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Meta-analyses, published in 2008–2010, have confirmed abnormally low serum brain-derived neurotrophic factor (BDNF) concentrations in depressed patients and normalization of this by antidepressant treatment. These findings are believed to reflect peripheral manifestations of the neurotrophin hypothesis , which states that depression is secondary to an altered expression of BDNF in the brain. Since the publication of these meta-analyses, the field has seen a huge increase in studies on these topics. This motivated us to update the evidence on the aforementioned associations and, in addition, to compile the data on serum BDNF concentrations in relation to the symptom severity of depression. Using a manifold of data as compared with earlier meta-analyses, we find low serum BDNF concentrations in 2384 antidepressant-free depressed patients relative to 2982 healthy controls and to 1249 antidepressant-treated depressed patients (Cohen’s d =−0.71 and −0.56, P -values <0.0000001). When publication bias is accounted for, these effect-sizes become substantially smaller ( d =−0.47 and −0.34, respectively, P -values<0.0001). We detect between-study heterogeneity in outcomes for which only year of publication and sample size are significant moderators, with more recent papers and larger samples sizes in general being associated with smaller between-group differences. Finally, the aggregated data negate consistent associations between serum BDNF concentrations and the symptom severity of depression. Our findings corroborate the claim that altered serum BDNF concentrations are peripheral manifestations of depression. However, here we highlight that the evidence for this claim is slimmer as was initially thought and amidst a lot of noise.

The etiology of bipolar disorder (BD) is still poorly understood, involving genetic and epigenetic mechanisms as well as environmental contributions. This study aimed to investigate the degree of DNA methylation at the promoter region of the brain-derived neurotrophic factor (BDNF) gene, as one of the candidate genes associated with major psychoses, in peripheral blood mononuclear cells isolated from 94 patients with BD (BD I=49, BD II=45) and 52 healthy controls. A significant BDNF gene expression downregulation was observed in BD II 0.53±0.11%; P<0.05), but not in BD I (1.13±0.19%) patients compared with controls (CONT: 1±0.2%). Consistently, an hypermethylation of the BDNF promoter region was specifically found in BD II patients (CONT: 24.0±2.1%; BDI: 20.4±1.7%; BDII: 33.3±3.5%, P<0.05). Of note, higher levels of DNA methylation were observed in BD subjects on pharmacological treatment with mood stabilizers plus antidepressants (34.6±4.2%, predominantly BD II) compared with those exclusively on mood-stabilizing agents (21.7±1.8%; P<0.01, predominantly BD I). Moreover, among the different pharmacological therapies, lithium (20.1±3.8%, P<0.05) and valproate (23.6±2.9%, P<0.05) were associated with a significant reduction of DNA methylation compared with other drugs (35.6±4.6%). Present findings suggest selective changes in DNA methylation of BDNF promoter in subjects with BD type II and highlight the importance of epigenetic factors in mediating the onset and/or susceptibility to BD, providing new insight into the mechanisms of gene expression. Moreover, they shed light on possible mechanisms of action of mood-stabilizing compounds vs antidepressants in the treatment of BD, pointing out that BDNF regulation might be a key target for their effects.

Serum levels of inflammatory cytokines, for example, tumor necrosis factor alpha (TNF α ), interleukin-6 (IL-6), and IL-1 beta (IL-1 β ), are elevated in subjects with major depressive disorder (MDD). The reason why this occurs is unclear. Elevated levels of inflammatory cytokines could be a result of brain dysfunction in MDD. It is also possible that inflammatory cytokines contribute to depressive symptoms in MDD. If the first assumption is correct, one would expect levels to normalize with resolution of the depressive episode after treatment. Several studies have measured changes in cytokine levels during antidepressant treatment; however, the results vary. The purpose of this study was to pool all available data on changes in serum levels of TNF α , IL-6, and IL-1 β during antidepressant treatment to determine whether these levels change. Studies were included if they used an approved pharmacological treatment for depression, patients had a diagnosis of MDD, and serum levels of TNF α , IL-6, and/or IL-1 β were measured before and after treatment. Twenty-two studies fulfilled these criteria. Meta-analysis of these studies showed that, overall, while pharmacological antidepressant treatment reduced depressive symptoms, it did not reduce serum levels of TNF α . On the other hand, antidepressant treatment did reduce levels of IL-1 β and possibly those of IL-6. Stratified subgroup analysis by class of antidepressant indicated that serotonin reuptake inhibitors may reduce levels of IL-6 and TNF α . Other antidepressants, while efficacious for depressive symptoms, did not appear to reduce cytokine levels. These results argue against the notion that resolution of a depressive episode is associated with normalization of levels of circulating inflammatory cytokines; however, the results are consistent with the possibility that inflammatory cytokines contribute to depressive symptoms and that antidepressants block the effects of inflammatory cytokines on the brain.

Apolipoprotein E (apoE) normally helps in the clearance of β-amyloid from the brain, a process that is compromised in Alzheimer's disease. Cramer et al. (p. 1503 , published online 9 February; see the Perspective by Strittmatter ) now show that a drug that increases apoE expression rapidly promoted soluble β-amyloid clearance in a mouse model of Alzheimer's disease. The drug also improved cognitive, social, and olfactory performance and rapidly improved neural circuit function. Similar therapeutics may potentially help to ameliorate the symptoms of Alzheimer's disease and its prodromal states. Bexarotene counters the effects of neurodegenerative disease in mice. Alzheimer’s disease (AD) is associated with impaired clearance of β-amyloid (Aβ) from the brain, a process normally facilitated by apolipoprotein E (apoE). ApoE expression is transcriptionally induced through the action of the nuclear receptors peroxisome proliferator–activated receptor gamma and liver X receptors in coordination with retinoid X receptors (RXRs). Oral administration of the RXR agonist bexarotene to a mouse model of AD resulted in enhanced clearance of soluble Aβ within hours in an apoE-dependent manner. Aβ plaque area was reduced more than 50% within just 72 hours. Furthermore, bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function. Thus, RXR activation stimulates physiological Aβ clearance mechanisms, resulting in the rapid reversal of a broad range of Aβ-induced deficits.

Cognitive abnormalities are a core feature of depression, and biases toward negatively toned emotional information are common, but are they a cause or a consequence of depressive symptoms? Here, we propose a 'cognitive neuropsychological' model of depression, suggesting that negative information processing biases have a central causal role in the development of symptoms of depression, and that treatments exert their beneficial effects by abolishing these biases. We review the evidence pertaining to this model: briefly with respect to currently depressed patients, and in more detail with respect to individuals at risk for depression and the effects of antidepressant treatments. As well as being present in currently depressed individuals, negative biases are detectable in those vulnerable for depression due to neuroticism, genetic risk, or previous depressive illness. Recent evidence provides strong support for the notion that both antidepressant drugs and psychological therapies modify negative biases, providing a common mechanism for understanding treatments for depression. Intriguingly, it may even be possible to predict which patients will benefit most from which treatments on the basis of neural responses to negative stimuli. However, further research is required to ascertain whether negative processing biases will be useful in predicting, detecting, and treating depression, and hence in preventing a chronic, relapsing course of illness.

We conducted meta-analyses of findings from randomized, placebo-controlled, short-term trials for acute mania in manic or mixed states of DSM (III–IV) bipolar I disorder in 56 drug–placebo comparisons of 17 agents from 38 studies involving 10 800 patients. Of drugs tested, 13 (76%) were more effective than placebo: aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperdone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone. Their pooled effect size for mania improvement (Hedges’ g in 48 trials) was 0.42 (confidence interval (CI): 0.36–0.48); pooled responder risk ratio (46 trials) was 1.52 (CI: 1.42–1.62); responder rate difference (RD) was 17% (drug: 48%, placebo: 31%), yielding an estimated number-needed-to-treat of 6 (all p <0.0001). In several direct comparisons, responses to various antipsychotics were somewhat greater or more rapid than lithium, valproate, or carbamazepine; lithium did not differ from valproate, nor did second generation antipsychotics differ from haloperidol. Meta-regression associated higher study site counts, as well as subject number with greater placebo (not drug) response; and higher baseline mania score with greater drug (not placebo) response. Most effective agents had moderate effect-sizes (Hedges ’ g =0.26–0.46); limited data indicated large effect sizes (Hedges ’ g =0.51–2.32) for: carbamazepine, cariprazine, haloperidol, risperidone, and tamoxifen. The findings support the efficacy of most clinically used antimanic treatments, but encourage more head-to-head studies and development of agents with even greater efficacy.

Most knowledge regarding the effects of antidepressant drugs is at the receptor level, distal from the nervous system effects that mediate their clinical efficacy. Using functional magnetic resonance imaging (fMRI), this study investigated the effects of escitalopram, a selective serotonin reuptake inhibitor (SSRI), on resting-state brain function in patients with major depressive disorder (MDD). Fourteen first-episode drug-naive MDD patients completed two fMRI scans before and after 8 weeks of escitalopram therapy. Scans were also acquired in 14 matched healthy subjects. Data were analyzed using the regional homogeneity (ReHo) approach. Compared to controls, MDD patients before treatment demonstrated decreased ReHo in the frontal (right superior frontal gyrus), temporal (left middle and right inferior temporal gyri), parietal (right precuneus) and occipital (left superior occipital gyrus and right cuneus) cortices, and increased ReHo in the left dorsal medial prefrontal gyrus and left anterior lobe of the cerebellum. Compared to the unmedicated state, ReHo in the patients after treatment was decreased in the left dorsal medial prefrontal gyrus, the right insula and the bilateral thalamus, and increased in the right superior frontal gyrus. Compared to controls, patients after treatment displayed a ReHo decrease in the right precuneus and a ReHo increase in the left anterior lobe of the cerebellum. Successful treatment with escitalopram may be associated with modulation of resting-state brain activity in regions within the fronto-limbic circuit. This study provides new insight into the effects of antidepressants on functional brain systems in MDD.

A neural circuit from the parabrachial nucleus to the central nucleus of the amygdala mediates appetite suppression. Neural circuitry closely linked to appetite modulation The parabrachial nucleus (PBN) is an area of the brainstem containing subpopulations of neurons associated with taste, sodium intake, respiration, pain, thermosensation and appetite suppression. Partly because of the heterogeneous mix of cells making up this structure, it has proved difficult to identify the specific pathways driving appetite suppression. Now, using a variety of tools including optogenetic and pharmacogenetic analysis, Richard Palmiter and colleagues identify active calcitonin gene-related peptide-expressing neurons, projecting from the PBN to the central nucleus of the amygdala as a critical circuit driving appetite suppression. By contrast, inhibition of these neurons leads to increased feeding, suggesting that this neural circuit may provide targets for therapeutic intervention to both suppress and promote appetite. Appetite suppression occurs after a meal and in conditions when it is unfavourable to eat, such as during illness or exposure to toxins. A brain region proposed to play a role in appetite suppression is the parabrachial nucleus 1 , 2 , 3 , a heterogeneous population of neurons surrounding the superior cerebellar peduncle in the brainstem. The parabrachial nucleus is thought to mediate the suppression of appetite induced by the anorectic hormones amylin and cholecystokinin 2 , as well as by lithium chloride and lipopolysaccharide, compounds that mimic the effects of toxic foods and bacterial infections, respectively 4 , 5 , 6 . Hyperactivity of the parabrachial nucleus is also thought to cause starvation after ablation of orexigenic agouti-related peptide neurons in adult mice 1 , 7 . However, the identities of neurons in the parabrachial nucleus that regulate feeding are unknown, as are the functionally relevant downstream projections. Here we identify calcitonin gene-related peptide-expressing neurons in the outer external lateral subdivision of the parabrachial nucleus that project to the laterocapsular division of the central nucleus of the amygdala as forming a functionally important circuit for suppressing appetite. Using genetically encoded anatomical, optogenetic 8 and pharmacogenetic 9 tools, we demonstrate that activation of these neurons projecting to the central nucleus of the amygdala suppresses appetite. In contrast, inhibition of these neurons increases food intake in circumstances when mice do not normally eat and prevents starvation in adult mice whose agouti-related peptide neurons are ablated. Taken together, our data demonstrate that this neural circuit from the parabrachial nucleus to the central nucleus of the amygdala mediates appetite suppression in conditions when it is unfavourable to eat. This neural circuit may provide targets for therapeutic intervention to overcome or promote appetite.

A study of compulsive drug-seeking behaviour in rats reveals that prolonged cocaine self-administration decreases prelimbic cortex activity resulting in increased compulsive drug-seeking actions; conversely, increasing activity in the prelimbic cortex decreases drug-seeking behaviour, a finding relevant to addiction treatment. Prefrontal cortex in drug compulsion Antonello Bonci and colleagues use a rodent model for compulsive cocaine usage to show that in animals expressing the strongest drug-seeking behaviours, there is a prolonged reduction in activity in the deeper layers of the prelimbic cortex, part of the brain thought to be associated with compulsive drug seeking. Correcting this hypoactivity using optogenetic strategies prevents cocaine-seeking behaviours. In addition, optogenetic inhibition of prelimbic activity was sufficient to drive compulsive drug seeking. This work identifies prelimbic stimulation as a possible therapy in compulsive drug users. Loss of control over harmful drug seeking is one of the most intractable aspects of addiction, as human substance abusers continue to pursue drugs despite incurring significant negative consequences 1 . Human studies have suggested that deficits in prefrontal cortical function and consequential loss of inhibitory control 2 , 3 , 4 could be crucial in promoting compulsive drug use. However, it remains unknown whether chronic drug use compromises cortical activity and, equally important, whether this deficit promotes compulsive cocaine seeking. Here we use a rat model of compulsive drug seeking 5 , 6 , 7 , 8 in which cocaine seeking persists in a subgroup of rats despite delivery of noxious foot shocks. We show that prolonged cocaine self-administration decreases ex vivo intrinsic excitability of deep-layer pyramidal neurons in the prelimbic cortex, which was significantly more pronounced in compulsive drug-seeking animals. Furthermore, compensating for hypoactive prelimbic cortex neurons with in vivo optogenetic prelimbic cortex stimulation significantly prevented compulsive cocaine seeking, whereas optogenetic prelimbic cortex inhibition significantly increased compulsive cocaine seeking. Our results show a marked reduction in prelimbic cortex excitability in compulsive cocaine-seeking rats, and that in vivo optogenetic prelimbic cortex stimulation decreased compulsive drug-seeking behaviours. Thus, targeted stimulation of the prefrontal cortex could serve as a promising therapy for treating compulsive drug use.

Route to fast antidepressants? Antidepressants such as selective serotonin re-uptake inhibitors can take months to take effect, but small doses of ketamine, a glutamatergic N-methyl-D-aspartate receptor (NMDAR) agonist, can have antidepressant effects within hours. The antidepressant mechanism of ketamine is not well understood. Work in mice shows that antidepressant-like effects of ketamine depend on rapid synthesis of brain-derived neurotrophic factor (BDNF). Ketamine-mediated NMDAR blockade deactivates eukaryotic elongation factor 2 (eEF2) kinase, resulting in reduced eEF2 phosphorylation and de-suppression of BDNF translation. These findings raise the possibility of this pathway as a therapeutic target for fast-acting antidepressants. Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR ( N -methyl- D -aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder, although the underlying mechanism is unclear 1 , 2 , 3 . Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks 1 , 2 , 3 , unlike traditional antidepressants (serotonin re-uptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder and faster-acting antidepressants are needed, particularly for suicide-risk patients 3 . The ability of ketamine to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII), resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor. Furthermore, we find that inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants.