Analysis of omega-3 and omega-6 polyunsaturated fatty acid metabolism by compound-specific isotope analysis in humans.

Natural variations in the 13C:12C ratio (carbon-13 isotopic abundance [δ13C]) of the food supply have been used to determine the dietary origin and metabolism of fatty acids, especially in the n-3 PUFA biosynthesis pathway. However, n-6 PUFA metabolism following linoleic acid (LNA) intake remains under investigation. Here, we sought to use natural variations in the δ13C signature of dietary oils and fatty fish to analyze n-3 and n-6 PUFA metabolism following dietary changes in LNA and eicosapentaenoic acid (EPA) + DHA in adult humans. Participants with migraine (aged 38.6 ± 2.3 years, 93% female, body mass index of 27.0 ± 1.1 kg/m2) were randomly assigned to one of three dietary groups for 16 weeks: 1) low omega-3, high omega-6 (H6), 2) high omega-3, high omega-6 (H3H6), or 3) high omega-3, low omega-6 (H3). Blood was collected at baseline, 4, 10, and 16 weeks. Plasma PUFA concentrations and δ13C were determined. The H6 intervention exhibited increases in plasma LNA δ13C signature over time; meanwhile, plasma LNA concentrations were unchanged. No changes in plasma arachidonic acid δ13C or concentration were observed. Participants on the H3H6 and H3 interventions demonstrated increases in plasma EPA and DHA concentration over time. Plasma δ13C-EPA increased in total lipids of the H3 group and phospholipids of the H3H6 group compared with baseline. Compound-specific isotope analysis supports a tracer-free technique that can track metabolism of dietary fatty acids in humans, provided that the isotopic signature of the dietary source is sufficiently different from plasma δ13C.

Are Patients With Schizophrenia Better Off With Lifetime Antipsychotic Medication?: Replication of a Naturalistic, Long-Term, Follow-Up Study of Antipsychotic Treatment.

PURPOSE/BACKGROUND: The question of whether people with schizophrenia should be treated with antipsychotics for life has been debated for decades. We recently reported results of 2 retrospective long-term naturalistic studies examining the association of medication adherence and global outcomes in different demographic samples. In both, we found that patients with a history of better adherence to antipsychotic medication had better quality of life outcomes. Using similar methodology, here we present such associations for a very different sample-patients with chronic schizophrenia with a long past history of antipsychotic treatment that had been treated for 19 to 53 years in a Veterans Affairs clinic. METHODS: This is a retrospective, naturalistic, longitudinal 19- to 53-year (mean average, 33.5 years) lifetime follow-up of a consecutive series of patients with schizophrenia, who had at least 8 years of antipsychotic treatment. Lifetime data were collected on (1) their medication adherence, (2) long-term global outcome, and (3) life satisfaction. Outcomes were rated by 2 different clinicians, one with information on medication adherence (nonblind rater) and one without (blind rater). Linear regression models, adjusted for age, family support, substance use disorder, race, marital status, and number of years in treatment were used to estimate the association between adherence and each outcome. RESULTS: A total of 20 patients were assessed. Medication adherence was positively associated with the blind clinician's rating of global outcome (P = 0.049) and the Global Assessment of Functioning (P = 0.021). In the nonblinded clinician's rating, medication adherence was positively related to global outcome (P = 0.001) and to the patient's report of life satisfaction (P = 0.028). IMPLICATIONS/CONCLUSIONS: This replication study, together with our previous 2 studies, is consistent with the recommendation for continuous, long-term treatment for chronic schizophrenia over many years of a patient's lifetime unless medically contraindicated.

Should antipsychotic medications for schizophrenia be given for a lifetime? Replication of a naturalistic, long-term, follow-up study of antipsychotic treatment.

OBJECTIVE: Because ethically and practically a randomized control trial of antipsychotics will never be done, we recently conducted and reported a 8- to 50-year, naturalistic follow-up from an academic clinic of patients with chronic schizophrenia on antipsychotic medication. We found that better medication adherence was a statistically significant predictor of better long-term global outcome and life satisfaction. Because there were important limitations on our findings, we now in this communication, using similar methodology, detail outcomes for a very different sample-inner city patients with chronic schizophrenia with a long past history of antipsychotic treatment, who were enrolled in clinical trials for new medications for schizophrenia. METHODS: This is a retrospective, naturalistic, longitudinal 6- to 49-years antipsychotic treatment (mean average, 20) follow-up of a consecutive series of patients volunteering for screening for studies with schizophrenia. Lifetime data were collected on (1) their medication adherence, (2) long-term global outcome, and (3) life satisfaction. Outcomes were rated by 2 different clinicians, 1 with information on medication adherence (nonblind rater) and 1 without (blind rater). We used linear regression models adjusted for age, family support, substance use disorder, race, marital status, and number of years in treatment to estimate the association between adherence and each outcome. RESULTS: A total of 34 patients were assessed. Medication adherence was positively associated with the blind clinician's rating of global outcome (P value=0.03) and the global assessment of functioning (P value=0.05). In the nonblinded clinician rating, medication adherence was unrelated to global outcome (P value=0.26) and to patients' report of life satisfaction (P value=0.54). CONCLUSION: This replication study, like our previous study, is not inconsistent with the recommendation for continuous, long-term treatment for chronic schizophrenia unless medically contraindicated.

Should Antipsychotic Medications for Schizophrenia Be Given for a Lifetime?: A Naturalistic, Long-Term Follow-Up Study.

BACKGROUND: Schizophrenia remains a major health problem despite antipsychotic medications that, for most patients, can decrease acute symptoms, decrease relapses, and contribute to partial and sometimes strong positive response in patients with chronic symptoms. What has not been clear-because a double-blind, randomized, placebo-controlled trial is not feasible or ethical-is how many years after the initial episode, or onset of antipsychotic treatment, should medication be continued to achieve the best global outcome. We designed a small, clinical study to retrospectively perform a detailed follow-up to examine antipsychotic medication because it relates to both global outcome and life satisfaction. METHODS: This is a naturalistic study of 35 patients with chronic schizophrenia examining antipsychotic medication adherence from 8 to 50 years (average, 21 y) after onset of antipsychotic treatment. The sample was derived from all patients treated for many years in 1 physician's academic clinic. Most were treated by community physicians before referral to the academic clinic. Information was gathered on (1) medication adherence, (2) long-term global outcomes (based on both the patient ratings and a blind clinician's assessment [blind to medication data] on both the Global Outcome Scale and the Global Assessment of Functioning Scale), and (3) a patient-rated Satisfaction With Life Scale. Spearman rank order correlations were used to relate medication adherence to global outcomes and life satisfaction, as were linear regression models adjusted for demographic and clinical characteristics. RESULTS: A total of 35 patients (mean age, 45 y; mean years of possible medication since onset of treatment, 21 y) were assessed. Medication adherence was a statistically significant predictor of better long-term global outcomes and life satisfaction, both in Spearman rank order correlations and in covariate-adjusted linear regressions (all P values <0.01). Poor medication adherence was associated with poor outcomes, often disastrous, with low life satisfaction. Other variables such as presence of substance use disorders or family support did not explain the difference between those who adhered and those who did not. CONCLUSIONS: In this naturalistic study, patients who adhered to antipsychotic medication had better long-term global outcomes than those who had poor adherence. Study limitations include the potential for residual confounding. This sample provides data consistent with the recommendation, in the absence of clinically important unwanted drug effects like tardive dyskinesia or large weight gain, for continuous, long-term antipsychotic treatment for chronic schizophrenia.

A randomized, double-blind, placebo- and risperidone-controlled study on valnoctamide for acute mania.

OBJECTIVES: Mood stabilizers administered for bipolar disorder during pregnancy, such as valproic acid, can increase the risk of congenital anomalies in offspring. Valnoctamide is a valproic acid derivative associated with a decreased risk for congenital abnormalities in animals. The present study evaluated the efficacy and safety of valnoctamide monotherapy, compared to placebo, in the treatment of patients in an acute manic episode. METHODS: A 3-week, double-blind, randomized, placebo- and risperidone-controlled, parallel group trial was conducted on 173 patients in an acute manic episode. Patients were randomized to receive valnoctamide 1500 mg/d (n=71), risperidone 6 mg/d (n=32), or matching placebo (n=70). The primary outcome measure was the change in Young Mania Rating Scale (YMRS) scores. RESULTS: Valnoctamide did not differ significantly from placebo on any of the study endpoints (YMRS, Positive and Negative Syndrome Scale, and the Clinical Global Impression Scale for Bipolar Disorder [CGI-BP] scales; all P>.60). Mixed models for repeated measures showed that risperidone produced significantly more improvement than placebo in the overall bipolar disorder CGI-BP severity scale (P=.036), and the CGI-BP severity scale for mania (P=.021). The Kaplan-Meier survival curve revealed higher all-cause discontinuation rates (mainly due to lack of efficacy) in the valnoctamide group compared to the other study groups (P=.026). Patients with higher valnoctamide plasma levels had a numerically higher YMRS response, but this was not statistically significant. CONCLUSIONS: Valnoctamide was well tolerated at 1500 mg/d but lacked efficacy in the treatment of symptoms in patients with acute mania. Possible differences between the biological mechanisms of action of valproic acid and valnoctamide are discussed.

Dietary linoleic acid-induced alterations in pro- and anti-nociceptive lipid autacoids: Implications for idiopathic pain syndromes?

BACKGROUND: Chronic idiopathic pain syndromes are major causes of personal suffering, disability, and societal expense. Dietary n-6 linoleic acid has increased markedly in modern industrialized populations over the past century. These high amounts of linoleic acid could hypothetically predispose to physical pain by increasing the production of pro-nociceptive linoleic acid-derived lipid autacoids and by interfering with the production of anti-nociceptive lipid autacoids derived from n-3 fatty acids. Here, we used a rat model to determine the effect of increasing dietary linoleic acid as a controlled variable for 15 weeks on nociceptive lipid autacoids and their precursor n-6 and n-3 fatty acids in tissues associated with idiopathic pain syndromes. RESULTS: Increasing dietary linoleic acid markedly increased the abundance of linoleic acid and its pro-nociceptive derivatives and reduced the abundance of n-3 eicosapentaenoic acid and docosahexaenoic acid and their anti-nociceptive monoepoxide derivatives. Diet-induced changes occurred in a tissue-specific manner, with marked alterations of nociceptive lipid autacoids in both peripheral and central tissues, and the most pronounced changes in their fatty acid precursors in peripheral tissues. CONCLUSIONS: The present findings provide biochemical support for the hypothesis that the high linoleic acid content of modern industrialized diets may create a biochemical susceptibility to develop chronic pain. Dietary linoleic acid lowering should be further investigated as part of an integrative strategy for the prevention and management of idiopathic pain syndromes.

Low-n-6 and low-n-6 plus high-n-3 diets for use in clinical research.

Few trials have evaluated the metabolic effects and health outcomes of lowering dietary n-6 PUFA. The objectives of the present paper were (1) to report the methods employed to lower dietary n-6 PUFA, while either increasing or maintaining n-3 PUFA intake and (2) to validate our methods with 24 h recalls and erythrocyte fatty acid analyses. A total of sixty-seven subjects were randomised to either (1) an average-n-3 PUFA, low-n-6 PUFA (L6) intervention designed to lower linoleic acid (LA; #2·5% of energy (en%)) and arachidonic acid (#60 mg/d), while maintaining an average US intake of n-3 PUFA or (2) a high-n-3 PUFA, low-n-6 PUFA (H3-L6) intervention designed to lower n-6 LA, while increasing the n-3 PUFA a-linolenic acid (ALA; $1·5 en%) and EPA þ DHA ($1000 mg/d). Pre- and intraintervention nutrient intakes were estimated with six 24 h dietary recalls per subject. Both groups achieved the targeted reductions in dietary LA to #2·5 en% (median LA 2·45 (2·1, 3·1); P,0·001). Intakes of n-3 PUFA did not change for the L6 group. Target increases in n-3 ALA (median 1·6 en%, (1·3, 2·0), P,0·001) and EPA þ DHA (1482 mg, (374, 2558), P,0·001) were achieved in the H3-L6 group. Dietary changes were validated by corresponding changes in erythrocyte n-6 and n-3 fatty acid composition. Dietary LA can be lowered to #2·5 en%, with or without concurrent increases in dietary n-3 PUFA, in an outpatient clinical trial setting using this integrated diet method.

ApoER2-Dab1 disruption as the origin of pTau-related neurodegeneration in sporadic Alzheimer's disease.

BACKGROUND: Sporadic Alzheimer's disease (sAD) is not a global brain disease. Specific regions, layers and neurons degenerate early while others remain untouched even in advanced disease. The prevailing model used to explain this selective neurodegeneration-prion-like Tau spread-has key limitations and is not easily integrated with other defining sAD features. Instead, we propose that in humans Tau hyperphosphorylation occurs locally via disruption in ApoER2-Dab1 signaling and thus the presence of ApoER2 in neuronal membranes confers vulnerability to degeneration. Further, we propose that disruption of the Reelin/ApoE/ApoJ-ApoER2-Dab1-P85α-LIMK1-Tau-PSD95 (RAAAD-P-LTP) pathway induces deficits in memory and cognition by impeding neuronal lipoprotein internalization and destabilizing actin, microtubules, and synapses. This new model is based in part on our recent finding that ApoER2-Dab1 disruption is evident in entorhinal-hippocampal terminal zones in sAD. Here, we hypothesized that neurons that degenerate in the earliest stages of sAD (1) strongly express ApoER2 and (2) show evidence of ApoER2-Dab1 disruption through co-accumulation of multiple RAAAD-P-LTP components. METHODS: We applied in situ hybridization and immunohistochemistry to characterize ApoER2 expression and accumulation of RAAAD-P-LTP components in five regions that are prone to early pTau pathology in 64 rapidly autopsied cases spanning the clinicopathological spectrum of sAD. RESULTS: We found that: (1) selectively vulnerable neuron populations strongly express ApoER2; (2) numerous RAAAD-P-LTP pathway components accumulate in neuritic plaques and abnormal neurons; and (3) RAAAD-P-LTP components were higher in MCI and sAD cases and correlated with histological progression and cognitive deficits. Multiplex-IHC revealed that Dab1, pP85αTyr607, pLIMK1Thr508, pTau and pPSD95Thr19 accumulated together within dystrophic dendrites and soma of ApoER2-expressing neurons in the vicinity of ApoE/ApoJ-enriched extracellular plaques. These observations provide evidence for molecular derangements that can be traced back to ApoER2-Dab1 disruption, in each of the sampled regions, layers, and neuron populations that are prone to early pTau pathology. CONCLUSION: Findings support the RAAAD-P-LTP hypothesis, a unifying model that implicates dendritic ApoER2-Dab1 disruption as the major driver of both pTau accumulation and neurodegeneration in sAD. This model provides a new conceptual framework to explain why specific neurons degenerate and identifies RAAAD-P-LTP pathway components as potential mechanism-based biomarkers and therapeutic targets for sAD.

ApoER2-Dab1 disruption as the origin of pTau-related neurodegeneration in sporadic Alzheimer's disease.

BACKGROUND: Sporadic Alzheimer's disease (sAD) is not a global brain disease. Specific regions, layers and neurons degenerate early while others remain untouched even in advanced disease. The prevailing model used to explain this selective neurodegeneration-prion-like Tau spread-has key limitations and is not easily integrated with other defining sAD features. Instead, we propose that in humans Tau hyperphosphorylation occurs locally via disruption in ApoER2-Dab1 signaling and thus the presence of ApoER2 in neuronal membranes confers vulnerability to degeneration. Further, we propose that disruption of the Reelin/ApoE/ApoJ-ApoER2-Dab1-P85α-LIMK1-Tau-PSD95 (RAAAD-P-LTP) pathway induces deficits in memory and cognition by impeding neuronal lipoprotein internalization and destabilizing actin, microtubules, and synapses. This new model is based in part on our recent finding that ApoER2-Dab1 disruption is evident in entorhinal-hippocampal terminal zones in sAD. Here, we hypothesized that neurons that degenerate in the earliest stages of sAD (1) strongly express ApoER2 and (2) show evidence of ApoER2-Dab1 disruption through co-accumulation of multiple RAAAD-P-LTP components. METHODS: We applied in situ hybridization and immunohistochemistry to characterize ApoER2 expression and accumulation of RAAAD-P-LTP components in five regions that are prone to early pTau pathology in 64 rapidly autopsied cases spanning the clinicopathological spectrum of sAD. RESULTS: We found that: (1) selectively vulnerable neuron populations strongly express ApoER2; (2) numerous RAAAD-P-LTP pathway components accumulate in neuritic plaques and abnormal neurons; and (3) RAAAD-P-LTP components were higher in MCI and sAD cases and correlated with histological progression and cognitive deficits. Multiplex-IHC revealed that Dab1, pP85αTyr607, pLIMK1Thr508, pTau and pPSD95Thr19 accumulated together within dystrophic dendrites and soma of ApoER2-expressing neurons in the vicinity of ApoE/ApoJ-enriched extracellular plaques. These observations provide evidence for molecular derangements that can be traced back to ApoER2-Dab1 disruption, in each of the sampled regions, layers, and neuron populations that are prone to early pTau pathology. CONCLUSION: Findings support the RAAAD-P-LTP hypothesis, a unifying model that implicates dendritic ApoER2-Dab1 disruption as the major driver of both pTau accumulation and neurodegeneration in sAD. This model provides a new conceptual framework to explain why specific neurons degenerate and identifies RAAAD-P-LTP pathway components as potential mechanism-based biomarkers and therapeutic targets for sAD.

Associations between Plasma Lipid Mediators and Chronic Daily Headache Outcomes in Patients Randomized to a Low Linoleic Acid Diet with or without Added Omega-3 Fatty Acids.

A previous report showed that 12-week lowering of dietary omega-6 linoleic acid (LA) coupled with increased omega-3 polyunsaturated fatty acid (PUFA) intake (H3-L6 diet) reduced headache frequency and improved quality of life in patients with chronic daily headaches (CDHs) compared to dietary LA reduction alone (L6 diet). The trial also showed that targeted dietary manipulation alters PUFA-derived lipid mediators and endocannabinoids. However, several additional classes of lipid mediators associated with pain in preclinical models were not measured. The current secondary analysis investigated whether the clinical benefits of the H3-L6 diet were related to changes in plasma unesterified PUFA-derived lipid mediators known to be involved in nociception, including prostanoids. Lipid mediators were measured by ultra-high-pressure liquid chromatography coupled with tandem mass-spectrometry. Compared to baseline, dietary LA lowering with or without added omega-3 fatty acids did not alter unesterified n-6 PUFA-derived lipid mediators, although several species derived from LA, di-homo-gamma-linolenic acid, and arachidonic acid were positively associated with headache frequency and intensity, as well as mental health burden. Alpha-linolenic acid (ALA)-derived metabolites were also associated with increased headache frequency and intensity, although they did not change from the baseline in either dietary group. Compared to baseline, docosahexaenoic acid (DHA)-derived epoxides were more elevated in the H3-L6 group compared to the L6 group. Diet-induced elevations in plasma DHA-epoxides were associated with reduced headache frequency, better physical and mental health, and improved quality of life (p < 0.05). Prostanoids were not detected, except for PGF2-alpha, which was not associated with any outcomes. This study demonstrates that diet-induced changes in DHA-epoxides were associated with pain reduction in patients with chronic headaches, whereas n-6 PUFA and ALA metabolites were associated with nociception. Lipid mediator associations with mental health and quality of life paralleled pain management outcomes in this population. The findings point to a network of multiple diet-modifiable lipid mediator targets for pain management in individuals with CDHs.

ApoER2-Dab1 disruption as the origin of pTau-associated neurodegeneration in sporadic Alzheimer's disease.

In sporadic Alzheimer's disease (sAD) specific regions, layers and neurons accumulate hyperphosphorylated Tau (pTau) and degenerate early while others remain unaffected even in advanced disease. ApoER2-Dab1 signaling suppresses Tau phosphorylation as part of a four-arm pathway that regulates lipoprotein internalization and the integrity of actin, microtubules, and synapses; however, the role of this pathway in sAD pathogenesis is not fully understood. We previously showed that multiple ApoER2-Dab1 pathway components including ApoE, Reelin, ApoER2, Dab1, pP85αTyr607, pLIMK1Thr508, pTauSer202/Thr205 and pPSD95Thr19 accumulate together within entorhinal-hippocampal terminal zones in sAD, and proposed a unifying hypothesis wherein disruption of this pathway underlies multiple aspects of sAD pathogenesis. However, it is not yet known whether ApoER2-Dab1 disruption can help explain the origin(s) and early progression of pTau pathology in sAD. In the present study, we applied in situ hybridization and immunohistochemistry (IHC) to characterize ApoER2 expression and accumulation of ApoER2-Dab1 pathway components in five regions known to develop early pTau pathology in 64 rapidly autopsied cases spanning the clinicopathological spectrum of sAD. We found that (1) these selectively vulnerable neuron populations strongly express ApoER2; and (2) multiple ApoER2-Dab1 components representing all four arms of this pathway accumulate in abnormal neurons and neuritic plaques in mild cognitive impairment (MCI) and sAD cases and correlate with histological progression and cognitive deficits. Multiplex-IHC revealed that Dab1, pP85αTyr607, pLIMK1Thr508, pTauSer202/Thr205 and pPSD95Thr19 accumulate together within many of the same ApoER2-expressing neurons and in the immediate vicinity of ApoE/ApoJ-enriched extracellular plaques. Collective findings reveal that pTau is only one of many ApoER2-Dab1 pathway components that accumulate in multiple neuroanatomical sites in the earliest stages of sAD and provide support for the concept that ApoER2-Dab1 disruption drives pTau-associated neurodegeneration in human sAD.

Dietary fatty acids improve perceived sleep quality, stress, and health in migraine: a secondary analysis of a randomized controlled trial.

Background: Migraine is a prevalent disabling condition often associated with comorbid physical and psychological symptoms that contribute to impaired quality of life and disability. Studies suggest that increasing dietary omega-3 fatty acid is associated with headache reduction, but less is known about the effects on quality of life in migraine. Methods: After a 4-week run-in, 182 adults with 5-20 migraine days per month were randomized to one of the 3 arms for sixteen weeks. Dietary arms included: H3L6 (a high omega-3, low omega-6 diet), H3 (a high omega-3, an average omega-6 diet), or a control diet (average intakes of omega-3 and omega-6 fatty acids). Prespecified secondary endpoints included daily diary measures (stress perception, sleep quality, and perceived health), Patient-Reported Outcome Measurement Information System Version 1.0 ([PROMIS©) measures and the Migraine Disability Assessment (MIDAS). Analyses used linear mixed effects models to control for repeated measures. Results: The H3L6 diet was associated with significant improvements in stress perception [adjusted mean difference (aMD): -1.5 (95% confidence interval: -1.7 to -1.2)], sleep quality [aMD: 0.2 (95% CI:0.1-0.2)], and perceived health [aMD: 0.2 (0.2-0.3)] compared to the control. Similarly, the H3 diet was associated with significant improvements in stress perception [aMD: -0.8 (-1.1 to -0.5)], sleep quality [aMD: 0.2 (0.1, 0.3)], and perceived health [aMD: 0.3 (0.2, 0.3)] compared to the control. MIDAS scores improved substantially in the intervention groups compared with the control (H3L6 aMD: -11.8 [-25.1, 1.5] and H3 aMD: -10.7 [-24.0, 2.7]). Among the PROMIS-29 assessments, the biggest impact was on pain interference [H3L6 MD: -1.8 (-4.4, 0.7) and H3 aMD: -3.2 (-5.9, -0.5)] and pain intensity [H3L6 MD: -0.6 (-1.3, 0.1) and H3 aMD: -0.6 (-1.4, 0.1)]. Discussion: The diary measures, with their increased power, supported our hypothesis that symptoms associated with migraine attacks could be responsive to specific dietary fatty acid manipulations. Changes in the PROMIS© measures reflected improvements in non-headache pain as well as physical and psychological function, largely in the expected directions. These findings suggest that increasing omega-3 with or without decreasing omega-6 in the diet may represent a reasonable adjunctive approach to reducing symptoms associated with migraine attacks. Trial Registration: ClinicalTrials.gov NCT02012790.

Lipid Peroxidation Induced ApoE Receptor-Ligand Disruption as a Unifying Hypothesis Underlying Sporadic Alzheimer's Disease in Humans.

BACKGROUND: Sporadic Alzheimer's disease (sAD) lacks a unifying hypothesis that can account for the lipid peroxidation observed early in the disease, enrichment of ApoE in the core of neuritic plaques, hallmark plaques and tangles, and selective vulnerability of entorhinal-hippocampal structures. OBJECTIVE: We hypothesized that 1) high expression of ApoER2 (receptor for ApoE and Reelin) helps explain this anatomical vulnerability; 2) lipid peroxidation of ApoE and ApoER2 contributes to sAD pathogenesis, by disrupting neuronal ApoE delivery and Reelin-ApoER2-Dab1 signaling cascades. METHODS: In vitro biochemical experiments; Single-marker and multiplex fluorescence-immunohistochemistry (IHC) in postmortem specimens from 26 individuals who died cognitively normal, with mild cognitive impairment or with sAD. RESULTS: ApoE and ApoER2 peptides and proteins were susceptible to attack by reactive lipid aldehydes, generating lipid-protein adducts and crosslinked ApoE-ApoER2 complexes. Using in situ hybridization alongside IHC, we observed that: 1) ApoER2 is strongly expressed in terminal zones of the entorhinal-hippocampal 'perforant path' projections that underlie memory; 2) ApoE, lipid aldehyde-modified ApoE, Reelin, ApoER2, and the downstream Reelin-ApoER2 cascade components Dab1 and Thr19-phosphorylated PSD95 accumulated in the vicinity of neuritic plaques in perforant path terminal zones in sAD cases; 3) several ApoE/Reelin-ApoER2-Dab1 pathway markers were higher in sAD cases and positively correlated with histological progression and cognitive deficits. CONCLUSION: Results demonstrate derangements in multiple ApoE/Reelin-ApoER2-Dab1 axis components in perforant path terminal zones in sAD and provide proof-of-concept that ApoE and ApoER2 are vulnerable to aldehyde-induced adduction and crosslinking. Findings provide the foundation for a unifying hypothesis implicating lipid peroxidation of ApoE and ApoE receptors in sAD.

Add-On Pramipexole for the Treatment of Schizophrenia and Schizoaffective Disorder: A Randomized Controlled Trial.

Objective: Several small clinical trials have reported that the dopamine agonist pramipexole was beneficial in treating patients with schizophrenia. A confirmatory trial was conducted to test this hypothesis.Methods: This 16-week, multicenter, double-blind, randomized, placebo-controlled study included 200 subjects meeting DSM-IV-TR criteria for schizophrenia or schizoaffective disorder. Patients were randomized to receive either pramipexole (0.75 mg twice daily, n = 100) or placebo (n = 100) as an add-on to their regular antipsychotic treatment. The primary outcome measure was the total score on the Positive and Negative Syndrome Scale (PANSS); secondary outcome measures included PANSS subscale and cognitive functioning scores. Recruitment was performed in 30 sites in Romania and 1 site in the Republic of Moldova between January and June 2011.Results: Analysis of covariance models showed no significant difference between pramipexole and placebo for total PANSS (P > .99) and PANSS positive (P > .99), negative (P = .73), and general psychopathology (P = .99) subscale scores. Changes in Clinical Global Impressions-Severity of Illness scale and Brief Assessment of Cognition in Schizophrenia scores showed no significant difference between pramipexole and placebo.Conclusions: The results of this large randomized controlled trial indicated that pramipexole was not efficacious as an add-on to antipsychotic medications for schizophrenia.Trial Registration: ClinicalTrials.gov identifier NCT01320982.

Changing the Antipsychotic in Early Nonimprovers to Amisulpride or Olanzapine: Randomized, Double-Blind Trial in Patients With Schizophrenia.

BACKGROUND AND HYPOTHESIS: Meta-analyses have shown that the majority of patients with schizophrenia who have not improved after 2 weeks of treatment with an antipsychotic drug are unlikely to fully respond later. We hypothesized that switching to another antipsychotic with a different receptor binding profile is an effective strategy in such a situation. STUDY DESIGN: In total, 327 inpatients with an acute exacerbation of schizophrenia were randomized to double-blind treatment with either olanzapine (5-20 mg/day) or amisulpride (200-800 mg/day). Those patients who had not reached at least 25% Positive-and-Negative-Syndrome-Scale (PANSS) total score reduction from baseline after 2 weeks (the "non-improvers") were rerandomized double-blind to either staying on the same compound ("stayers") or to switching to the other antipsychotic ("switchers") for another 6 weeks. The primary outcome was the difference in the number of patients in symptomatic remission between the combined "switchers" and the "stayers" after 8 weeks of treatment, analyzed by logistic regression. STUDY RESULTS: A total of 142 nonimprovers were rerandomized at week two. 25 (45.5 %) of the 'stayers' compared to 41 (68.3 %) of the "switchers" reached remission at endpoint (p = .006). Differences in secondary efficacy outcomes were not significant, except for the PANSS negative subscore and the Clinical-Global-Impression-Scale. "Switchers" and "stayers" did not differ in safety outcomes. CONCLUSIONS: Switching "non-improvers" from amisulpride to olanzapine or vice-versa increased remission rates and was safe. The superiority in the primary outcome was, however, not paralleled by significant differences in most secondary efficacy outcomes and the effect was only apparent at the last visit making replications of longer duration necessary.

Evaluating pimavanserin as a treatment for psychiatric disorders: A pharmacological property in search of an indication.

Introduction: Pimavanserin is FDA-approved to treat hallucinations and delusions associated with Parkinson's disease psychosis. As a potent 5-HT2A inverse agonist/antagonist, it could be efficacious in other psychiatric disorders. Recently, several studies have investigated this potential.Areas covered: The authors review the efficacy and adverse effects of pimavanserin for hallucinations in dementia, major depression, and schizophrenia.Expert opinion: Two controlled studies suggest pimavanserin has potential as a treatment for hallucinations in dementia. In patients with depression who did not respond to antidepressant treatment, pimavanserin augmentation was efficacious in a phase 2 study. Pimavanserin augmentation also alleviated sexual side effects of SSRI and SSNI. However, Acadia Pharmaceuticals stated in a press release that it does not plan further antidepressant trials based on its phase 3 trial, which showed a nonsignificant trend toward an antidepressant effect. Since almost all existing antipsychotics fail to substantially benefit negative symptoms, better treatments are needed. Pimavanserin augmentation of antipsychotics did benefit negative symptoms (effect size≈0.2) but failed to reduce the total PANSS score significantly in two large, well-controlled double-blind studies. Pimavanserin has a good safety profile.

Adjunctive Aspirin vs Placebo in Patients With Schizophrenia: Results of Two Randomized Controlled Trials.

Two previous randomized controlled trials (RCTs) suggested that adjunctive aspirin is efficacious in treating schizophrenia. We conducted two 16-week double-blind randomized placebo-controlled RCTs of adjunctive 1000 mg aspirin vs placebo in schizophrenia. Study 1 included 200 patients, with Positive and Negative Syndrome Scale (PANSS) total score as the primary outcome. Study 2 included 160 patients with C-reactive protein (CRP) >1 mg/L at baseline; the primary outcome was PANSS-positive score. Dropout rates for aspirin/placebo were 12% in study 1 and 20% in study 2. Differences in outcome between aspirin and placebo were calculated with linear regression, adjusting for the baseline value of the outcome. No statistically significant between-group differences were found in primary or secondary outcomes in either study. Study 1: mean difference in PANSS at 16 weeks was -3.9 (95% CI: -8.4 to 0.5, P = .10, effect size (ES) = -0.25) and at 8 weeks was -3.5 (95% CI: -7.5 to 0.5, P = .11, ES = -0.22). Study 2: mean difference in PANSS at 16 weeks was 0.3 (95% CI: -4.1 to 4.7, P = .90, ES = 0.02) and in positive PANSS was 0.5 (95% CI: -1.0 to 2.1, P = .50, ES = 0.11). A meta-analysis of these data with the existing studies, excluding one with large baseline differences in total PANSS, found that the overall estimate of the effect of adjunctive aspirin on the PANSS total score comparing group means at the end of the study was -2.9 (95% CI: -6.6 to 0.7; P = .21), favoring aspirin. Our studies and meta-analysis failed to find a statistically significant improvement in the symptoms of schizophrenia from adjunctive aspirin therapy in comparison to placebo in schizophrenia. Trial registration: study 1: Clinicaltrials.gov: NCT01320982; study 2 (high CRP): EudraCT Number: 2014-000757-36.

Methodology for altering omega-3 EPA+DHA and omega-6 linoleic acid as controlled variables in a dietary trial.

BACKGROUND & AIMS: Increasing dietary intake of n-3 EPA+DHA and lowering dietary n-6 LA is under investigation as a therapeutic diet for improving chronic pain syndromes as well as other health outcomes. Herein we describe the diet methodology used to modulate intake of n-3 and n-6 PUFA in a free living migraine headache population and report on nutrient intake, BMI and diet acceptability achieved at week 16 of the intensive diet intervention and week 22 follow-up time-point. METHODS: A total of 178 participants were randomized and began one of three diet interventions: 1) a high n-3 PUFA, average n-6 PUFA (H3) diet targeting 1500 mg EPA+DHA/day and 7% of energy (en%) from n-6 linoleic acid (LA), 2) a high-n-3 PUFA, low-n-6 PUFA (H3L6) targeting 1500 mg EPA+DHA/day and <1.8 en% n-6 LA or 3) a Control diet with typical American intakes of both EPA+DHA (<150 mg/day) and 7 en% from n-6 LA. Methods used to achieve diet change to week 16 include diet education, diet counseling, supply of specially prepared foods, self-monitoring and access to online diet materials. Only study oils and website materials were provided for the follow-up week 16 to week 22 periods. Diet adherence was assessed by multiple 24 h recalls administered throughout the trial. Diet acceptability was assessed in a subset of participants at 4 time points by questionnaire. RESULTS: At week 16 H3 and H3L6 diet groups significantly increased median n-3 EPA+DHA intake from 48 mg/2000 kcals at baseline to 1484 mg/2000 kcals (p < 0.0001) and from 44 mg/2000 kcals to 1341 mg/2000 kcals (p < 0.0001), respectively. In the Control group, EPA+DHA intake remained below the typical American intake with baseline median at 60 mg/2000 kcals and 80 mg/2000 kcals (p = 0.6) at week 16. As desired, LA intake was maintained in the H3 and Control group with baseline median of 6.5 en% to 7.1 en% (p = 0.4) at week 16 and from 6.5 en% to 6.8 en% (p = 1.0) at week 16, respectively. In the H3L6 group, n-6 LA decreased from 6.3 en% at baseline to 3.2 en% (p < 0.0001) at week 16. There were no significant changes in BMI or diet acceptability throughout the trial or between diet groups. CONCLUSIONS: We find this diet method to be acceptable to research participants and successful in altering dietary n-3 EPA+DHA with and without concurrent decreases in n-6 LA. If n-6 LA of less than 3 en% is desired, additional techniques to limit LA may need to be employed.

Dietary alteration of n-3 and n-6 fatty acids for headache reduction in adults with migraine: randomized controlled trial.

OBJECTIVE: To determine whether dietary interventions that increase n-3 fatty acids with and without reduction in n-6 linoleic acid can alter circulating lipid mediators implicated in headache pathogenesis, and decrease headache in adults with migraine. DESIGN: Three arm, parallel group, randomized, modified double blind, controlled trial. SETTING: Ambulatory, academic medical center in the United States over 16 weeks. PARTICIPANTS: 182 participants (88% women, mean age 38 years) with migraines on 5-20 days per month (67% met criteria for chronic migraine). INTERVENTIONS: Three diets designed with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and linoleic acid altered as controlled variables: H3 diet (n=61)-increase EPA+DHA to 1.5 g/day and maintain linoleic acid at around 7% of energy; H3-L6 diet (n=61)-increase n-3 EPA+DHA to 1.5 g/day and decrease linoleic acid to ≤1.8% of energy; control diet (n=60)-maintain EPA+DHA at <150 mg/day and linoleic acid at around 7% of energy. All participants received foods accounting for two thirds of daily food energy and continued usual care. MAIN OUTCOME MEASURES: The primary endpoints (week 16) were the antinociceptive mediator 17-hydroxydocosahexaenoic acid (17-HDHA) in blood and the headache impact test (HIT-6), a six item questionnaire assessing headache impact on quality of life. Headache frequency was assessed daily with an electronic diary. RESULTS: In intention-to-treat analyses (n=182), the H3-L6 and H3 diets increased circulating 17-HDHA (log ng/mL) compared with the control diet (baseline-adjusted mean difference 0.6, 95% confidence interval 0.2 to 0.9; 0.7, 0.4 to 1.1, respectively). The observed improvement in HIT-6 scores in the H3-L6 and H3 groups was not statistically significant (-1.6, -4.2 to 1.0, and -1.5, -4.2 to 1.2, respectively). Compared with the control diet, the H3-L6 and H3 diets decreased total headache hours per day (-1.7, -2.5 to -0.9, and -1.3, -2.1 to -0.5, respectively), moderate to severe headache hours per day (-0.8, -1.2 to -0.4, and -0.7, -1.1 to -0.3, respectively), and headache days per month (-4.0, -5.2 to -2.7, and -2.0, -3.3 to -0.7, respectively). The H3-L6 diet decreased headache days per month more than the H3 diet (-2.0, -3.2 to -0.8), suggesting additional benefit from lowering dietary linoleic acid. The H3-L6 and H3 diets altered n-3 and n-6 fatty acids and several of their nociceptive oxylipin derivatives in plasma, serum, erythrocytes or immune cells, but did not alter classic headache mediators calcitonin gene related peptide and prostaglandin E2. CONCLUSIONS: The H3-L6 and H3 interventions altered bioactive mediators implicated in headache pathogenesis and decreased frequency and severity of headaches, but did not significantly improve quality of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT02012790.

Identifying oxidized lipid mediators as prognostic biomarkers of chronic posttraumatic headache.

Chronic posttraumatic headache (PTH) is among the most common and disabling sequelae of traumatic brain injury (TBI). Current PTH treatments are often only partially effective and have problematic side effects. We previously showed in a small randomized trial of patients with chronic nontraumatic headaches that manipulation of dietary fatty acids decreased headache frequency, severity, and pain medication use. Pain reduction was associated with alterations in oxylipins derived from n-3 and n-6 fatty acids, suggesting that oxylipins could potentially mediate clinical pain reduction. The objective of this study was to investigate whether circulating oxylipins measured in the acute setting after TBI could serve as prognostic biomarkers for developing chronic PTH. Participants enrolled in the Traumatic Head Injury Neuroimaging Classification Protocol provided serum within 3 days of TBI and were followed up at 90 days postinjury with a neurobehavioral symptom inventory (NSI) and satisfaction with life survey. Liquid chromatography-tandem mass spectrometry methods profiled 39 oxylipins derived from n-3 docosahexaenoic acid (DHA), and n-6 arachidonic acid and linoleic acid. Statistical analyses assessed the association of oxylipins with headache severity (primary outcome, measured by headache question on NSI) as well as associations between oxylipins and total NSI or satisfaction with life survey scores. Among oxylipins, 4-hydroxy-DHA and 19,20-epoxy-docosapentaenoate (DHA derivatives) were inversely associated with headache severity, and 11-hydroxy-9-epoxy-octadecenoate (a linoleic acid derivative) was positively associated with headache severity. These findings support a potential for DHA-derived oxylipins as prognostic biomarkers for development of chronic PTH.