Preclinical discovery of duloxetine for the treatment of depression

Introduction: Affective disorders, including major depressive disorder (MDD), are among the most severely disabling mental disorders, and in many cases areIntroduction: Affective disorders, including major depressive disorder (MDD), are among the most severely disabling mental disorders, and in many cases are associated with poor treatment outcomes. From the emergence of the monoamine hypothesis of depression, the first-line treatment for MDD had mainly acted by inhibiting monoamine reuptake, and thereby increasing these levels in the synaptic cleft. However, in recent years, several newantidepressant drugs have appeared, including duloxetine, a dual serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor recommended for the treatment of MDD. Areas covered: The article reviews and discusses the biochemical and functional profile of duloxetine splitting the review into acute and long-term treatment with this dual monoamine reuptake inhibitor. In addition, the authors summarize available preclinical behavioral research data, which have demonstrated among other effects, the antidepressant-like activity of duloxetine in several animal models. The authors focus on the most recent literature on synaptic neuroplasticity modulation of this antidepressant drug. Finally, the authors briefly mention other approved indications of duloxetine. Expert opinion: Duloxetine inhibits 5-HT and NA reuptake, effectively desensitizes various autoreceptors and promotes neuroplasticity. Clinically, duloxetine is an effective antidepressant that is well tolerated and has significant efficacy in the treatment of MDD. associated with poor treatment outcomes. From the emergence of the monoamine hypothesis of depression, the first-line treatment for MDD had mainly acted by inhibiting monoamine reuptake, and thereby increasing these levels in the synaptic cleft. However, in recent years, several new antidepressant drugs have appeared, including duloxetine, a dual serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor recommended for the treatment of MDD

Neurotrophins Role in Depression Neurobiology: A Review of Basic and Clinical Evidence

Depression is a neuropsychiatric disorder affecting a huge percentage of the active population especially in developed countries. Research has devoted much of its attention to this problematic and many drugs have been developed and are currently prescribed to treat this pathology. Yet, many patients are refractory to the available therapeutic drugs, which mainly act by increasing the levels of the monoamines serotonin and noradrenaline in the synaptic cleft. Even in the cases antidepressants are effective, it is usually observed a delay of a few weeks between the onset of treatment and remission of the clinical symptoms. Additionally, many of these patients who show remission with antidepressant therapy present a relapse of depression upon treatment cessation. Thus research has focused on other possible molecular targets, besides monoamines, underlying depression. Both basic and clinical evidence indicates that depression is associated with several structural and neurochemical changes where the levels of neurotrophins, particularly of brain-derived neurotrophic factor (BDNF), are altered. Antidepressants, as well as other therapeutic strategies, seem to restore these levels. Neuronal atrophy, mostly detected in limbic structures that regulate mood and cognition, like the hippocampus, is observed in depressed patients and in animal behavioural paradigms for depression. Moreover, chronic antidepressant treatment enhances adult hippocampal neurogenesis, supporting the notion that this event underlies antidepressants effects. Here we review some of the preclinical and clinical studies, aimed at disclosing the role of neurotrophins in the pathophysiological mechanisms of depression and the mode of action of antidepressants, which favour the neurotrophic/neurogenic hypothesis

The Role of the Locus Coeruleus in Pain and Associated Stress-Related Disorders

The locus coeruleus (LC)-noradrenergic system is the main source of noradrenaline in the central nervous system and is involved intensively in modulating pain and stress-related disorders (e.g., major depressive disorder and anxiety) and in their comorbidity. However, the mechanisms involving the LC that underlie these effects have not been fully elucidated, in part owing to the technical difficulties inherent in exploring such a tiny nucleus. However, novel research tools are now available that have helped redefine the LC system, moving away from the traditional view of LC as a homogeneous structure that exerts a uniform influence on neural activity. Indeed, innovative techniques such as DREADDs (designer receptors exclusively activated by designer drugs) and optogenetics have demonstrated the functional heterogeneity of LC, and novel magnetic resonance imaging applications combined with pupillometry have opened the way to evaluate LC activity in vivo. This review aims to bring together the data available on the efferent activity of the LC-noradrenergic system in relation to pain and its comorbidity with anxiodepressive disorders. Acute pain triggers a robust LC stress response, producing spinal cord–mediated endogenous analgesia while promoting aversion, vigilance, and threat detection through its ascending efferents. However, this protective biological system fails in chronic pain, and LC activity produces pain facilitation, anxiety, increased aversive memory, and behavioral despair, acting at the medulla, prefrontal cortex, and amygdala levels. Thus, the activation/deactivation of specific LC projections contributes to different behavioral outcomes in the shift from acute to chronic pain

Induced Dipoles and Possible Modulation of Wireless Effects in Implanted Electrodes. Effects of Implanting Insulated Electrodes on an Animal Test to Screen Antidepressant Activity

There is evidence that Deep Brain Stimulation (DBS) produces health benefits in patients even before initiating stimulation. Furthermore, DBS electrode insertion in rat infralimbic cortex (ILC) provokes antidepressant-like effects before stimulation, due to local inflammation and astrogliosis. Consequently, a significant effect of implanting electrodes is suspected. External fields, similar in magnitude to the brain's endogenous fields, induce electric dipoles in conducting materials, in turn influencing neural cell growth through wireless effects. To elucidate if such dipoles influence depressive-like behavior, without external stimulation, the comparative effect of conducting and insulated electrodes along with the glial response is studied in unstressed rats. Naive and implanted rats with electrically insulated or uninsulated steel electrodes were evaluated in the modified forced swimming test and expression of ILC-glial markers was assessed. An antidepressant-like effect was observed with conducting but not with insulated electrodes. Gliosis was detected in both groups, but astroglial reactivity was larger near uninsulated electrodes. Thus, induced dipoles and antidepressant-like effects were only observed with conducting implants. Such correlation suggests that dipoles induced in electrodes by endogenous fields in turn induce neuron stimulation in a feedback loop between electrodes and neural system. Further research of the effects of unwired conducting implants could open new approaches to regulating neuronal function, and possibly treat neurological disorders.This study was also supported by grants co-financed by the "Fondo Europeo de Desarrollo Regional" (FEDER)-UE "A way to build Europe" from the "Ministerio de Economia y Competitividad" (MINECO: RTI2018-099778-B-I00 (to E.B.), RTI2018-098269-B-I00 (to J.N.) and RTI2018-097753-B-I00 (to N.C.P.) and "Juan de la Cierva Formacion" postdoctoral grant FJC2018-037958-I (to L.P.C.)) and PID2019-108562GB-I00 (to V.T.M); the "Consejeria de Economia, Innovacion, Ciencia y Empleo de la Junta de Andalucia" (CTS-510, to E.B.); the Severo Ochoa Program CEX2019-000917-S (to N.C.P.) and the "Centro de Investigacion Biomedica en Red de Salud Mental-CIBERSAM" (CB/07/09/0033 and CB/07/09/0006

Depressive-like states heighten the aversion to painful stimuli in a rat model of comorbid chronic pain and depression.

BACKGROUND: Chronic pain and depression are two complex states with sensory/somatic and emotional components, and they may mutually exacerbate one another in conditions of comorbidity, leading to a poorer prognosis. METHODS: The authors have evaluated the sensory and emotional components in a rat model combining chronic constriction injury (CCI, a model of chronic neuropathic pain) with unpredictable chronic mild stress (CMS, an experimental model of depression). In addition, the phosphorylation/activation of the extracellular signal-regulated kinases 1 and 2 and neuronal density was also evaluated in the anterior cingulate cortex. Four groups were tested: sham-control, sham-CMS, CCI-control, and CCI-CMS. RESULTS: CMS selectively heightens aversion to painful experiences in animals subjected to CCI, as measured in the place escape/avoidance test at 20, 25, and 30 min (CCI-CMS (mean±SEM): 75.68±3.32, 66.75±4.70, 77.54±3.60 vs. CCI-control: 44.66±6.07, 43.17±6.92, 52.83±5.92, respectively), in conjunction with an increase in the accumulation of phosphorylation/activation of the extracellular signal-regulated kinases (CCI-CMS: 4.17±0.52 vs. sham-control: 0.96±0.05) and a decrease in neuronal density in the anterior cingulate cortex. In contrast, chronic pain did not exacerbate the characteristic profile of depression (anhedonia and behavioral despair) in rats subjected to CMS. Furthermore, depression enhances the perception of some specific modalities of sensorial pain such as cold allodynia but has no influence on mechanical threshold. CONCLUSIONS: These findings support the theory that depression leads to emotional dysfunction in the interpretation of pain in patients suffering chronic pain. In addition, combined animal models of pain-depression may provide a valuable tool to study the comorbidity of pain and depression

Shared decision making with schizophrenic patients: a randomized controlled clinical trial with booster sessions (DECIDE Study)

Background: The treatment of schizophrenia requires a prolonged, multidimensional intervention that includes antipsychotic drugs. Treatment adherence is essential to effectively control the disorder. Shared decision-making (SDM) is a strategy, supported by numerous practical and ethical arguments, that seeks to involve patients in the therapeutic process to improve treatment adherence and satisfaction. The use of this model in mental health has been limited for many intrinsic and extrinsic reasons. The results of clinical trials conducted to date have largely been disappointing, potential due to study design-related limitations. Aim/Question: To evaluate the efficacy, in terms of treatment adherence and improvement in clinical variables, such as severity of symptoms, days of hospitalization or insight, of a carefully timed SDM model initiated immediately prior to hospital discharge in patients with schizophrenia. Methods: Single-blind, randomized clinical trial in an acute psychiatric care unit within the Andalusian Health Department to compare SDM (experimental group) to treatment as usual (TAU; control group) in a sample of patients hospitalized for an acute episode of schizophrenia or schizoaffective disorder. The study was performed between January 2014 and June 2017. The experimental group participated in SDM sessions prior to discharge with regular booster sessions over the one-year follow-up. The health care team responsible for SDM was predisposed to concordance (LatCon II scale) and received specific training in SDM. A hierarchical multiple linear regression analysis was performed to evaluate the factors independently associated with adherence, controlling for sociodemographic, clinical, and admission-related variables. Variables were assessed at admission, discharge and at 3, 6 and 12 months after discharge during the one year follow up. BARS, DAI, WAI-S, COMRADE and PANSS were used to evaluate adherence, attitude to treatment, therapeutic alliance, satisfaction and confidence with decision and clinical status, respectively. Results: A total of 227 schizophrenic patients hospitalized with acute decompensation were evaluated; of these, 102 met all inclusion criteria and were included in the study. Most patients (95%) had prior experience with antipsychotics and most (82%) had experienced related side effects. Despite randomization, psychopathologic severity was greater in the experimental group, with a mean (SD) PANSS score of 104.08 (80) vs. 93.45 (20.30) (p < 0.05). The final regression model to explain adherence was significant (adjusted R2 = 0.384; F [df= 6] = 4.386; p < 0.001), with a direct, significant and independent association with SDM mediated by the number of booster sessions. Discussion: Shared decision making with booster sessions appears to increase treatment adherence in patients with severe mental disorders. Implication on practice: Ethical, practical, and clinical reasons support the use of strategies designed promote the use of long-term, shared decision-making in psychiatric patients, especially in schizophrenia spectrum disorder. Background: Adherence is essential for the successful treatment of schizophrenia. Shared decision making is a strategy that aims to involve patients in the treatment process to improve satisfaction with treatment. However, the evidence to support this approach remains inconclusive. Aim/Question: To assess the efficacy, in terms of treatment adherence and clinical variables, of a shared decision-making approach initiated immediately prior to hospital discharge and at regular intervals during one-year follow-up in patients with schizophrenia. Methods: Single-blind randomized clinical trial with in an acute psychiatric care unit within the Andalusian Health Department, with booster sessions at months 3, 6, and 12 during the follow-up. A hierarchical multiple linear regression was performed to assess adherence, controlling for sociodemographic, clinical, and admission-related variables, and the application or not of shared decision-making. Results: 102 patients with acute decompensation were included. Despite randomization, psychopathologic severity was greater in the experimental group, with a mean (SD) PANSS score of 104.08 (80) vs. 93.45 (20.30) (p < 0.05). The final explanatory adherence model was significant (adjusted R2 = 0.384; F [df = 16] = 4.386; p < 0.001), with a significant and independent association of shared decision-making mediated by the number of booster sessions applied. Conclusions: The application of shared decision making with booster sessions appears to increase the likelihood of treatment adherence in schizophrenia spectrum disorder. © 2023 The Author

Pain and depression comorbidity causes asymmetric plasticity in the locus coeruleus neurons

There is strong comorbidity between chronic pain and depression, although the neural circuits and mechanisms underlying this association remain unclear. By combining immunohistochemistry, tracing studies and western blotting, with the use of different DREADDS (designer receptor exclusively activated by designer drugs) and behavioural approaches in a rat model of neuropathic pain (chronic constriction injury), we explore how this comorbidity arises. To this end, we evaluated the time-dependent plasticity of noradrenergic locus coeruleus neurons relative to the site of injury: ipsilateral (LCipsi) or contralateral (LCcontra) locus coeruleus at three different time points: short (2 days), mid (7 days) and long term (30-35 days from nerve injury). Nerve injury led to sensorial hypersensitivity from the onset of injury, whereas depressive-like behaviour was only evident following long-term pain. Global chemogenetic blockade of the LCipsi system alone increased short-term pain sensitivity while the blockade of the LCipsi or LCcontra relieved pain-induced depression. The asymmetric contribution of locus coeruleus modules was also evident as neuropathy develops. Hence, chemogenetic blockade of the LCipsi -> spinal cord projection, increased pain-related behaviours in the short term. However, this lateralized circuit is not universal as the bilateral chemogenetic inactivation of the locus coeruleus-rostral anterior cingulate cortex pathway or the intra-rostral anterior cingulate cortex antagonism of alpha1- and alpha2-adrenoreceptors reversed long-term pain-induced depression. Furthermore, chemogenetic locus coeruleus to spinal cord activation, mainly through LCipsi, reduced sensorial hypersensitivity irrespective of the time post-injury. Our results indicate that asymmetric activation of specific locus coeruleus modules promotes early restorative analgesia, as well as late depressive-like behaviour in chronic pain and depression comorbidity.This study was supported by grants cofinanced by the 'Fondo Europeo de Desarrollo Regional' (FEDER)-UE 'A way to build Europe' from the `Ministerio de Economia y Competitividad' (MINECO: RTI2018-099778-B-I00) and by the 'Ministerio de SaludInstituto de Salud Carlos III' (PI18/01691); the 'Consejeria de Salud de la Junta de Andalucia' (PI-0134-2018); the 'Programa Operativo de Andalucia FEDER, Iniciativa Territorial Integrada ITI 2014-2020 Consejeria Salud, Junta de Andalucia' (PI-0080-2017); the "Consejeri ' a de Transformacion Economica, Industria, Conocimiento y Universidades, Junta de Andalucia" (PEMP-00082020), Instituto de Investigacion e Innovacion en Ciencias Biomedicas de Cadiz (INiBICA LI19/06IN-CO22); the `Consejeri ' a de Economia, Innovacion, Ciencia y Empleo de la Junta de Andalucia' (CTS-510); the 'Centro de Investigacion Biomedica en Red de Salud Mental-CIBERSAM' (CB/07/09/0033) and the Academy of Finland (315043)

The Absence of Caspase-8 in the Dopaminergic System Leads to Mild Autism-like Behavior

In the last decade, new non-apoptotic roles have been ascribed to apoptotic caspases. This family of proteins plays an important role in the sculpting of the brain in the early stages of development by eliminating excessive and nonfunctional synapses and extra cells. Consequently, impairments in this process can underlie many neurological and mental illnesses. This view is particularly relevant to dopamine because it plays a pleiotropic role in motor control, motivation, and reward processing. In this study, we analyze the effects of the elimination of caspase-8 (CASP8) on the development of catecholaminergic neurons using neurochemical, ultrastructural, and behavioral tests. To do this, we selectively delete the CASP8 gene in cells that express tyrosine hydroxylase with the help of recombination through the Cre-loxP system. Our results show that the number of dopaminergic neurons increases in the substantia nigra. In the striatum, the basal extracellular level of dopamine and potassium-evoked dopamine release decreased significantly in mice lacking CASP8, clearly showing the low dopamine functioning in tissues innervated by this neurotransmitter. This view is supported by electron microscopy analysis of striatal synapses. Interestingly, behavioral analysis demonstrates that mice lacking CASP8 show changes reminiscent of autism spectrum disorders (ASD). Our research reactivates the possible role of dopamine transmission in the pathogenesis of ASD and provides a mild model of autism

A Characterization of the Effects of Minocycline Treatment During Adolescence on Structural, Metabolic, and Oxidative Stress Parameters in a Maternal Immune Stimulation Model of Neurodevelopmental Brain Disorders

Background: Minocycline (MIN) is a tetracycline with antioxidant, anti-inflammatory, and neuroprotective properties. Given the likely involvement of inflammation and oxidative stress (IOS) in schizophrenia, MIN has been proposed as a potential adjuvant treatment in this pathology. We tested an early therapeutic window, during adolescence, as prevention of the schizophrenia-related deficits in the maternal immune stimulation (MIS) animal model. Methods: On gestational day 15, Poly I:C or vehicle was injected in pregnant Wistar rats. A total 93 male offspring received MIN (30 mg/kg) or saline from postnatal day (PND) 35-49. At PND70, rats were submitted to the prepulse inhibition test. FDG-PET and T2-weighted MRI brain studies were performed at adulthood. IOS markers were evaluated in frozen brain tissue. Results: MIN treatment did not prevent prepulse inhibition test behavioral deficits in MIS offspring. However, MIN prevented morphometric abnormalities in the third ventricle but not in the hippocampus. Additionally, MIN reduced brain metabolism in cerebellum and increased it in nucleus accumbens. Finally, MIN reduced the expression of iNOS (prefrontal cortex, caudate-putamen) and increased the levels of KEAP1 (prefrontal cortex), HO1 and NQO1 (amygdala, hippocampus), and HO1 (caudate-putamen). Conclusions: MIN treatment during adolescence partially counteracts volumetric abnormalities and IOS deficits in the MIS model, likely via iNOS and Nrf2-ARE pathways, also increasing the expression of cytoprotective enzymes. However, MIN treatment during this peripubertal stage does not prevent sensorimotor gating deficits. Therefore, even though it does not prevent all the MIS-derived abnormalities evaluated, our results suggest the potential utility of early treatment with MIN in other schizophrenia domains.M.L.S. was supported by the Ministerio de Ciencia, Innovacion y Universidades, Instituto de Salud Carlos III (projects PI14/00860 and PI17/01766, and grant CPII14/00005), co-financed by European Regional Development Fund (ERDF), "A way of making Europe", CIBER of Mental Health (CIBERSAM), Delegacion del Gobierno para el Plan Nacional sobre Drogas (2017/085), Fundacion Mapfre and Fundacion Alicia Koplowitz. M.C.-V. was supported by Fundacion Tatiana Perez de Guzman el Bueno. D.R.-M. was supported by Consejeria de Educacion e Investigacion, Comunidad de Madrid, co-funded by European Social Fund "Investing in your future" (grant, PEJD-2018-PRE/BMD-7899). N.L.-R. was supported by Instituto de investigacion Sanitaria Gregorio Maranon. A.R.-M. was supported by Consejeria de Educacion e Investigacion, Comunidad de Madrid, co-funded by European Social Fund "Investing in your future" (grant, PEJ15/BIO/TL-0216). The CNIC was supported by the Spanish Ministerio de Ciencia, Innovacion y Universidades (MCIU) and the Pro-CNIC Foundation. J.C.L. was supported by the Spanish Ministry of Economy, Industry and Competitiveness (MINECOEU-FEDER) SAF2016-75500-R and CIBERSAM. E.B.D., S.T.-S., and J.A.G.-P. were supported by grants: co-financed by the "Fondo Europeo de Desarrollo Regional" (FEDER)-UE "A way to build Europe" from the "Ministerio de Economia y Competitividad" (MINECO: RTI2018-099778-B-I00) and the "Ministerio de SaludInstituto de Salud Carlos III (PI18/01691); from the "Plan Nacional sobre Drogas, Ministerio de Sanidad, Consumo y Bienestar Social" (2019I041); from the "Programa Operativo de Andalucia FEDER, Iniciativa Territorial Integrada ITI 2014-2020 Consejeria Salud, Junta de Andalucia" (PI-0080-2017 and PI-0009-2017); from the Consejeria de Salud de la Junta de Andalucia (PI-0134-2018); from the University of Cadiz (PR2019-046); from the "Instituto de Investigacion e Innovacion en Ciencias Biomedicas de Cadiz-INiBICA" (IN-C22; LI19/06IN-CO22); from the "Consejeria de Economia, Innovacion, Ciencia y Empleo de la Junta de Andalucia" (CTS-510); from the "CIBERSAM" (CB/07/09/0033)

Selective deletion of Caspase-3 gene in the dopaminergic system exhibits autistic-like behaviour

Apoptotic caspases are thought to play critical roles in elimination of excessive and non-functional synapses and removal of extra cells during early developmental stages. Hence, an impairment of this process may thus constitute a basis for numerous neurological and psychiatric diseases. This view is especially relevant for dopamine due to its pleiotropic roles in motor control, motivation and reward processing. Here, we have analysed the effect of caspase-3 depletion on the development of catecholaminergic neurons and performed a wide array of neurochemical, ultrastructural and behavioural assays. To achieve this, we performed selective deletion of the Casp3 gene in tyrosine hydroxylase (TH)-expressing cells using Cre-loxP-mediated recombination. Histological evaluation of most relevant catecholaminergic nuclei revealed the ventral mesencephalon as the most affected region. Stereological analysis demonstrated an increase in the number of TH-positive neurons in both the substantia nigra and ventral tegmental area along with enlarged volume of the ventral midbrain. Analysis of main innervating tissues revealed a rather contrasting profile. In striatum, basal extracellular levels and potassium-evoked DA release were significantly reduced in mice lacking Casp3, a clear indication of dopaminergic hypofunction in dopaminergic innervating tissues. This view was sustained by analysis of TH-labelled dopaminergic terminals by confocal and electron microscopy. Remarkably, at a behavioural level, Casp3-deficient mice exhibited impaired social interaction, restrictive interests and repetitive stereotypies, which are considered the core symptoms of autism spectrum disorder (ASD). Our study revitalizes the potential involvement of dopaminergic transmission in ASD and provides an excellent model to get further insights in ASD pathogenesis.This work was supported by grants from the Spanish Ministerio de Economía y Competitividad (SAF2015-64171-R and RTI2018-098645-B-I00). J.A.A. and E.P.V. was supported by a MINECO (BFU2015-64536) grant. I.S.P., E.B. and L.B. were co-financed by the “Fondo Europeo de Desarrollo Regional” (FEDER)-UE “A way to build Europe” from the “Ministerio de Ciencia, Innovación y Universidades” (RTI2018-099778-B-I00) and the Ministerio de Salud-Instituto de Salud Carlos III (PI18/01691), as well as funding from the “Consejería de Salud de la Junta de Andalucía” (PI-0134-2018); the “Programa Operativo de Andalucía FEDER, Iniciativa Territorial Integrada ITI 2014-2020 Consejería Salud, Junta de Andalucía” (PI-0080-2017); the “Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía” (CTS-510); and the “Centro de Investigación Biomédica en Red de Salud Mental- CIBERSAM” (CB/07/09/0033)