RESUMEN
INTRODUCTION: Peripheral levels of inflammatory markers are elevated in major depressive disorder (MDD). Selective serotonin reuptake inhibitors (SSRIs) affect levels of inflammatory markers in patients with MDD, but studies have reported inconsistent findings. This systematic review and meta-analysis aims to investigate the effects of SSRI treatment on peripheral levels of a range of inflammatory markers in MDD patients. METHODS: Systematic literature search (Pubmed, Web of Science, Embase, Cochrane) for studies published before November 2018. Studies were included if they used SSRI monotherapy and peripheral levels of interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were measured before and after treatment in patients with MDD. Meta-analysis was conducted using Comprehensive Meta-analysis (version 2). Effect sizes were calculated using bias-corrected standardized mean difference (Hedges' g) between pre- and post-treatment. Sub-group analyses, meta-regression and publication bias estimates were undertaken; sensitivity analyses were performed using different estimated pre- and post-treatment correlations and after removing poor quality studies. RESULTS: Twenty two eligible studies including 827 MDD patients were included in the meta-analysis: fifteen studies for IL-6; eleven for TNF-α; eight for IL-10; seven for IL-1ß; six for IL-4; five for IL-2; and four for IFN-γ. The pooled effect estimate indicates SSRI treatment decreased levels of pro-inflammatory markers IL-6 (Hedges' g, -0.418; 95%CI, -0.663 to -0.174; I2â¯=â¯89.412), TNF-α (Hedges' g, -0.554; 95%CI, -0.990 to -0.118; I2â¯=â¯95.438) and IL-1ß (Hedges' gâ¯=â¯-0.574; 95%CI, -1.014 to -0.135; I2â¯=â¯91.622), and anti-inflammatory marker IL-10 (Hedges' gâ¯=â¯-0.615; 95%CI, -0.989 to -0.242; I2â¯=â¯90.406). There were no significant treatment effects on levels of IL-2, IL-4, or IFN-γ. There was a high level of heterogeneity between studies. Sensitivity analyses indicated the robustness of the primary analyses. CONCLUSIONS: The current review and meta-analysis indicates moderate immunomodulating effects of SSRI treatment for MDD, which suggests SSRIs may owe some of their therapeutic effect to their anti-inflammatory properties. High heterogeneity across studies may limit interpretation of the findings and larger randomized clinical trials are warranted.
Asunto(s)
Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/inmunología , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Biomarcadores , Citocinas/efectos de los fármacos , Citocinas/inmunología , Humanos , Inmunidad/efectos de los fármacos , Inmunidad/inmunología , Inflamación/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/inmunologíaRESUMEN
BACKGROUND: Antenatal depression and use of serotonin reuptake inhibitors (SSRI) in pregnancy have both been associated with an increased risk of poor pregnancy outcomes, such as preterm birth and impaired fetal growth. While the underlying biological pathways for these complications are poorly understood, it has been hypothesized that inflammation may be a common physiological pathway. The aim of the present study was to assess peripheral inflammatory markers in healthy women, women with antenatal depression, and in women using SSRI during pregnancy. METHODS: 160 healthy pregnant controls, 59 women with antenatal depression and 39 women on treatment with SSRIs were included. The relative levels of 92 inflammatory proteins were analyzed by proximity extension assay technology. RESULTS: Overall, 23 of the inflammatory markers were significantly lower in women with antenatal depression and in women on treatment with SSRIs in comparison with the healthy controls. No difference in any of the inflammatory markers was observed between women with antenatal depression and those who were using SSRI. Top three inflammatory markers that were down-regulated in women with antenatal depression were TNF-related apoptosis-inducing ligand (TRAIL), p=0.000001, macrophage colony-stimulating factor 1 (CSF-1), p=0.000004, and fractalkine (CX3CL1), p=0.000005. Corresponding inflammatory markers in SSRI users were CSF-1, p=0.000011, vascular endothelial growth factor A (VEGF-A), p=0.000016, and IL-15 receptor subunit alpha (IL-15RA), p=0.000027. The inflammatory markers were negatively correlated with cortisone serum concentrations in controls, but not in the cases. Differential DNA methylation of was found for seven of these inflammatory markers in an independent epigenetics cohort. CONCLUSION: Women with antenatal depression or on SSRI treatment have lower levels of a number of peripheral inflammatory markers than healthy pregnant controls. Hypothetically, this could be due to dysregulated switch to the pro-M2 milieu that characterizes normal third trimester pregnancy. However, longitudinal blood sampling is needed to elucidate whether the presumably dysregulated M2 shift is driving the development of antenatal depression or is a result of the depression.
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Depresión/inmunología , Complicaciones del Embarazo/inmunología , Complicaciones del Embarazo/psicología , Adulto , Estudios de Cohortes , Depresión/complicaciones , Trastorno Depresivo/tratamiento farmacológico , Femenino , Humanos , Recién Nacido , Inflamación/inmunología , Inflamación/metabolismo , Macrófagos/metabolismo , Masculino , Embarazo , Complicaciones del Embarazo/metabolismo , Resultado del Embarazo , Tercer Trimestre del Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Inhibidores Selectivos de la Recaptación de Serotonina/inmunología , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéuticoRESUMEN
The majority of peripheral serotonin is stored in platelets, which secrete it on activation. Serotonin releases Weibel-Palade bodies (WPBs) and we asked whether absence of platelet serotonin affects neutrophil recruitment in inflammatory responses. Tryptophan hydroxylase (Tph)1deficient mice, lacking non-neuronal serotonin, showed mild leukocytosis compared with wild-type (WT), primarily driven by an elevated neutrophil count. Despite this, 50% fewer leukocytes rolled on unstimulated mesenteric venous endothelium of Tph1(-/-) mice. The velocity of rolling leukocytes was higher in Tph1(-/-) mice, indicating fewer selectin-mediated interactions with endothelium. Stimulation of endothelium with histamine, a secretagogue of WPBs, or injection of serotonin normalized the rolling in Tph1(-/-) mice. Diminished rolling in Tph1(-/-) mice resulted in reduced firm adhesion of leukocytes after lipopolysaccharide treatment. Blocking platelet serotonin uptake with fluoxetine in WT mice reduced serum serotonin by > 80% and similarly reduced leukocyte rolling and adhesion. Four hours after inflammatory stimulation, neutrophil extravasation into lung, peritoneum, and skin wounds was reduced in Tph1(-/-) mice, whereas in vitro neutrophil chemotaxis was independent of serotonin. Survival of lipopolysaccharide-induced endotoxic shock was improved in Tph1(-/-) mice. In conclusion, platelet serotonin promotes the recruitment of neutrophils in acute inflammation, supporting an important role for platelet serotonin in innate immunity.
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Plaquetas/inmunología , Inflamación/inmunología , Neutrófilos/inmunología , Serotonina/inmunología , Enfermedad Aguda , Animales , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Quimiotaxis/efectos de los fármacos , Quimiotaxis/inmunología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/inmunología , Endotelio Vascular/metabolismo , Citometría de Flujo , Fluoxetina/inmunología , Fluoxetina/farmacología , Histamina/inmunología , Histamina/farmacología , Inflamación/genética , Inflamación/metabolismo , Estimación de Kaplan-Meier , Selectina L/inmunología , Selectina L/metabolismo , Rodamiento de Leucocito/efectos de los fármacos , Rodamiento de Leucocito/genética , Rodamiento de Leucocito/inmunología , Leucocitosis/genética , Leucocitosis/inmunología , Leucocitosis/metabolismo , Lipopolisacáridos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila/inmunología , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Serotonina/sangre , Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/inmunología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Choque Séptico/inducido químicamente , Choque Séptico/genética , Choque Séptico/inmunología , Triptófano Hidroxilasa/deficiencia , Triptófano Hidroxilasa/genética , Cuerpos de Weibel-Palade/efectos de los fármacos , Cuerpos de Weibel-Palade/inmunología , Cuerpos de Weibel-Palade/metabolismoRESUMEN
BACKGROUND: Adults with major depressive disorder (MDD) show elevated levels of IL-6 and TNF-alpha. Studies of adolescents with MDD or anxiety disorders (AD) are few and present conflicting results. METHODS: We studied plasma cytokines in a clinical sample of adolescent females with MDD and/or clinical AD (n=60, mean age 16.8 years), compared to healthy controls (n=44; mean age 16.5 years). RESULTS: The clinical sample showed significantly higher values of IL-2 (Z=-4.09, p>0.0001), IL1-beta (Z=-2.40, p<0.05) and IL-10 (Z=-2.38, p<0.05) as compared to controls. The subgroup of the clinical sample not treated with SSRIs had a significant difference of IL-6 (Z=-2.26, p<0.05) in addition to the difference of IL-2 and IL1-beta, but showed no difference of IL-10 as compared to the controls. SSRI treatment was related to IL-6, explaining 26% of the variance in the clinical sample after controlling for BMI and symptom severity. In the clinical sample, levels of IL-6 and IFN-gamma were positively correlated with self-assessed symptoms of anxiety and/or depression (corr.coeff 0.35 resp 0.40 at p<0.05). LIMITATIONS: The cross-sectional design does not allow for conclusions on causality. The sample sizes were relatively small and a large drop-out in the clinical sample may have influenced the representativity. DISCUSSION: The study suggests that pro-inflammatory cytokines are part of the pathophysiology of emotional disorders in adolescent females and that SSRIs have anti-inflammatory properties. The findings prompt further studies on the specific mechanisms involved and may contribute to the development of more effective treatment and prevention.
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Adolescente , Trastornos de Ansiedad/sangre , Citocinas/sangre , Trastorno Depresivo Mayor/sangre , Inhibidores Selectivos de la Recaptación de Serotonina/inmunología , Antidepresivos/inmunología , Antidepresivos/uso terapéutico , Trastornos de Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/inmunología , Estudios Transversales , Citocinas/inmunología , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/inmunología , Femenino , Humanos , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéuticoRESUMEN
Recent data have shown the presence of immunological alterations in adult patients suffering from obsessive-compulsive disorder (OCD). The objective of this study was to examine the possible effects of 12 months of treatment with different serotonergic drugs, such as clomipramine and selective serotonin reuptake inhibitors (SSRIs) on peripheral immunological cells of 18 OCD patients. Both the absolute number and percent of CD4+, CD8+, CD3+, CD19+ and CD56+ cells were measured in peripheral blood before and after treatment by means of a Facstar Flow Sorter apparatus. At baseline, all patients showed a significant increase of CD8+ and decrease of CD4+ lymphocytes when compared with a similar group of healthy control subjects; after the treatment, CD8+ and CD4+ cells, respectively, decreased and increased significantly, and the CD4+/CD8+ ratio increased, when compared with baseline values, in parallel with the clinical improvement. These data suggest that the alterations of immune cells reported in patients with OCD at baseline may be reverted by treatment with SRIs and should be considered a state-dependent marker, perhaps related to a condition of stress.
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Antígenos CD/efectos de los fármacos , Clomipramina/farmacología , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Adolescente , Adulto , Antígenos CD/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Clomipramina/inmunología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Trastorno Obsesivo Compulsivo/inmunología , Inhibidores Selectivos de la Recaptación de Serotonina/inmunología , Factores de Tiempo , Adulto JovenRESUMEN
Delirium, depression and other psychiatric difficulties are commonly encountered by posttransplantation patients, and antipsychotic medicines are frequently used to treat these difficulties. This article reviews previous research data concerning the immunological effects of these medicines, with particular focus on the consequences of prolactin elevation. Unproven but of concern is that these effects may influence graft fate. Older antipsychotic medicines such as haloperidol and chlorpromazine have a high likelihood of elevating prolactin. Prolactin is an immunologically active molecule generally promoting bone marrow function. This may be of benefit post-stem-cell transplant, helping engraftment, but could further rejection of solid-organ transplants. Elevated prolactin is implicated in the facilitation of graft-versus-host disease. Aripiprazole is the antipsychotic medicine least likely to increase prolactin (and may actually decrease prolactin); risperidone, the most likely to increase prolactin. Olanzapine, quetiapine and ziprazadone are antipsychotic medicines with a lower likelihood of elevating prolactin. Older ("neuroleptic") antipsychotics, such as chlorpromazine, droperidol and haloperidol, perphenazine and many others, are likely to elevate serum prolactin. Among antidepressants, most serotonin reuptake inhibitors, with the exception of sertraline, can slightly elevate prolactin. The atypical (i.e., alone in their class) antidepressants bupropion and mirtazapine are prolactin neutral. The immunological consequences of psychiatric medicines should be considered when treating transplant patients for delirium, depression and thought disorders; in addition, if elevation of prolactin is thought to be of immunological importance during psychiatric treatment, then it should be monitored and treated. The dopamine agonists used to treat Parkinson's disease--bromocriptine, pergolide, pramipexole, ropinerole--usually reverse antipsychotic-induced prolactin increases without compromising psychiatric effectiveness.
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Rechazo de Injerto , Prolactina/efectos de los fármacos , Trasplante/psicología , Antipsicóticos/inmunología , Antipsicóticos/uso terapéutico , Dopamina/inmunología , Dopamina/uso terapéutico , Humanos , Prolactina/sangre , Prolactina/inmunología , Inhibidores Selectivos de la Recaptación de Serotonina/inmunología , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Inmunología del Trasplante , Estados UnidosRESUMEN
Dystonia-associated features of anaphylaxis, including tongue swelling, and chest and throat tightness, have been rarely reported with selective serotonin reuptake inhibitor (SSRI) use. The patient is a 44-year-old woman who presented with palpitations, diaphoresis, dyspnea, swelling of the lips and tongue, and fixed upward deviation of her right eye following inadvertent ingestion of 20 mg of escitalopram in addition to her usual 10-mg dose. She reported transient resolution of all symptoms after autoinjector aqueous epinephrine administration (0.3 mg), with recurrence of symptoms after 35 min. The patient presented with one prior episode of anaphylactic symptoms and dystonia. She also reported one episode with purely anaphylactic features of swelling of lips and tongue, difficulty breathing and syncope. This case represents a unique dose-dependent episode of escitalopram-associated oculogyric dystonia with anaphylactic features. The transient resolution of the associated features of dystonia with intramuscular epinephrine administration is unique and suggests a common pathophysiology of the dystonic and anaphylactic symptoms.