Genesis Of Depression Research Articles

Berberine attenuates depression-like behavior by modulating the hippocampal NLRP3 ubiquitination signaling pathway through Trim65

ObjectiveIncreasing evidence suggests that inflammation appears to play a role in the genesis of depression. Berberine has potent anti-inflammatory effects and potential antidepressant activity, although the mechanism by which it works is yet unclear. Our study aimed to investigate the molecular mechanisms through which berberine treats depression and reduces inflammation. MethodsThe CUMS model and behavioral evaluation were utilized in this study to evaluate the efficacy of berberine in the treatment of depression. Berberine’s effect on the inflammatory response in CUMS mice was evaluated via ELISA assays and western blotting. Nissl staining was used to observe hippocampal neuronal functional damage. Western blotting, ELISA, ubiquitination tests, and immunoprecipitation were utilized in conjunction with in vitro experiments to study the involvement of Trim65 in the antidepressant effects of berberine. ResultsThe results suggest that berberine effectively alleviates depressive symptoms, suppresses the expression of genes associated with the NLRP3 inflammasome (NLRP3, cleaved caspase-1, ASC, GSDMD-N, Pro-IL-1β, IL-1β, Pro-IL-18, and IL-18), and reduces hippocampal neuronal functional damage in CUMS mice. Further studies showed that knockdown of Trim65 reversed the effects of berberine and increased NLRP3 inflammasome activity. Finally, K285, an important site for Trim65 binding to NLRP3, was identified. ConclusionOur study describes the mechanism of berberine limiting NLRP3 inflammasome activity by promoting the conjugation of Trim65 to NLRP3 and NLRP3 ubiquitination, and suggests NLRP3 inflammasome activation as a prospective target for treating inflammation-associated disorders such as depression.

Involvement of oxidative stress and pro-inflammatory cytokines in copper sulfate-induced depression-like disorders and abnormal neuronal morphology in mice.

Epidemiological studies have implicated copper as one of the key environmental risk factors for the pathogenesis of depression. However, the precise mechanism by which copper contribute to the genesis of depression particularly the involvement of oxidative stress-driven neuroinflammation is yet to be fully investigated. Thus, this study was designed to evaluate the effects of copper sulfate (CuSO4) on depression-like behaviors and the role of oxidative stress and pro-inflammatory cytokines in mice. Forty male Swiss mice were distributed into control and three test groups (n = 10), and were treated orally with distilled water (10mL/kg) or CuSO4(25, 50 and 100mg/kg) daily for 28days. Afterwards, the tail suspension, forced swim, and sucrose splash tests were used for the detection of depression-like effects. The animals were then euthanized and the brains were processed for the estimation of biomarkers of oxidative stress and pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6). The histomorphological features and neuronal viability of the prefrontal cortex, hippocampus and striatum were also determined. Mice exposed to CuSO4 displayed depression-like features when compared with controls. The brain concentrations of malondialdehyde, nitrite and pro-inflammatory cytokines were elevated in CuSO4-treated mice. Mice exposed to CuSO4 also had reduced brain antioxidant status (glutathione, glutathione-s-transferase, total thiols, superoxide-dismutase and catalase), as well as altered histomorphological features, and decreased population of viable neuronal cells. These findings suggest that CuSO4 increases oxidative stress and pro-inflammatory cytokines to elicit depression-like effects in mice.

The human P2X7 receptor alters microglial morphology and cytokine secretion following immunomodulation.

Introduction: In recent years, purinergic signaling via the P2X7 receptor (P2X7R) on microglia has repeatedly been implicated in depression genesis. However, it remains unclear which role the human P2X7R (hP2X7R) plays in regulating both microglia morphology and cytokine secretion upon different environmental and immune stimuli, respectively. Methods: For this purpose, we used primary microglial cultures derived from a humanized microglia-specific conditional P2X7R knockout mouse line to emulate different gene-environment interactions between microglial hP2X7R and molecular proxies of psychosocial and pathogen-derived immune stimuli. Microglial cultures were subjected to treatments with the agonists 2'(3')-O-(4-benzoylbenzoyl)-ATP (BzATP) and lipopolysaccharides (LPS) combined with specific P2X7R antagonists (JNJ-47965567, A-804598). Results: Morphotyping revealed overall high baseline activation due to the in vitro conditions. Both BzATP and LPS + BzATP treatment increased round/ameboid microglia and decreased polarized and ramified morphotypes. This effect was stronger in hP2X7R-proficient (CTRL) compared to knockout (KO) microglia. Aptly, we found antagonism with JNJ-4796556 and A-804598 to reduce round/ameboid microglia and increase complex morphologies only in CTRL but not KO microglia. Single cell shape descriptor analysis confirmed the morphotyping results. Compared to KO microglia, hP2X7R-targeted stimulation in CTRLs led to a more pronounced increase in microglial roundness and circularity along with an overall higher decrease in aspect ratio and shape complexity. JNJ-4796556 and A-804598, on the other hand, led to opposite dynamics. In KO microglia, similar trends were observed, yet the magnitude of responses was much smaller. Parallel assessment of 10 cytokines demonstrated the proinflammatory properties of hP2X7R. Following LPS + BzATP stimulation, IL-1β, IL-6, and TNFα levels were found to be higher and IL-4 levels lower in CTRL than in KO cultures. Vice versa, hP2X7R antagonists reduced proinflammatory cytokine levels and increased IL-4 secretion. Discussion: Taken together, our results help disentangle the complex function of microglial hP2X7R downstream of various immune stimuli. In addition, this is the first study in a humanized, microglia-specific in vitro model identifying a so far unknown potential link between microglial hP2X7R function and IL-27 levels.

Characterization of a microglia-specific humanized P2X7 receptor knock-out mouse line: Implications for translational psychoneuroimmunology

IntroductionDepression is a common psychiatric disorder and chronic stress is considered its main environmental risk factor. Recently, immune processes including adenosine triphosphate mediated P2X7 receptor (P2X7R) signalling via microglia and macrophages (M/Ms) were found to play a critical role in depression genesis, by linking environmental stress to depression biology and symptoms.ObjectivesTo characterize the role of human P2X7R (hP2X7R) in psychosocial and immune stress conditions, both in vitro and in vivo.MethodsSeveral, custom designed mouse lines expressing the loxP-flanked, hP2X7R-sequence in the murine P2X7R locus were established. In addition, these mice possess a Cre-sensitive reporter and express a Cre recombinase fused to a mutant estrogen receptor ligand-binding domain in M/Ms. This enables conditional, tamoxifen-inducible hP2X7R inactivation and simultaneous tdTomato expression. First, we established primary microglia cell cultures and characterized them at baseline and following immune stimulation. Next, we performed behavioural assessment of hP2X7Rwt and microglia-specific hP2X7RKO mice following chronic psychosocial stress. Last, we developed a novel in vivo two-photon microscopy (TPM) approach by use of frontolimbic cranial windows.ResultsPrimary hP2X7RKO microglia displayed significantly lower IL-1β production, increased survival and decreased morphological activation upon immune stimulation. Although hP2X7RKO mice showed a significant increase of locomotor activity at baseline, there was no impact on anxiety- and depressive-like phenotypes. Longitudinal in vivo TPM enabled morphometric characterization of cortical M/Ms over several weeks.ConclusionsOur results illustrate the great potential of this humanized mouse line for translational psychiatry. In the future, this system could proof useful to evaluate immunomodulatory approaches in chronic stress and depression.DisclosureNo significant relationships.

MODELING THE DEPRESSIVE STATE IN RATS BY STEREOTAXIC INJECTION OF LIPOPOLYSACCHARIDE INTO THIRD VENTRICLE OF THE BRAIN

Introduction: More than 4.4% of the world's population suffers from depression, which dramatically reduces both quality and life expectancy. For an accurate understanding of the links of pathogenesis and the possibility of correcting the depressive state, translational studies are widely used - in laboratory rodents. According to the modern concept of the inflammatory genesis of depression, the creation of animal models with nonspecific inflammation on the territory of the central nervous system is an urgent task. Purpose of the work: creation of a model of the depressive state in rats by injecting LPS into the third ventricle of the brain. Materials and methods: the study was carried out on female rats Wistar 280-300g. (n = 10), divided into 3 groups: 1 - with the introduction of LPS (n = 4), 2 - sham-operated (n = 3) and 3 - intact (n = 3). LPS was administered at a dose of 50 μg / animal in at volume of 4 μl in 15 minutes, according to the following stereotaxic coordinates: AP-0.8 ML-1.5 DV-3.5. Depression was assessed using the sucrose test and the behavior of animals in the open field tests, the elevated plus maze, the dark-light chamber, and the Porsolt test. Confirmation of the correct administration was carried out using MRI scanning (7 days) and postmortem on histological sections. Results: Animals treated with LPS showed a decrease in sucrose consumption, both compared to the sham-operated group and compared to the intact group. In behavioral tests, there was a decrease in locomotor activity in rats with the influence of LPS, but the differences between the group of sham-operated rats were insignificant. The experimental group had a sharp increase in the time of immobility in the Parsolt test (89.6 s VS 32.6 s VS 22.2 s) for the first, second and third groups, respectively. In the behavior of animals in the burrow chamber and in the open field, the presence of a neurological deficit in the experimental group was noted, consisting in a violation of gait in three out of four rats, in other groups this effect was not observed. When analyzing MRI images, the trace from the needle is traced exactly to the third ventricle. On a histological section in rats with neurological deficit, a demyelination area is visible (Fig. 1). Conclusion: The introduction of LPS into the cavity of the third ventricle causes depressive-like behavior in rats, a decrease in locomotor activity, but causes manifestations of neurological deficit as a result of local demyelination of the nervous tissue. The work was carried out within the framework of the state assignment of the Federal State Budgetary Educational Institution of Higher Education named after V.I. N.I. Pirogov for 2021–2023, state no. registration research work AAAA-A18-118051590108-1

The Role of Random Vorticity Stretching in Tropical Depression Genesis

Abstract Tropical deep convection plays a key role in the tropical depression stage of tropical cyclogenesis by aggregating vorticity, but no existing theory can depict such a stochastic vorticity aggregation process. A vorticity probability distribution function (PDF) is proposed as a tool to predict the horizontal structure and wind speed of the tropical depression. The reason lies in the tendency for a vortex to adjust to an axisymmetric and monotonic vorticity structure. Assuming deep convection as independent and uniformly distributed vortex tube stretching events in the low–midtroposphere, repetitive vortex tube stretching will make the air column area shrink many times and significantly increase vorticity. A theory of the vorticity PDF is established by modeling the random stretching process as a Markov chain. The PDF turns out to be a weighted Poisson distribution, in good agreement with a randomly forced divergent barotropic model (weak temperature gradient model), and in rough agreement with a cloud-permitting simulation. The result shows that a stronger and sparser deep convective mode tends to produce more high-vorticity air columns, which leads to a more compact major vortex with a higher maximum wind. Based on the vorticity PDF theory, a parameterization of the eddy acceleration effect on the tangential flow is proposed.

MTHFR GENE MUTATION AND ITS REPERCUSSION IN THE GENESIS AND TREATMENT OF DEPRESSION: CASE REPORT

This study aims to report the correlation of MTHFR gene mutation with the genesis of depression and antidepressants non-response in a patient, highlighting the importance of genetic investigation and indicating the replacement of L-methylfolate as an effective treatment adjuvant. This is a case report of a patient diagnosed with major depressive disorder, refractory to pharmacological therapies, in monotherapy or combination therapy, and psychotherapy. After 1 year and 4 months of persistent residual symptoms, genetic testing of the MTHFR gene was requested with confirmation of a heterozygous double mutation of MTHFR. This gene polymorphism can result in deficiency of L-methylfolate, which is related to psychiatric diseases and refractoriness to antidepressant therapy. With the introduction of l-methylfolate 15mg, the patient reported remission of depressive symptoms in 4 months of follow-up. MTHFR gene mutations influence the action of folate, favoring depression and leading to refractory response to conventional treatment.

Micro-separations: how to traumatise your spouse on a daily basis

Back in 1917, Professor Sigmund Freud highlighted the role of loss and bereavement in the development of melancholia. During the 1930s and 1940s, pioneering psychoanalysts such as Dr John Bowlby and Dr René Spitz underscored the ways in which profound separations might contribute to the genesis of depression, delinquency, and other forms of severe psychopathology. But what impact do brief, or even tiny, separations— micro-separations —have upon individuals and, moreover, upon partners in intimate couple relationships? In this essay, we shall offer a typology of the micro-separations which occur between the members of long-established couples, ranging from fleeting moments of misattunement, to periods of vanishing into laptops and mobile telephones, to those of a more overtly dramatic nature. We shall also explore the "frequent-flyer couple", in which one or both members of the pair might travel extensively for work. Above all, we will consider the cumulative traumatic impact of micro-separations upon the atmosphere and dynamics of the couple relationship and we will discuss how the powerful attentivity of the psychotherapeutic situation both exposes and heals this potentially toxic and, often, invisible pathogen.

Contribution of DNA methyltransferases to spared nerve injury induced depression partially through epigenetically repressing Bdnf in hippocampus: Reversal by ketamine

Long-lasting pain can induce depression, which seriously affects life quality of the patients, but little is known about the underlying mechanism. Chronic neuropathic pain can modulate DNA methylation in target genes related to neuroplasticity and mood regulation, which was induced by DNA methyltransferases (DNMTs). Methylation changes of brain-derived neurotrophic factor (Bdnf) in the hippocampus are critical for neuropathic pain and depression. Thus, we hypothesized that DNMTs are required for depression genesis, probably by repressing hippocampus Bdnf gene expression in rats with neuropathic pain, which can be rescued by ketamine. In the present study, rats were randomly subjected to spared nerve injury (SNI) or sham surgery. SNI upregulated DNMTs and downregulated Bdnf and exon I in the hippocampus and induced depression behaviors, whereas blocking the upregulation of DNMTs with RG108 alleviated SNI-induced depression by up-regulation of the expression of Bdnf and exon I. In addition, we showed that a single dose of ketamine could ameliorate SNI-induced depression-like behaviors, which was related to normalization of DNMTs and Bdnf. In conclusion, our study suggested that DNMTs-induced decreased expression of Bdnf may induce the comorbid of pain and depression, which can be prevented by ketamine.

Характеристика внутрішньої картини хвороби у жінок, хворих на депресивні розлади різного генезу та рівня психосоціальної дезадаптації

Для вивчення специфіки внутрішньої картини хвороби у жінок, хворих на депресивні розлади різного генезу й вираженості психосоціальної дезадаптації, для визначення, в подальшому, таргетних мішеней диференційованої психосоціальної реабілітації даного контингенту пацієнтів, було обстежено 252 жінки, яким було встановлено діагноз депресивного розладу. У дослідження були включені 94 особи з депресивним розладом психогенного генезу (пролонгована депресивна реакція, обумовлена розладом адаптації), 83 жінки з ендогенною депресією (депресивний епізод; рекурентно депресивний розлад; біполярний афективний розлад, поточний епізод депресії) і 75 пацієнток з депресивним розладом органічної генези (органічні афективні розлади). Дослідження проводилося з використанням клініко-психопатологічного та психодіагностичного методів. В результаті дослідження у хворих з різним генезом депресії та наявністю або відсутністю ознак психосоціальної дезадаптації, виявлено різні варіанти і типи внутрішньої картини хвороби. Встановлено, що за умови наявності ознак психосоціальної дезадаптації у жінок наявне більш дезадаптивне ставлення до хвороби, у порівнянні з пацієнтками без дезадаптивних проявів, незалежно від генезу депресивного розладу. Ці закономірності повинні враховуватися при розробці лікувально-реабілітаційних та профілактичних заходів для хворих на депресію

Evaluation of hormonal and metabolic factors related to depression in reproductive age women

Introduction. Major depressive disorder (MDD) is a prevalent disease affecting women more than men worldwide. Various factors are involved in the genesis of depression, including hormones such as testosterone and certain metabolic factors Objective. To evaluate hormone levels and metabolic variables in women with major depression and healthy controls. Method. A cross-sectional, comparative analytical study was conducted in 40 participants, 23 patients with an MDD diagnosis and 17 controls, all of women in reproductive age between the ages of 18 and 45. Sociodemographic variables, hormonal profile, and metabolic variables were assessed and the 17-item Hamilton Depression Scale was used to evaluate depressive symptoms. Results. No statistically significant differences were observed between the groups in the hormonal and metabolic variables explored. Nevertheless, it was observed that the lower the testosterone levels and the higher the serum glucose levels, the more intense depressive symptoms were. Discussion and conclusion. Testosterone is associated with a lower depressive symptoms score on the Hamilton Depression scale, suggesting a potential antidepressant effect, whereas high glucose levels are associated with a higher score on this scale. We believe that the measurement of hormonal and metabolic variables in women can contribute to a better understanding of the pathophysiology of depression.

Features of the relationship between severity of macrosocial maladaptation and anxiety-depressive symptoms in women with different genesis depressive disorders

Background. The leading position in the structure of the pathology of the psyche today is convincingly held by depressive disorders. In recent years, the number of publications showing a combination of the frequency of depression and psychosocial maladaptation, which acts both as a derivative in the clinic of depressive disorders and as an independent phenomenon that provokes and aggravates their course, has increased.
 Objective – to study the correlation of the structure and severity of the manifestations of macrosocial maladaptation and anxiety-depressive symptoms in women with depressive disorders of various genesis, in order to further determine the targeted points for differentiated psychosocial rehabilitation of this patient population.
 Materials and methods. 252 women with a diagnosis of depressive disorder were examined: 94 women with depressive disorder of psychogenic genesis (F43.21), 83 women with endogenous depression, (F32.0, F32.1, F32.2, F32.3, F33.0, F33. 1, F33.2, F33.3, F31.3, F31.4, F31.5) and 75 women with depressive disorder of organic genesis (F06.3). According to the results of assessing the degree of macrosocial maladaptation, two groups were distinguished: women without signs of maladaptation were assigned to the first group (n=48); the second group (n=204) consisted women with identified signs of maladaptation. We used such research methods: clinical-psychopathological, psychodiagnostic, statistical.
 Results. The regularities between the genesis of depression and the severity of signs of macrosocial maladaptation and anxiety are established and described. Macrosocial maladaptation of various severity occurs in the vast majority of patients with depression of any genesis. The severity and variability of pathological anxiety is the lowest in women with psychogenic depression with no or mild macrosocial disadaptation, and high in severe maladaptation, meanwhile in patients with endogenous depression the severity of anxiety is highest with mild maladaptation and low with severe macrosocial maladaptation.
 Conclusions. The severity of macrosocial maladaptation does not demonstrate a direct association with the severity of depressive phenomena and a clear comparability with the genesis of depressive disorder. Anxiety is less dependent on the genesis of depression, and is more determined by the degree of maladaptation. Received data should be taken into account when developing diagnostic, treatment and rehabilitation measures for women with depressive disorders.

Design, synthesis and molecular modelling of new bulky Fananserin derivatives with altered pharmacological profile as potential antidepressants

It is now known that many neurotransmitter systems are responsible for diseases of the central nervous system (CNS). One of the most common CNS disease is depression. Considering that in the treatment and the genesis of depression, the most important are the serotonin receptors from 5-HT1A, 5-HT2A, 5-HT6 and 5-HT7 groups, and dopamine D2R this article describes searching for group of new ligands for mentioned receptors. In the searching for potentially useful compound, we decided to start from the structure of well-known Fananserin. We tried to developed new derivatives, with changed profile of activity compared to Fananserin. Literature analysis and virtual screening emerged group of halogenated long-chain arylpiperazines derivatives of 1,8 naphthosultam/lactam with hexyl carbon chain to synthesis. The compounds obtaining method was developed with a microwave assisted synthesis. Reactions were carried out in acetonitrile, water or in solvent-free conditions. The obtained compounds were tested for their affinity for the serotonin receptors mentioned above. The work managed to obtain compounds acting on selected serotonin receptors, including multifunctional 5-HT1A/5-HT7/D2 ligand 5k, dual 5-HT1A/D2 ligand 5j and selective 5-HT1A ligands 5r and 5c. The SAR analysis showed a visible dependence of affinity for the 5-HT6 receptors from structure of ligands. This relationship was discussed using molecular docking methods. A conformal analysis was also performed for selected ligands and the Fukui indexes were calculated using the DFT (B3LYP/6-311+G (d,p) level of theory) methods. The conducted research and analysis using molecular docking methods allows for selecting further pathways of structural modifications in the design of new ligands for serotonin receptors belonging to the group mentioned. What is more, conducted research show the potential using of Fukui indices to predict the biological activity of new molecules.

A complex relation between depression and multiple sclerosis: a descriptive review.

Multiple sclerosis (MS) is a demyelinating neurodegenerative disease that affects central nervous system (CNS). MS patients are more likely to develop depressive symptoms than patients with other chronic diseases. In this review, we have analysed if there is a correlation between brain lesions (BL), structural damage (SD) and depressive symptoms (DS). We Searched on PubMed and Web of Science databases and screening references of included studied and some review article for additional citations. From initial 745 studies, only 9 met the inclusion criteria. All studies conducted research on 389 patients with MS associated with DS and 120 HC (healthy controls). The selected researches highlighted the involvement of limbic system, the role of hippocampus and the impact of brain lesions on the emotional status of MS patients. In the genesis of depression are implicated many mechanisms including genetic, biochemical, immunological and psychosocial factors, even if a prominent role in the onset of DS seem to be associated with structural and functional brain alterations.

Contributions of gravity and field data on the structural scheme updating of the Tellian domain and its foreland (Nefza-Bizerte region, northern Tunisia)

The Nefza-Bizerte region, eastern part of the Tunisian Alpine chain, covers the thrust sheets domain called the Tell and its Atlassic foreland. The deep structures under the Tellian thrust sheets are not enough explored. The structural interpretation of magmatic rocks, Triassic outcrops and the depressions are still a subject of discussion. In this work, we intend to investigate deep faults and their eventual role in magmatism and Triassic salt setting up and to explain the depression genesis. Analysis of the Bouguer anomaly map and its derivatives reveals the main gravity lineaments, organized in major NE- and NW-trending systems. The NE-trending system, dipping towards the NW, is the main component of the structural scheme and has controlled the tectonic evolution of this area. After the immobilization of the Tellian thrust sheets during the uppermost Langhian, the Tell and its Atlassic foreland were affected by the Tortonian compressive event with a NW-trending maximum horizontal stress. The reverse kinematics of the NE-trending deep-seated faults created at their front continental environments filled later by post-nappes Neogene deposits. After the early Pleistocene, a NNW-directed compressional stress regime deformed the post-nappes Neogene series and generated NW-trending grabens. This coexistence of compression-extension continues until present day.

Certain Bio-Cognitive and Quantum Views of Depression

Depression has been considered essentially a psycho-bio, social condition. In this paper, a hypnotic/quantum approach to understanding depression is attempted and parallel or co-thinking is designated as quantum thinking, one of the main sources of depressive cognitions. It is the flexibility of the quantum brain that accounts for cognitive distortions. Hypnosis may involve a spectrum of quantum consciousness and has great research value in uncovering non-biological depression. Like many of the alternate states of consciousness, hypnosis may be a neuro-quantum state. In the earlier part of the 2oth century, Frederic Myers recognised that the middle realm of the unconscious mind is the “hypnotic stratum” and is associated with deep hypnosis. The unconscious is increasingly allied with the quantum and it is time to revise the concept of the Freudian unconscious accordingly. The co-existence of a quantum mechanical body and brain is all the time more recognised now in parasciences. If consciousness is transmitted through rather than actually produced by the brain, depression may have a downward causation rather than an upward causation arguable in biological disorders like schizophrenia and bipolar disorder. Consciousness-based healing is warranted in the treatment of depression. Whether consciousness is the primary generator of clinical depression or it only contributes to the genesis of depression will continue to be a matter for debate in the foreseeable future.

Depletion of 5 hydroxy-triptamine (5-HT) affects the antidepressant-like effect of neuronal nitric oxide synthase inhibitor in mice.

Clinical and experimental evidence indicates that nitric oxide (NO) is involved in the genesis of depression as well as in antidepressant drug effects. Inhibitors of nitric oxide synthases (NOS) exert antidepressant-like effect in several animal models, but also interfere with the locomotor activity. The involvement of different isoforms of NOS in the antidepressant-like effects is not clearly established. The objective of this study was to investigate the effects of acute or repeated administration of selective inhibitors of neuronal NOS (nNOS) and induced NOS (iNOS), 7 nitroindazole (7NI) and 1400W, respectively, in mice subjected to open field (OF) and forced swim test (FST). We also investigated if the antidepressant-like effect of nNOS inhibitor, 7NI, was dependent on hippocampal serotonin. The results demonstrated that single or repeated (3 and 7days) administration of 7NI resulted in antidepressant-like effects in mice, evidenced by a significant decrease in immobility time in the FST. However, antidepressant-like effects of the iNOS inhibitor, 1400W, were only identified after repeated administration for 3 or 7days. The effects of both inhibitors were comparable to those obtained with the classical antidepressant fluoxetine. It was also demonstrated that the effect of 7NI was dependent of hippocampal serotonin. We concluded that inhibition of nNOS and iNOS result in antidepressant-like effects, and that these effects hold up after repeated administration.

Diagnostics and multimodal treatment of depression in old age : New developments

Depressive disorders in elderly persons are frequent and can either first be manifested at a younger age and show a recurrent pattern during later life (ICD10, F33.*) or have an onset beyond 60years, which is termed late onset depression (LOD). This LOD has a higher tendency to chronification and implies an increased risk of progression, especially to vascular dementia. The multifactorial genesis of depression in old age includes psychosocial, vascular and metabolic factors and requires multimodal therapy modules at the biological and psychosocial level, which is now increasingly being empirically proven. Depressive disorders with executive and cognitive deficits have to be considered adefined entity with respect to prognosis and treatment. As afirst step of treatment watchful waiting is appropriate, especially in depressive adjustment disorders triggered by acute psychosocial stressors (e.g. loss of relatives and conflicts). After 2-4weeks pharmacological antidepressant therapy should be initiated, at least in amoderate depressive episode. Furthermore, the revised national guidelines for depressive disorders also explicitly recommend psychotherapy as an alternative or supplement to pharmacotherapy in the elderly. Several forms of psychotherapy are emphasized: cognitive behavioral therapy, interpersonal therapy and in particular problem solving, as this is aform of treatment that can also be carried out by other professional groups, thus alleviating the treatment gap caused by the lack of psychotherapists. In summary, adepressive disorder in old age should not induce therapeutic nihilism: after stepped diagnostic assessments, multimodal therapies are individually adapted to the physical, cognitive and social resources of the patients.

ASPREE-D: Aspirin for the prevention of depression in the elderly.

Not only is depression associated with increased inflammation but inflammation is a risk factor for the genesis of depression. Many of the environmental risk factors for depression are transduced through inflammatory signaling. Anti-inflammatory agents show promise for the management of depression in preclinical, epidemiological, and early clinical studies. This opens the door to the potential for anti-inflammatory agents to treat and prevent depression. There are no evidence-based pharmacotherapies for depression prevention. ASPREE-D, aspirin in the prevention of depression in the elderly, is a sub study of ASPREE, which explores the potential of aspirin to prevent a range of inflammation related disorders in the elderly. With a sample size of 19,114, and a duration of 5 years, this placebo controlled study will be one of the largest randomized controlled trials in psychiatry and will provide definitive evidence on the ability of aspirin to prevent depression. This paper presents the rationale for the study and presents a summary of the study design. ASPREE-D may not only define novel therapy but will provide mechanistic proof of concept of the role of inflammation in depression.

The Psycho-Neurology of Cross-Species Affective/Social Neuroscience: Understanding Animal Affective States as a Guide to Development of Novel Psychiatric Treatments.

During the past half century of research with preclinical animal models, affective neuroscience has helped identify and illuminate the functional neuroanatomies and neurochemistries of seven primary process, i.e., genetically provided emotional systems of mammalian brains. All are subcortically localized, allowing animal models to guide the needed behavioral and neuroscientific analyses at levels of detail that cannot be achieved through human research, including modern brain imaging. They consist of the following neuronal processes: SEEKING/Enthusiasm, RAGE/Anger, FEAR/Anxiety, sexual LUST/Passion, maternal CARE/Nurturance, separation-distress PANIC/Grief and PLAY/Social Joy. Several of these systems figure heavily in social bonding. I will focus here especially on the genesis of depression. Its genesis is significantly influenced by (i) sustained overactivity of the separation-distress PANIC system reflecting severed social bonds and the excessive "psychological pain" of loneliness that can, if sustained, lead to a downward cascade known as psychological despair, and (ii) the despair phase that follows the acute PANIC response, which is characterized by abnormally low activity of the SEEKING, the so-called brain reward networks, leading to amotivational states that characterize depression. Depressive affect is promoted by such brain affective mechanisms of social attachments and social loss as well as diminished arousability of the SEEKING system, leading to chronic dysphoria. To understand why depression feels so bad, we must understand the neural mechanisms that mediate such social feelings.