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. 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. 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. 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.

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.

Targeted manipulation of dietary omega-3 and omega-6 fatty acids has previously been shown to decrease nontraumatic headaches in controlled trials. This study assessed the effects of a diet high in omega-3 fatty acids and low in omega-6 linoleic acid (H3L6 diet) on headache frequency and severity, headache impact, and plasma nociceptive mediators in a persistent post-traumatic headache (pPTH) population. One hundred and twenty-two participants with pPTH were randomized 1:1 to 12 weeks of either the H3L6 ( n = 62) or a control (n = 60) diet. A priori primary end-points were the plasma levels of the antinociceptive docosahexaenoic acid (DHA) derivative 17-hydroxy-DHA and the Headache Impact Test (HIT-6) score. Secondary end-points included headache days/month and average daily headache pain intensity (0–10 scale). Statistical analyses followed intention-to-treat principles and were adjusted for baseline values. Relative to the control group, the H3L6 group significantly reduced headache days/month (−2.1, 95% confidence interval [CI]: −3.5 to −0.8, p = 0.002) and average headache intensity (−0.9, 95% CI: −1.2 to −0.5, p < 0.001) and increased circulating 17-hydroxy-DHA (nanograms/milliliter; difference 0.07, 95% CI: 0.02–0.11, p = 0.003), although it did not significantly improve HIT-6 scores (−1.6, 95% CI: −4.0 to 0.8, p = 0.18). In conclusion, the H3L6 diet reduced headache pain and increased antinociceptive mediators, supporting its potential as an adjunct nonpharmacological pPTH therapy.

Omega‐3 and omega‐6 polyunsaturated fatty acids (PUFAs) are precursors to oxylipins that modulate pain and inflammation. We previously demonstrated that (1) a dietary intervention increasing omega‐3 and reducing omega‐6 PUFAs alters the concentration of these oxylipin precursors in blood, and (2) these changes are associated with reduced headache pain in humans. However, the extent to which blood levels reflect trigeminovascular tissues remains unclear. We sought to determine whether oxylipin precursor PUFA levels in blood reflect those in the meninges, cranial arteries, and trigeminal ganglia. Precursor PUFA compositions of post‐mortem blood and trigeminovascular tissue specimens from 70 individuals, procured from the Human Brain Collection Core at the National Institute of Mental Health, were quantified. Regression models adjusted for confounders examined relationships between blood and tissue PUFA levels. Eicosapentaenoic acid in blood was associated with levels in cranial arteries, meninges, and trigeminal ganglia [ logged coefficients ( p value): 0.29 (0.019); 0.37 (< 0.001); 0.25 (0.009)]. Other PUFAs, including linoleic acid, arachidonic acid, n‐6 docosapentaenoic acid, and docosahexaenoic acid, also showed significant associations between blood and meninges and/or trigeminal ganglia levels. These findings support using blood measurements of certain PUFAs as a proxy for their concentration in tissues directly involved in headache pathogenesis.

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, pP85α _Tyr607 , pLIMK1 _Thr508 , pTau and pPSD95 _Thr19 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.

INTRODUCTION The ApoE receptor 2-Disabled homolog-1 (ApoER2-Dab1) pathway suppresses Tau phosphorylation as part of a multi-arm pathway that regulates cytoskeletal and synaptic integrity. We previously showed that multiple ApoER2-Dab1 pathway components accumulate in regions affected in early Alzheimer’s disease (AD). Since the amygdala is a hub for emotional regulation and fear memory, we hypothesized that accumulation of ApoER2-Dab1 components in amygdala may correlate with cognitive or neuropsychiatric manifestations of AD. METHODS We used single-marker and multiplex immunohistochemistry to label ApoER2-Dab1 components in amygdala from 32 cases spanning the clinicopathological spectrum of AD. RESULTS Seven ApoER2-Dab1 pathway components accumulated in amygdala and correlated with histological progression and cognitive or neurobehavioral deficits in AD. ApoER2-Dab1 components accumulated within ApoER2-expressing neurons and dystrophic neurites surrounding ApoE-enriched extracellular plaques. DISCUSSION Findings add to growing evidence implicating ApoER2-Dab1 disruption in neurodegeneration and suggest that ApoER2-Dab1 disruption in amygdala may contribute to neuropsychiatric manifestations of AD.