteins phosphorylated neurofilament and SNAP-25 was measured by enzyme-linked immunoadsorbent assay (ELISA). Metabolite concentrations were quantified by proton nuclear magnetic resonance ((1)H NMR) spectroscopy. Levels of myelin- or axonal-associated proteins did not differ between groups. Overall differences in metabolite concentrations were observed between the two groups (MANOVA F=2.685, p=0.036), with post-hoc tests revealing lower lactate (19%) and alanine (24%) levels in the schizophrenia group relative to controls. Observed changes in lactate and alanine levels indicate metabolic abnormalities within the ALIC in schizophrenia.

Plasma polyunsaturated fatty acids and regional cerebral glucose metabolism in major depression.

Deficiencies in polyunsaturated essential fatty acids (PUFA) are implicated in mood disorders, although mechanisms of action and regional specificity in the brain are unknown. We hypothesized that plasma phospholipid PUFA levels are correlated with regionally specific relative cerebral metabolic rates of glucose (rCMRglu). Medication-free depressed subjects (N=29) were studied using [(18)F]-fluoro-2-deoxyglucose positron emission tomography. Docosahexaenoic acid (22:6n-3), arachidonic acid (20:4n-6), and eicosapentaenoic acid (20:5n-3) were assessed as a percentage of total phospholipid PUFA (DHA%, AA%, and EPA%, respectively). DHA% and AA% correlated positively with rCMRglu in temporoparietal cortex. In addition, DHA% correlated negatively with rCMRglu in prefrontal cortex and anterior cingulate. No correlations were seen with EPA%. Thus, under conditions of low plasma DHA, rCMRglu was higher in temporoparietal cortex and lower in anterior cingulate/prefrontal cortex. Opposing effects of DHA on these regions is a hypothesis that could be addressed in future prospective studies with n-3 supplementation. This pilot study is the first to demonstrate fatty acid and regionally specific correlations in the brain between plasma PUFA and rCMRglu in humans.

Synthesis and in vivo evaluation of a novel 5-HT1A receptor agonist radioligand [O-methyl- 11C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione in nonhuman primates.

PURPOSE: Serotonin1A (5-HT1A) receptors exist in high- and low-affinity states, and agonist ligands bind preferentially to the high-affinity state of the receptor and provide a measure of functional 5-HT1A receptors. Although the antagonist tracers are established PET ligands in clinical studies, a successful 5-HT1A receptor agonist radiotracer in living brain has not been reported. [11C]MPT, our first-generation agonist radiotracer, shows in vivo specificity in baboons; however, its utility is limited owing to slow washout and immeasurable plasma free fraction. Hence we performed structure-activity relationship studies of MPT to optimize a radiotracer that will permit valid quantification of 5-HT1A receptor binding. We now report the synthesis and evaluation of [11C]MMP as an agonist PET tracer for 5-HT1A receptors in baboons. METHODS: In vitro binding assays were performed in bovine hippocampal membranes and membranes of CHO cells expressing 5-HT1A receptors. [11C] labeling of MMP was performed by reacting desmethyl-MMP with [11C]CH(3)OTf. In vivo studies were performed in baboons, and blocking studies were conducted by pretreatment with 5-HT1A receptor ligands WAY-100635 and (+/-)-8-OH-DPAT. RESULTS: MMP is a selective 5-HT1A receptor agonist (Ki 0.15 nM). Radiosynthesis of [11C]MMP was achieved in 30 +/- 5% (n = 15) yield at EOS with a specific activity of 2,600 +/- 500 Ci/mmol (n = 12). PET studies in baboons demonstrated specific binding of [11C]MMP to 5-HT1A receptor-enriched brain regions, as confirmed by blockade with WAY-100635 and (+/-)-8-OH-DPAT. CONCLUSION: We identified [11C]MMP as an optimal agonist PET tracer that shows quantifiable, specific binding in vivo to 5-HT1A receptors in baboons.

Neuroanatomic correlates of psychopathologic components of major depressive disorder.

BACKGROUND: The Hamilton Depression Rating Scale (HDRS) is widely used to measure the severity of depression in mood disorders. Total HDRS score correlates with brain metabolism as measured by fludeoxyglucose F 18 ([(18)F]-FDG) positron emission tomography. The HDRS comprises distinct symptom clusters that may be associated with different patterns of regional brain glucose metabolism. OBJECTIVE: To examine associations between HDRS component psychopathologic clusters and resting glucose cerebral metabolism assessed by [(18)F]-FDG positron emission tomography. Patients We evaluated 298 drug-free patients who met the DSM-III-R criteria for major depressive disorder. MAIN OUTCOME MEASURES: Five principal components were extracted from the 24-item HDRS for all subjects and ProMax rotated: psychic depression, loss of motivated behavior, psychosis, anxiety, and sleep disturbance. The [(18)F]-FDG scans were acquired in a subgroup of 43 drug-free patients in twelve 5-minute frames. Voxel-level correlation maps were generated with HDRS total and factor scores. RESULTS: Total HDRS score correlated positively with activity in a large bilateral ventral cortical and subcortical region that included limbic, thalamic, and basal ganglia structures. Distinct correlation patterns were found with the 3 individual HDRS factors. Psychic depression correlated positively with metabolism in the cingulate gyrus, thalamus, and basal ganglia. Sleep disturbance correlated positively with metabolism in limbic structures and basal ganglia. Loss of motivated behavior was negatively associated with parietal and superior frontal cortical areas. CONCLUSIONS: Different brain regions correlate with discrete symptom components that compose the overall syndrome of major depression. Future studies should extend knowledge about specific regional networks by identifying responsible neurotransmitters related to specific psychopathologic components of mood disorders.