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UNLABELLED: 22q11.2 deletion syndrome (22q11.2DS) is characterised by high rates of psychotic disorders and immune abnormalities. Blood-brain barrier (BBB) permeability is known to be a risk factor for schizophrenia and immune aberrations. OBJECTIVE: To evaluate the relationship between psychosis and BBB permeability in this population. METHODS: We examined two biomarkers for BBB permeability, s100β and neuron-specific enolase (NSE), in 22q11.2DS individuals with/without psychosis. The first cohort of this Israeli-Belgium study was comprised of 20 22q11.2DS adults (30.58 ± 9.42 years) afflicted with a psychotic disorder, another group of 69 non-psychotic 22q11.2DS adults (23.42 ± 8.36 years), and 58 healthy controls (26.39 ± 7.77 years). A second cohort was comprised of 18 non-psychotic 22q11.2DS Israeli children (5.83 ± 1.55 years) and 14 healthy controls (5.34 ± 1.43 years). NSE and s100β serum levels were detected in all participants. RESULTS: Both factors were elevated in adults with 22q11.2DS compared to healthy controls, specifically in the non-psychotic sub-group. In contrast, there were no significant differences in their levels between the two groups of the paediatric cohort. CONCLUSIONS: Increased BBB permeability seems to be a trait of 22q11.2DS that evolves sometime in early adulthood. Our findings are in line with previous reports on non-syndromic schizophrenia, and suggest potential novel neural pathways to psychosis in 22q11.2DS. ispartof: WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY vol:23 issue:6 pages:475-482 ispartof: location:England status: published

Major depressive disorder (MDD) is associated with alterations in circulatory cytokines, in adults as well as in children and adolescents. Administration of selective serotonin reuptake inhibitors (SSRIs) to MDD pediatric patients modifies cytokine levels. However, most studies only assessed changes over a short time period. In this study, we evaluated long-term effects of the SSRI fluoxetine (FLX) in children and adolescents treated for anxiety and/or MDD, including a high-risk group with pre-treatment suicidality. The study group included ninety-two patients (35 boys and 57 girls) with MDD and/or anxiety disorders, aged 13.90 ± 2.41 years. All patients were treated with FLX and followed for 6 months. The study group included children with pretreatment suicidality (high-risk group;N = 62) and without pretreatment suicidality (N = 30) according to the Columbia Suicide Severity Rating Scale. Plasma concentrations of TNFα, IL-6, and IL-1β were measured by enzyme linked immunosorbent assays before and after six months of treatment. IL-6 and IL-1β significantly increased as a factor of time after 6 months of treatment. The elevation was statistically significant confined to children with pretreatment suicidality. Within the children with pretreatment suicidality, IL-6 levels increased significantly after 6 months only in the children who developed SSRI-associated suicidality. To summarize, an increase in IL-6 levels after 6 months of treatment may be associated with SSRI-emergent suicidality in children with pretreatment suicidality. Further studies are needed to clarify the role and mechanism(s) of IL-6 in the pathogenesis of this life-threatening adverse event.

Recent studies suggest immune function dysregulation in depression and anxiety disorders. Elevated pro-inflammatory cytokines may be a marker for immune system dysregulation. No study assessed the correlation between the levels of cytokines in children and adolescents with depression/anxiety disorders and their parents. In this study, 92 children and adolescents (mean age 13.90 ± 2.41 years) with depression and/or anxiety disorders were treated with fluoxetine. Blood samples were collected before initiation of treatment. One hundred and sixty-four of their parents (mean age 50.6 ± 6.2 years) and 25 parents of healthy children (mean age 38.5 ± 6.2 years) also gave blood samples. Plasma levels of three pro-inflammatory cytokine (TNF-α, IL-6, IL-1β) were measured by enzyme linked immunosorbent assays (ELISA) and compared between depressed/anxious children and their parents. We also compared cytokine levels between parents of children with depression/anxiety and control parents. Mothers of depressed children had higher TNF-α levels than mothers of controls. No significant difference was detected in the fathers. A positive correlation was found between the IL-1β levels of the depressed/anxious boys and their mothers. No such correlation was observed in the fathers. Our conclusions are that higher levels of proinflammatory cytokines may indicate immune system activation in mothers in response to the distress associated with having depressed/anxious offspring. The correlation between IL-1β levels in the mothers and their depressed/anxious children may indicate familial vulnerability to depression and anxiety. Our observation highlights the need for a better understanding of sexual dimorphism in inflammatory responses to stress.

Background Individuals with 22q11.2 deletion syndrome (22q11.2DS) are at risk for having both psychotic and immune disorders, thus, implying a possible link between the two. The aim of the current study was to evaluate the usefulness of the neutrophiles to leukocytes ratio (NLR), an inflammatory marker, as a bio-marker for overt and prodromal psychotic symptoms in 22q11.2DS. Methods Forty-nine individuals with 22q11.2DS (13 with psychotic disorders and 36 without psychotic disorders) and 30 age- and sex-matched healthy controls underwent psychiatric evaluation using a structured psychiatric interview, the Scale of Prodromal Symptoms (SOPS) and the Global Assessment of Functioning (GAF) scale. Blood samples were collected from all participants on the day of assessment. NLR was calculated, compared among the study groups and correlated with SOPS and GAF scores. The non-psychotic 22q11.2DS group was further divided into high- and low-inflammation groups by NLR values and the analyses were done again. Results NLR was higher in the psychotic- and the high-inflammation non-psychotic 22q11.2DS groups compared to the low-inflammation non-psychotic 22q11.2DS group and controls. In the high-inflammation non-psychotic 22q11.2DS group NLR increase was associated with an increase of total negative symptoms scores on SOPS and a decrease in GAF scores. Conclusion Our results suggest the potential utility of NLR as a bio-marker for psychotic disorders and subthreshold prodromal symptoms in 22q11.2DS. Furthermore, they imply that a disequilibrium between the innate and adaptive arms of the immune system facilitates the progression of psychosis in at risk populations. Further longitudinal studies are warranted to validate our findings, as this was a cross sectional observation.

Aquaporin-4 (AQP4), an astrocyte water channel protein, is the target antigen of serum immunoglobulin G (IgG) autoantibody in neuromyelitis optica spectrum disorders (NMOsd), a group of inflammatory, demyelinating diseases of the central nervous system. Recently, a reduction in blood vessels coverage by AQP4-immunoreactive astrocytes was demonstrated in depressed patients, indicating a role for AQP4 in mood disorders. Moreover, a possible association between depression and serum AQP4-IgG was suggested in a case report of a treatment resistant depression (TRD) patient diagnosed with NMOsd with positive serum AQP4 autoantibodies. We investigated, for the first time, the presence of serum AQP4-IgG in patients with unipolar and bipolar depression and healthy controls (HCs). In this multicenter study, 25 major depressive disorder (MDD) and 25 bipolar disorder (BD) patients, during an acute major depressive episode (MDE), and 30 matched HCs were screened for the presence of serum AQP4-IgG, using a cell-based assay. The MDE patients underwent a repeated AQP4-IgG assessment at a 3-month follow-up visit. The MDE group (N = 50) had illness duration of 12.7 years (SD = 10.5), 12% of them were psychotropic medication-free and 26% were defined as TRD. All MDE patients and HCs, including three BD patients who experienced a manic switch, were seronegative for AQP4-IgG at baseline and follow-up assessments. In conclusion, contrary to our hypothesis, AQP4 autoantibodies were not detected in serum of unipolar and bipolar depressed patients. However, AQP4 may still play a role in the pathogenesis of mood disorders through different mechanisms of action such as altered brain AQP4 expression.

OBJECTIVE 22q11.2 deletion syndrome (22q11.2DS) is a neurogenetic disorder whose phenotype includes high rates of a schizophrenia-like psychotic disorder and immune system abnormalities. Thus, 22q11.2DS is an ideal model for studying the relationship between psychosis and inflammation. The aim of the present study was to identify inflammatory markers that may play a role in the pathophysiologic pathways associated with psychosis and cognitive deficits in 22q11.2DS. METHODS Forty-nine individuals with 22q11.2DS (13 with psychotic disorders according to DSM-IV criteria and 36 without psychotic disorders) and 30 age- and sex-matched healthy controls underwent psychiatric and cognitive assessments at an outpatient clinic. Blood samples from all participants were analyzed for C-reactive protein (CRP), interleukin (IL)-6, IL-10, tumor necrosis factor alpha (TNFα), and IL-1 receptor antagonist levels. The study was conducted between August 2014 and September 2015. RESULTS The 22q11.2DS participants had elevated levels of CRP (P = .004), IL-6 (P = .001), TNFα (P < .001), and IL-10 (P = .028) compared with controls. Furthermore, the psychotic 22q11.2DS participants had higher levels of IL-6 (P < .001) and IL-6/IL-10 ratio (used as an indicator for proinflammatory activation, P < .001) compared with the nonpsychotic 22q11.2DS individuals and controls. IL-6 levels and the IL-6/IL-10 ratio correlated with the severity of the cognitive deficits in the 22q11.2DS participants. CONCLUSIONS Our preliminary findings indicate an involvement of inflammatory processes in the pathophysiology of psychosis and cognitive deficits in 22q11.2DS and are in line with the accumulating evidence for the role of neuroinflammation in nonsyndromic schizophrenia.

Background Animal models of dementia associated with metabolic abnormalities play an important role in understanding the bidirectional relationships between these pathologies. Rodent strains develop cognitive dysfunctions without alteration of peripheral metabolism following intracerebroventricular administration of streptozotocin (icv-STZ). Objective We aimed to estimate the effect of icv-STZ on cognitive functions and peripheral metabolism in Lewis rats, which are rarely used for the induction of cognitive abnormalities. Methods Inbred adult Lewis rats were treated with single icv-STZ (3 mg/kg). Cognitive functions were assessed using Morris water maze (MWM) test and locomotion by the Open Field test. Metabolic alterations were studied using histological and biochemical analysis of brain and peripheral tissues. Results The icv-STZ induced rapid weight decline during the first two weeks. Thereafter, the rats showed an accelerated weight gain. Three months after the icv-STZ treatment, the rats were severely obese and revealed fatty liver, pancreatic islet hypertrophy, significantly elevated levels of blood insulin, leptin, and adiponectin, but intact peripheral glucose homeostasis. The icv-STZ rats expressed amyloid-β deposits in blood vessels of leptomeningeal area, microgliosis, astrogliosis, and spongiosis in fimbria-fornix area of hippocampus. Locomotor activities of icv-STZ treated and sham-operated rats were similar. In the MWM test, the icv-STZ treated rats demonstrated severely impaired spatial learning during both acquisition and reversal phases. Conclusions Icv-STZ treated Lewis rats develop severe dementia associated with obesity and peripheral metabolic abnormalities. This animal model may be useful for exploring the pathophysiological relationship between obesity and dementia and provides a new tool for development of effective therapy.

Low levels of vitamin D are prevalent among patients with schizophrenia and have been linked to the risk and outcome of the disorder. Vitamin D has a regulatory effect on the inflammatory system, which is dysfunctional in schizophrenia. We investigated the association between serum vitamin D levels, inflammatory status, and severity of schizophrenia symptoms. A total of 39 clozapine-treated schizophrenia patients were recruited to the study. Blood samples for biochemical analysis were collected from all participants. Serum levels of vitamin D and cytokines (IL-4, IL-6, IL-10, and TNF-α) were analyzed and the association between biochemical and clinical measures was assessed. Most of the sample (82%) had insufficient levels of vitamin D. There was a significant inverse correlation between serum vitamin D and IL-6 levels (Pearson's r = -0.38, P < 0.05). Vitamin D levels correlated with the severity of positive symptoms (r = 0.39, P < 0.05). These results suggest that within clozapine-treated schizophrenia patients, high levels of vitamin D are associated with lower serum levels of the proinflammatory cytokine IL-6. This relationship may indicate an immunomodulatory effect of vitamin D in treatment-resistant patients with schizophrenia maintained on clozapine.

22q11.2 deletion syndrome (22q11.DS) is a neurogenetic disorder caused by a microdeletion in chromosome 22. Its phenotype includes high rates of psychiatric disorders, immune system abnormalities, and cognitive impairments. We assessed the quality of sleep in 22q11.2DS and its potential link to inflammatory markers and cognitive deficits. Thirty-three 22q11.2DS individuals and 24 healthy controls were studied. Sleep parameters were assessed by the Pittsburgh sleep quality index (PSQI) questionnaire and correlated with serum cytokine levels and cognitive functioning, measured using the Penn computerized neurocognitive battery (CNB). The 22q11.2DS individuals had significantly worse sleep quality scores than the controls, unrelated to the psychiatric or physical comorbidities common to 22q11.2DS. Interleukin 6 levels were correlated with the overall score of the PSQI questionnaire for nonpsychotic 22q11.2DS participants only. Several domains of the CNB were associated with poorer sleep quality, suggesting that cognitive impairments in 22q11.2DS may be at least partially explained by poor sleep quality. Our findings confirm sleep impairments in individuals with 22q11.2DS, which might negatively affect their cognitive functioning, and corroborate a potential role of immunological pathways in the 22q11.2DS neuro-phenotype.

Background Alzheimer's disease (AD) is often associated with brain insulin resistance and peripheral metabolic dysfunctions. Recently, we developed a model of sporadic AD associated with obesity-related peripheral metabolic abnormalities in Lewis rats using intracerebroventricular administration of streptozotocin (icv-STZ). Objective We aimed to assess the effect of intracranially grafted pancreatic islets on cognitive and peripheral metabolic dysfunctions in the icv-STZ Lewis rats. Methods AD-like dementia associated with obesity was induced in inbred Lewis rats using a single icv-STZ. Two months after icv-STZ, syngeneic islets (100 islets per recipient) were implanted in the cranial subarachnoid cavity of icv-STZ rats. Morris water maze and marble burying tests were used for studying cognitive and behavioral functions. Central and peripheral metabolic alterations were assessed by histological and biochemical assays. Results The icv-STZ induced increases in food intake, body weight, and blood levels of insulin and leptin without alteration of glucose homeostasis. Grafted islets reduced body weight gain, food consumption, peripheral insulin resistance, and hyperleptinemia. Biochemical and histological analysis of the brain revealed viable grafted islets expressing insulin and glucagon. The grafted islets did not affect expression of brain insulin receptors and peripheral glucose homeostasis. Two months after islet transplantation, cognitive and behavioral functioning in transplanted rats were significantly better than the sham-operated icv-STZ rats. No significant differences in the locomotor activity between transplanted and non-transplanted icv-STZ rats were found. Conclusions Intracranial islet transplantation attenuates cognitive decline and peripheral metabolic dysfunctions providing a novel therapeutic approach for sporadic AD associated with peripheral metabolic dysfunctions.

Olanzapine-induced weight gain is associated with atherosclerosis, hypertension, dyslipidemia, and diabetes. We synthesized a novel antipsychotic drug (PGW5) possessing an olanzapine moiety linked to sarcosine, a glycine transporter 1 inhibitor. In this study, we compared the metabolic effects of PGW5 and olanzapine in a female rat model of weight gain. Female rats were treated daily with oral olanzapine (4 mg/kg), PGW5 (25 mg/kg), or vehicle for 16 days. Behavioral tests were conducted on days 12-14. Biochemical analyses were performed at the end of the treatment. A significant increase in body weight was observed in the olanzapine-treated group, while the PGW5 group did not differ from the controls. The open field test showed hypo-locomotion in the olanzapine-treated animals as compared to PGW5 and control groups. A significant increase in hypothalamic protein expression of the neuropeptide Y5 receptor and a decrease in pro-opiomelanocortin messenger ribonucleic acid (mRNA) levels were detected following PGW5 treatment, but not after olanzapine administration. PGW5 appears to possess minor metabolic effects compared with the parent compound olanzapine. The differential modulation of brain peptides associated with appetite regulation is possibly involved in the attenuation of metabolic effects by PGW5.

BACKGROUND: Low levels of vitamin D are prevalent among patients with schizophrenia and previously had been linked to the risk and outcome of the disorder. While vitamin D has a regulatory effect on the inflammatory system, schizophrenia had also been associated with inflammatory dysregulation. Therefore, we investigated the association between vitamin D level, inflammatory status, and severity of schizophrenia symptoms. METHODS: A sample of 39 chronic clozapine-treated patients with schizophrenia had been recruited to the study. Each patient went through a clinical assessment and gave a blood sample for biochemical analysis. Serum levels of vitamin D and cytokines (IL-4, IL-6, IL-10, and TNF-α) were analyzed for correlation between variables as well as with clinical severity measures. RESULTS: Most of the sample (82%) had non-satisfactory levels of vitamin D. There was a significant negative association between vitamin D levels and IL-6 (Pearson’s r=-0.38, p

BACKGROUND: About a third of schizophrenia patients would not have sufficient clinical response to antipsychotic treatment. The only drug approved for this population is clozapine, yet worldwide reports suggest underuse of clozapine and significant delay in initiating treatment. Moreover, as a robust clinical response is evident in only about half of patients treated with clozapine, the common practice is to augment the compound with another antipsychotic compound. However, little is known about the nature of this augmentation and the outcome in real-world setting. In this study, we aimed to explore in a real-world database, the details of clozapine use in patients with schizophrenia and the use of augmentation with other compounds as well as to explore the outcome of this augmentation in relation to physical health, medical care utilization, and mortality. METHODS: A retrospective cohort study of “Clalit Health Services” electronic records. People diagnosed with schizophrenia (F.20 ICD 10 code) and had at least one prescription filled for clozapine were followed up between 2012 and 2014. RESULTS: of 28,983 people diagnosed with schizophrenia, clozapine was prescribed and purchased by 1817 (6.5%) patients during the study period. Of them, 60% had polypharmacotherapy with another antipsychotic compound or lithium. The most prevalent augmentation was with sulpride (28%), perphenazine (17%) and zuclopenthixole (14.3%). Levels of physical comorbidity (metabolic and cardiovascular) were similar among groups (clozapine monotherapy vs. augmentation). However, polytherapy was associated with HR of 2.1 for mortality during the follow-up period. High mortality rate, during follow-up, was associated with haloperidol augmentation (12%) and sulpride (11.2%). Patients with augmentation were more referred to general emergency department and hospitalization while using similar rate of primary medical services as patients with clozapine monotherapy. DISCUSSION: Clozapine is under-utilized in Israel and data suggests that when treatment is given it is not optimized as reflected by high rates of polytherapy. This real-world practice is associated with increased mortality and higher use of tertiary medical service although patients had similar levels of metabolic and cardiovascular morbidity and similar primary medical service utilization rate. This data suggests that considering augmentation of clozapine with another antipsychotic compound should be done cautiously and after careful consideration of clozapine optimization.

Mesenchymal stem cells (MSCs) are an attractive cell source for regenerative medicine strategies in brain diseases. Experimental studies have shown that repeated administration of phencyclidine (PCP) leads to schizophrenia-like behavioral changes in mice. The aim of the present study was to explore the effectiveness of MSC transplantation into the hippocampus in attenuating PCP-induced social behavior deficits. PCP was administered subcutaneously to C57bl mice (10 mg/kg daily) for 2 weeks. On the first day of PCP administration, adult human MSCs were transplanted into the hippocampus. A week after the last PCP dose, the mice underwent social preference testing. MSC transplantation was associated with a significant reduction in the adverse social behavior induced by PCP. Immunohistochemical analysis revealed that the stem cells survived in the mouse brain, and hippocampal Western blot analysis revealed a statistical trend towards a decrease in cleaved caspase 3 protein levels in the stem cell treated group. Upon in vitro co-culture of astrocytes and MSCs, the MSCs, in the presence of PCP, positively regulated astrocyte expression of genes involved in glutamate metabolism and antioxidant defenses. These findings suggest that MSC transplantation into the hippocampus may serve as a novel neuroprotective tool for the treatment of the PCP-induced schizophrenia-like social endophenotype. The mechanism underlying the beneficial behavioral effect may involve modulation of host astrocyte functioning, including glutamate processing and antioxidant capacity.

Chronic mild stress (CMS) in rats is an established rodent depression model. Antidepressants attenuate the depression-like symptoms and prevent the biochemical changes caused by stress. In the present study, we examined the effect of CMS and the selective norepinephrine reuptake inhibitor (NRI) reboxetine (REB) treatment on behavioral parameters in rats and on hippocampal and cortical neurotrophic factors. Male Sprague Dawley rats were exposed for 5 weeks to a variety of mild stressors. REB (5 mg/kg/i.p.) was daily injected to half of the stressed and unstressed groups. Animal behavior following CMS was tested using the Morris Water Maze (MWM) cognitive paradigm and by monitoring sucrose intake and weight gain. After 5 weeks of CMS, stressed rats showed decreased sucrose intake, and REB treatment normalized this decrease. CMS reduced hippocampal brain-derived neurotrophic factor (BDNF) levels, and REB treatment reversed this alteration and increased BDNF receptor (TrkB) levels. REB elevated hippocampal extracellular signal-regulated kinase (ERK) phosphorylation of both stressed and unstressed rats. In conclusion, our study shows that BDNF, its receptor TrkB, and ERK participate in the neurobiological response to chronic stress and in the molecular and cellular activities of REB in the hippocampus.

BackgroundNot enough is known about predicting therapeutic response to serotonin-specific reuptake inhibitors, and specifically to fluoxetine. This exploratory study used psychological and biological markers for (retrospective) prediction of treatment-response to fluoxetine in depressed and/or anxious adolescents.MethodsForty-one consecutive adolescent outpatients with a primary diagnosis of severe affective and/or anxiety disorders were assessed and treated with an open-label 8-week trial of fluoxetine. Type D personality was assessed with the 14-item questionnaire, the DS14. In addition, TNFα, IL-6, and IL-1b were measured pre- and post-treatment.ResultsThere was an elevation of Type D personality in patients, compared to the adolescent population rate. Post-treatment, 44% of patients were classified as non-responders; the relative risk of non-response for Type D personality patients was 2.8. Binary logistic regression predicting response vs. non-response showed a contribution of initial TNFα levels as well as Type D personality to non-response.ConclusionsIn this exploratory study, the most significant contributor to non-response was Type D personality. However, the measurement of Type D was not prospective, and thus may be confounded with psychiatric morbidity. The measurement of personality in psychiatric settings may contribute to the understanding of treatment response and have clinical utility.

The treatment of rodents with non-competitive antagonist of the N-Methyl- d -aspartate (NMDA) receptor, MK-801 (dizocilpine), induces symptoms of psychosis, deficits in spatial memory and impairment of synaptic plasticity. Recent studies have suggested that insulin administration might attenuate the cognitive dysfunctions through the modulatory effect on the expression of NMDA receptors and on the brain insulin signaling. Intrahepatic pancreatic islet transplantation is known as an efficient tool for correcting impaired insulin signaling. We examined the capacity of syngeneic islets grafted into the cranial subarachnoid cavity to attenuate behavioral dysfunctions in rats exposed to MK-801. Animals were examined in the open field (OF) and the Morris Water Maze (MWM) tests following acute or subchronic administration of MK-801. We found well-vascularized grafted islets expressing insulin, glucagon and somatostatin onto the olfactory bulb and prefrontal cortex. Significantly higher levels of insulin were detected in the hippocampus and prefrontal cortex of transplanted animals compared to the non-transplanted rats. All animals expressed normal peripheral glucose homeostasis for two months after transplantation. OF tests revealed that rats exposed to MK-801 treatment, showed hyper-responsiveness in motility parameters and augmented center field exploration compared to intact controls and these effects were attenuated by the grafted islets. Moreover, in the MWM, the rats treated with MK-801 showed impairment of spatial memory that were partially corrected by the grafted islets. In conclusion, intracranial islet transplantation leads to the expression of islet hormones in the brain and attenuates behavioral and cognitive dysfunctions in rats exposed to MK-801 administration without altering the peripheral glucose homeostasis.

Selective serotonin reuptake inhibitors (SSRIs) stimulate synaptic plasticity and neurogenesis, most likely via the MAP-kinase signal transduction pathway (by phosphorilation of ERK) and by stimulating neurotrophic factors such as brain derived neurotrophic factor (BDNF) and the neuroprotective protein (Bcl-2). Using human neuroblastoma cells (SHSY5Y), we found that sertraline and its derivative, desmethylsertraline, at low concentrations (1-10 μM), induced potent neurotrophic activity. Subsequently, we have treated for 21 days young and aged mice with sertraline. Sertraline in certain doses improved significantly spatial memory learning, in both young and old mice. Sertraline treatment resulted in up-regulation of brain BDNF, phospho-ERK and Bcl-2 that may be involved in the pro-cognitive effect of sertraline.

Objective: Previous studies suggest that selective serotonin reuptake inhibitors (SSRIs) modulate immune system functionality. SSRIs are the preferred treatment for major depressive disorder (MDD). A high rate of MDD is observed in rheumatoid arthritis (RA) patients. The aim of this study was to evaluate immunological effects of SSRIs in a rat model of RA. Methods: Adjuvant arthritis was induced in 8-week-old Lewis rats; in the first set of experiments following the induction, 15.3 or 30.6 mg/kg of sertraline was daily injected into the ankle joint of the left rear leg. Clinical disease activity was evaluated and the findings compared with the 3 untreated legs and with control groups given methotrexate (MTX) or vehicle only at the same site. In a second set of experiments, the effect of 5, 25 and 50 mg/kg daily oral sertraline was evaluated in the same rat model. Splenocyte viability and inflammatory mediators were evaluated. Results: The sertraline-treated rats showed a significant reduction in clinical arthritis compared to controls, at all doses given, accompanied by a significant increase in interleukin 10 and a decrease in tumor necrosis factor-α levels and cycloxygenase-2 production, without lymphotoxicity. There was no significant difference from MTX, the first-line treatment for RA patients. Oral sertraline had a significant anti-inflammatory effect at all doses. There was no treatment × time effect. Conclusion: The beneficial effects of sertraline in this rat model of arthritis have clinical implications for its use in humans. Large-scale clinical efficacy trials are needed.

Background: We have previously demonstrated the immunomodulatory activity of some selective serotonin reuptake inhibitors. Objectives: In this research, we performed an in vivo/ex vivo study to evaluate the potential immunosuppressive effect of sertraline in an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Methods: Mice (C57/bl EAE) were treated with sertraline (5 mg/kg) or dexamethasone (1 mg/kg) 7 days after EAE induction and then 3 times weekly (for 3 weeks). Results: Sertraline modestly improved the clinical score of EAE and attenuated the disease-induced weight loss. Sertraline also significantly decreased ex-vivo splenocyte viability, proliferation and secretion of pro-inflammatory cytokines in EAE mice. Conclusions: We suggest that sertraline might be an add-on option for multiple sclerosis treatment.

To investigate the possible effect of fetal exposure to selective serotonin reuptake inhibitors (SSRIs) on somatic growth and on hormones of the hypothalamic-pituitary-adrenal (HPA) and insulin-like growth factor (IGF)-I axes, we compared the anthropometric parameters and hormonal profile of 21 SSRI-exposed infants and 20 matched controls. The SSRI group was characterized by lower crown-heel length (p < 0.01), smaller head circumference (p = 0.08), and higher percentage of infants with birth weight, birth length, and head circumference below the 10th percentile (p < 0.045, p = 0.08, p < 0.04, respectively), in addition to a significantly lower cord blood level of cortisol (p < 0.03) and higher level of thyroid-stimulating hormone (TSH) (p < 0.004). Infants exposed to citalopram had a lower cord blood IGF-I level than infants exposed to paroxetine (p < 0.001) and controls (p < 0.003). Placental IGF-I receptor (IGF-IR) expression was significantly higher in the SSRI group than in controls (p < 0.01). Urine 5-hydroxyindoleacetic acid (5-HIAA) level was negatively correlated with birth weight (r = -0.71, p < 0.025) and with dehydroepiandrosterone (DHEA) level (r = -0.71, p < 0.025). The Finnegan score was correlated with dehydroepiandrosterone sulfate (DHEAS) (r = 0.8, p < 0.005) and cortisol (r = 0.62, p = 0.05). Fetal exposure to SSRIs causes impaired intrauterine growth accompanied by alterations in the IGF-I and HPA axes. The findings may raise concern regarding maternal use of SSRIs during pregnancy.

Antidepressants have been found to possess antiproliferative effect. In the immune system depression may activate pro-inflammatory cytokines. Therefore, the aim of this study was to assess the immunomodulatory activity of antidepressants in naive rat. Rat splenocytes were activated with con A and treated with paroxetine, sertraline or clomipramine ex vivo. We found that the antidepressants inhibit cell viability and proliferation at IC50 of 5–8 μM of mitogen-stimulated rat splenocytes. This inhibitory effect was accompanied by cell cycle arrest and increase in apoptotic events as assayed by FACS. Moreover, antidepressants decrease the secretion of the TH1 factor — TNFα. In addition, the antidepressants reduced the expression of the enzyme cyclooxygenase2 which is involved in inflammation. On the cellular level we show the up-regulation of MAPK death signaling pathway and suppression of the anti-apoptotic factor — Bcl-2. These findings reveal the immunomodulatory effect of the selected antidepressants. These data suggest a novel use of antidepressants or their derivatives.

Evidence has been provided of the anti-proliferative activity of certain antidepressants, mainly the selective serotonin reuptake inhibitors (SSRIs). We tested the effect of different antidepressants on cell viability and proliferation of human colorectal carcinoma cell lines HT29 and the multi-drug resistant (MDR) LS1034. The SSRIs, paroxetine and sertraline, induced a dose-dependent inhibition of cell viability and proliferation in the two cell lines (IC50 8-15 micro M). When compared to cytotoxic agents e.g. doxorubicin, vincristine and 5-fluorouracil, the SSRIs showed comparable activity (HT29) or a superior effect (LS1034). Using flow cytometry analysis, we found that the two SSRIs arrested cells at the G0/G1 stage and stimulated DNA fragmentation in a dose-dependent manner. The SSRIs (10 and 20 microM) increased caspase-3 activation. Western blot analysis showed an increase after 24 h in c-Jun and a decrease in the expression of the anti-apoptotic protein Bcl-2. The results suggest a proapoptotic activity for the active SSRIs accompanied by mitogen-activated protein kinase cascade activation and Bcl-2 inhibition. In vivo, we used CD1 nude mice xenografted subcutaneously with HT29 cells. On day 8, after cell inoculation sertraline or paroxetine (15 mg/kg x3/week i.p.) were administered to animals (6/group), which were monitored weekly (for 5 weeks) for tumor volume and body weight. At 5 weeks, the animals survived, with no significant difference in body weight. Sertraline, though not paroxetine, significantly inhibited tumor growth. Collectively, our results suggest that the widely-used antidepressant, sertraline, possesses a potential anti-tumor activity, which circumvents the MDR mechanism. Since SSRI therapy is frequently indicated in cancer patients, the use of sertraline in colon cancer patients with co-morbidity of depression seems attractive.