Abstract: Vortioxetine is a novel antidepressant with multimodal activity currently approved for the treatment of major depressive disorder. Vortioxetine is orally administered once daily at 5- to 20-mg doses. The pharmacokinetics of vortioxetine are linear and dose proportional, with a mean terminal half-life of approximately 66 h and steady-state plasma concentrations generally achieved within 2 weeks of dosing. The mean absolute oral bioavailability of vortioxetine is 75%. No food effect on pharmacokinetics was observed. Vortioxetine is metabolized by cytochrome P450 enzymes and subsequently by uridine diphosphate glucuronosyltransferase. The major metabolite is pharmacologically inactive, and the minor pharmacologically active metabolite is not expected to cross the blood-brain barrier, making the parent compound primarily responsible for in-vivo activity. No clinically relevant differences were observed in vortioxetine exposure by sex, age, race, body size, and renal or hepatic function. Dose adjustment is only recommended for cytochrome P450 2D6 poor metabolizers based on polymorphism of the cytochrome P450 enzymes involved. Similarly, except for bupropion, a strong cytochrome P450 2D6 inhibitor, and rifampin, a broad cytochrome P450 inducer, co-administration of other drugs evaluated did not affect the vortioxetine exposure or safety profile in any clinically meaningful way. Pharmacodynamic studies demonstrated that vortioxetine achieved high levels of serotonin transporter occupancy in relevant brain areas, affected neurotransmitter levels in the cerebrospinal fluid, and modified abnormal resting state networks in the brain over the therapeutic dose range. Overall, vortioxetine can be administered in most populations studied to date without major dose adjustments; however, dose adjustments should be considered on a patient-by-patient basis.

Chen G, Højer AM, Areberg J, Nomikos G: Vortioxetine: Clinical Pharmacokinetics and Drug Interactions. Clin. Pharmacokinet.  (Epub ahead of print, Nov. 30, 2017; doi: 10.1007/s40262-017-0612-7).

https://www.ncbi.nlm.nih.gov/pubmed/29189941

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The prefrontal cortex maintains working memory information in the presence of distracting stimuli. It has long been thought that sustained activity in individual neurons or groups of neurons was responsible for maintaining information in the form of a persistent, stable code. This study shows that, upon the presentation of a distractor, information in the lateral prefrontal cortex was reorganized into a different pattern of activity to create a morphed stable code without losing information. In contrast, the code in the frontal eye fields persisted across different delay periods but exhibited substantial instability and information loss after the presentation of a distractor. Neurons with mixed-selective responses were necessary and sufficient for the morphing of code and it was observed that these neurons were more abundant in the lateral prefrontal cortex than the frontal eye fields. The authors suggest that mixed selectivity provides populations with code-morphing capability, a property that may underlie cognitive flexibility.

Parthasarathy A, Herikstad R, Bong JH, Medina FS, Libedinsky C, Yen SC: Mixed selectivity morphs population codes in prefrontal cortex. Nature Neuroscience 20(12): 1770-1779 (2017).

https://www.ncbi.nlm.nih.gov/pubmed/29184197

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Mutations in presenilin 1 and 2, which encode components of the γ-secretase complex, cause familial Alzheimer’s disease. It is hypothesized that altered γ-secretase mediated processing of the amyloid precursor protein to the Aβ42 fragment, which is accumulated in diseased brain, may be pathogenic. This paper describes an in vitro model system that enables analysis of neuronal disease mechanisms in non-neuronal patient cells using CRISPR gene activation of endogenous disease-relevant genes. In familial Alzheimer patient-derived fibroblast cultures, CRISPR activation of amyloid precursor protein or BACE unmasked an occult processivity defect in downstream γ-secretase -mediated carboxypeptidase cleavage of amyloid precursor protein, ultimately leading to higher Aβ42 levels. These data suggest that, selectively in neurons, relatively high levels of BACE1 activity lead to substrate pressure on familial Alzheimer-mutant γ-secretase complexes, promoting CNS Aβ42 accumulation. These results introduce an additional platform for analysis of neurological disease.

Inoue K, Oliveira LMA, Abeliovich A:  CRISPR Transcriptional Activation Analysis Unmasks an Occult γ-Secretase Processivity Defect in Familial Alzheimer’s Disease Skin Fibroblasts. Cell Rep. 21(7):1727-1736 (2017); doi: 10.1016/j.celrep.2017.10.075.

https://www.ncbi.nlm.nih.gov/pubmed/29141208

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During exposure to chronic stress, some individuals engage in active coping behaviors that promote resiliency to stress. Other individuals engage in passive coping that is associated with vulnerability to stress and with anxiety and depression. In an effort to identify novel molecular mechanisms that underlie vulnerability or resilience to stress, the authors used nonbiased analyses of microRNAs in the ventral hippocampus to identify those miRNAs differentially expressed in active (long-latency (LL)/resilient) or passive (short-latency (SL)/vulnerable) rats following chronic social defeat.

Additionally, pharmacological approaches were used to determine the contribution of inflammatory processes in mediating vulnerability and resiliency. Administration of the pro-inflammatory cytokine vascular endothelial growth factor-164 increased vulnerability to stress, while the non-steroidal anti-inflammatory drug meloxicam attenuated vulnerability. The authors suggest that vulnerability to stress is determined by a re-designed neurovascular unit characterized by increased neural activity, vascular remodeling and pro-inflammatory mechanisms in the ventral hippocampus. Dampening inflammatory processes by administering anti-inflammatory agents appeared to reduce vulnerability to stress. These results have translational relevance as they suggest that administration of anti-inflammatory agents may reduce the impact of stress or trauma in vulnerable individuals.

Pearson-Leary J, Eacret D, Chen R, Takano H, Nicholas B, Bhatnagar S: Inflammation and vascular remodeling in the ventral hippocampus contributes to vulnerability to stress. Transl. Psychiatry 7(6):e1160 (2017); doi: 10.1038/tp.2017.122.

https://www.ncbi.nlm.nih.gov/pubmed/28654094

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Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promise as an intervention for patients with chronic, unremitting depression. To test the safety and efficacy of DBS for treatment-resistant depression, a prospective, randomised, sham-controlled trial was conducted.

Participants with treatment-resistant depression were implanted with a DBS system targeting bilateral subcallosal cingulate white matter and randomised to 6 months of active or sham DBS, followed by 6 months of open-label subcallosal cingulate DBS. The study is registered at ClinicalTrials.gov, number NCT00617162.

90 participants were randomly assigned to active or sham stimulation between April 10, 2008, and Nov 21, 2012. Both groups showed improvement, but there was no statistically significant difference in response during the double-blind, sham-controlled phase (12 [20%] patients in the stimulation group vs five [17%] patients in the control group). 28 patients experienced 40 serious adverse events; eight of these (in seven patients) were deemed to be related to the study device or surgery.

This study confirmed the safety and feasibility of subcallosal cingulate DBS as a treatment for treatment-resistant depression but did not show statistically significant antidepressant efficacy in a 6-month double-blind, sham-controlled trial. Future studies are needed to investigate factors such as clinical features or electrode placement that might improve efficacy.

Holtzheimer PE, Husain MM, Lisanby SH, Taylor SF, Whitworth LA, McClintock S, Slavin KV, Berman J, McKhann GM, Patil PG, Rittberg BR, Abosch A, Pandurangi AK, Holloway KL, Lam RW, Honey CR, Neimat JS, Henderson JM, DeBattista C, Rothschild AJ, Pilitsis JG, Espinoza RT, Petrides G, Mogilner AY, Matthews K, Peichel D, Gross RE, Hamani C, Lozano AM, Mayberg HS: Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial. Lancet Psychiatry 4(11):839-849 (2017).

https://www.ncbi.nlm.nih.gov/pubmed/28988904

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“GABAergic interneurons play important roles in cortical circuit development. However, there are multiple populations of interneurons and their respective developmental contributions remain poorly explored. Neuregulin 1 (NRG1) and its interneuron-specific receptor ERBB4 are critical genes for interneuron maturation. Using a conditional ErbB4 deletion, (the authors) tested the role of vasoactive intestinal peptide (VIP)-expressing interneurons in the postnatal maturation of cortical circuits in vivo. ErbB4 removal from VIP interneurons during development leads to changes in their activity, along with severe dysregulation of cortical temporal organization and state dependence. These alterations emerge during adolescence, and mature animals in which VIP interneurons lack ErbB4 exhibit reduced cortical responses to sensory stimuli and impaired sensory learning. (The) data support a key role for VIP interneurons in cortical circuit development and suggest a possible contribution to pathophysiology in neurodevelopmental disorders. These findings provide a new perspective on the role of GABAergic interneuron diversity in cortical development.”

Batista-Brito R, Vinck M, Ferguson KA, Chang JT, Laubender D, Lur G, Mossner JM, Hernandez VG, Ramakrishnan C, Deisseroth K, Higley MJ, Cardin JA: Developmental Dysfunction of VIP Interneurons Impairs Cortical Circuits. Neuron 95(4): 884-895 (2017).

https://www.ncbi.nlm.nih.gov/pubmed/28817803

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Epigenetic modifications may underlie the influence of early life experiences on neuronal development and function, yet the molecular mechanisms are poorly understood.  In this paper, Stroud and colleagues report that deposition of repressive mCA marks by the methyltransferase DNMT3A across specific brain genes during early postnatal life is important for their regulation throughout life. DNMT3A preferentially binds across transcribed regions of lowly expressed genes, and changes in gene transcription activity affect this binding. Thus early life gene activity in the brain affects gene methylation and these changes persist into adulthood. This work has implications for drug treatments and other environmental factors which affect early life gene activity in the brain.

Stroud H, Su SC, Hrvatin S, Greben AW, Renthal W, Boxer LD, Nagy MA, Hochbaum DR, Kinde B, Gabel HW, Greenberg ME: Early-Life Gene Expression in Neurons Modulates Lasting Epigenetic States. Cell 171: 1-14 (2017).

https://www.ncbi.nlm.nih.gov/pubmed/29056337

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“The acetylcholine arousal system in the brain is needed for robust attention and working memory functions, but the receptor and cellular bases for its beneficial effects are poorly understood in the newly evolved primate brain. The current study found that cholinergic stimulation of nicotinic receptors comprised of α4 and β2 subunits (α4β2-nAChR) enhanced the firing of neurons in the primate prefrontal cortex that subserve top-down attentional control and working memory. α4β2-nAChR stimulation also protected neuronal responding from the detrimental effects of distracters presented during the delay epoch, when information is held in working memory. These results illuminate how acetylcholine strengthens higher cognition and help to explain why genetic insults to the α4 subunit weaken cognitive and attentional abilities.”

Sun Y, Yang Y, Galvin VC, Yang S, Arnsten AF and Wang M: Nicotinic α4β2 Cholinergic Receptor Influences on Dorsolateral Prefrontal Cortical Neuronal Firing during a Working Memory Task. J. Neurosci. 37(21): 5366-5377 (2017).

https://www.ncbi.nlm.nih.gov/pubmed/28450546

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“Migration status is one of the best-established risk factors for schizophrenia. An increase in risk is observed in both first- and second-generation immigrants, with a varying magnitude depending on the ethnic background of the individuals. The underlying mechanisms for the increased risk are only recently coming into focus. A causal role for social stress has been widely proposed, and recent work indicated altered neural stress processing in the perigenual anterior cingulate cortex (pACC) in migrants.” Since previous work shows that social stress may lead to enduring changes in the gray matter volume of vulnerable brain regions, this study investigated the impact of migration background on brain structure. Subjects were matched for sociodemographic characteristics including age, gender, urban exposure, and education.  A significant group by gender interaction effect was found in pACC gray matter volume, which was reduced in males with migration background only. This mirrors previous findings in urban upbringing, another risk factor for schizophrenia. The authors concluded that the results show convergent evidence for an impact of environmental risk factors linked to schizophrenia on gray matter volume and highlighted the possibility that” the pACC structure may be particularly sensitive to the convergent risk factors linked to schizophrenia”.

Akdeniz C, Schäfer A, Streit F, Haller L, Wüst S, Kirsch P, Tost H, Meyer-Lindenberg A: Sex-Dependent Association of Perigenual Anterior Cingulate Cortex Volume and Migration Background, an Environmental Risk Factor for Schizophrenia. Schizophr. Bull. 43(4):925-934 (2017).

https://www.ncbi.nlm.nih.gov/pubmed/28969352

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The reward generated by social interactions is critical for promoting prosocial behaviors. Here Hung and colleagues present evidence that oxytocin release in the ventral tegmental area, a key component of the brain’s reward circuitry, is necessary to elicit social reward. During social interactions, activity in paraventricular nucleus oxytocin neurons was observed to be increased. Direct activation of these neurons in the paraventricular nucleus or their terminals in the ventral tegmental area also enhanced prosocial behaviors. Conversely, inhibition of paraventricular oxytocin axon terminals in the ventral tegmental area decreased social interactions. Specifically, oxytocin increased excitatory drive onto reward-specific ventral tegmental dopamine neurons. This report demonstrates that oxytocin promotes prosocial behavior through direct effects on dopamine neurons, providing insight into how social interactions can generate rewarding experiences.

Hung LW, Neuner S, Polepalli JS, Beier KT, Wright M, Walsh JJ, Lewis EM, Luo L, Deisseroth K, Dölen G, Malenka RC: Gating of social reward by oxytocin in the ventral tegmental area. Science 357(6358): 1406-1411 (2017).

https://www.ncbi.nlm.nih.gov/pubmed/28963257

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