Fluoxetine-treated Group Research Articles

The effects of combined hyperbaric oxygen therapy on patients with post-stroke depression.

[Purpose] To observe the effect of combined hyperbaric oxygen therapy on patients with post-stroke depression. [Subjects] Ninety patients with post-stroke depression were randomly divided into 3 groups: fluoxetine treatment group (n = 30), hyperbaric oxygen therapy group (n = 30), and hyperbaric oxygen combined treatment group (n = 30). [Methods] Fluoxetine treatment group received anti-depression drugs (fluoxetine, 20 mg/day), hyperbaric oxygen therapy group received hyperbaric oxygen (once a day, 5 days/week), hyperbaric oxygen combined treatment group received fluoxetine and hyperbaric oxygen treatments as described above. All patients received routine rehabilitation therapy. Hamilton Depression Scale (HAMD), and Scandinavian Stroke Scale (SSS) scores were evaluated before and at the end of 4th week. The total effective rate of depression release between the 3 groups was also compared at the end of study. [Results] The end scores of HAMD and SSS in the 3 groups were significantly lower than those before treatment. The total effective rate of combined hyperbaric oxygen therapy group after treatment was higher than the other two groups. [Conclusions] Combined hyperbaric oxygen therapy plays an important role in the treatment of patients with post-stroke depression. The total effective rate of combined hyperbaric oxygen therapy was higher than other routine anti post-stroke depression treatments.

Antidepressant-like effects of a novel 5-HT3 receptor antagonist 6z in acute and chronic murine models of depression.

To investigate the antidepressant-like effects of a novel 5-HT3 receptor antagonist N-(benzo[d]thiazol-2-yl)-3-methoxyquinoxalin-2-carboxamide (6z) in acute and chronic murine models of depression. 5-HT3 receptor antagonism was examined in guinea pig ileum in vitro. A tail suspension test (TST) was used as acute depression model to evaluate the antidepressant-like behavior in mice treated with 6z (0.5-2 mg/kg, ip). In chronic depression model, mice were exposed to a 4-week chronic unpredictable stress (CUS) protocol, and treated with 6z (0.5-2 mg·kg(-1)·d(-1), po) or a positive drug fluoxetine (10 mg·kg(-1)·d(-1), po) in the last 2 weeks, followed by behavioral and biochemical assessments. The 5-HT3 receptor antagonism of 6z (pA2=7.4) in guinea pig ileum was more potent than that of a standard 5-HT3 receptor antagonist ondansetron (pA2=6.9). In acute depression model, 6z administration significantly decreased the immobility duration. In chronic depression model, 6z administration reversed CUS-induced depressive-like behavior, as evidenced by increased immobility duration in the forced swim test and sucrose preference in the sucrose preference test. Furthermore, chronic administration of 6z prevented CUS-induced brain oxidative stress, with significant reduction of pro-oxidant markers and elevation of antioxidant enzyme activity. Moreover, chronic administration of 6z attenuated CUS-induced hypothalamic-pituitary-adrenal axis hyperactivity, as shown by reduced plasma corticosterone levels. Similar results were observed in the fluoxetine-treated group. 6z is a novel 5-HT3 receptor antagonist with potential antidepressant-like activities, which may be related to modulating hypothalamic-pituitary-adrenal axis and attenuating brain oxidative damage.

51. Developing a novel animal model of depression to study the role of inflammation in disease progression and in the mechanism of antidepressant action

To study the role of inflammation in depression and in the mechanisms of antidepressant action a valid animal model is required. To develop such a model, we proposed to combine exposure to inflammatory stimulus modelled by peripheral lipopolysaccharide (LPS) injection with an environmental stress-based model of depression – unpredictable chronic mild stress (UCMS) to achieve an immunologically-relevant depression-like phenotype. In a pilot experiment, we treated 8 weeks old male BALB/c mice with 0.33 mg/kg LPS and subsequently exposed them to UCMS for 7 weeks. Fluoxetine-treated groups (10 mg/kg daily) were also included in our experimental design (N = 12). LPS and UCMS exposed mice displayed significant coat state deterioration (UCMS factor H (7) = 37.5, p < 0.0001) and locomotor hyperactivity in a novel arena (UCMS factor F (1,74) = 20.8, p < 0.0001). When coat state was assessed 4 days after the end of UCMS paradigm, the UCMS-only group already displayed signs of recovery with the coat deterioration score indistinguishable from control, while animals exposed to both LPS and UCMS did not show improvement of the coat state. Fluoxetine treatment of the LPS and UCMS exposed group promoted the recovery of the coat state with the coat deterioration score returning to control levels. Future assessment of the neurobiological phenotype (corticosterone response to stress, peripheral cytokines and hippocampal neurogenesis levels) will be presented to allow us to further unravel the neurobiological basis of the observed behavioural changes.

Concentration increase in Hcy and anti-CCP antibody in the serum of depression rat model induced by chronic unpredictable mild stress

To observe the change of serum homocysteine (Hcy) and anti-citrullinated peptide (CCP) antibody concentration in depression rat model induced by chronic unpredictable mild stress (CUMS), and to explore the immunologic mechanism of depression and the relation between depression and its autoimmunity. Sixty adult male SD rats were randomly divided into 2 groups, 30 rats in each group, which were divided into 3 subgroups: a normal control group, a model group and a fluoxetinetreated group. The depression rat model was established under CUMS and seperated feeding, after which, open field, sugar consumption and forced swimming test were applied in the first group. After the blood was taken in the second group of rats through heart puncture, the level of serum Hcy was detected by enzymatic cycling assay and serum anti-CCP antibody by ELISA. Compared with the control group and the fluoxetine treatment group, spontaneous activity and sucrose consumption and preference percentage of the rats in the model group significantly reduced, while the immobility time in forced swimming test and the level of Hcy and anti-CCP antibody in the rat serum significantly increased. Immunity inflammation and autoimmune reaction exist in CUMS depression model rats, and fluoxetine treatment can improve these immune response.

Differential prefrontal gray matter correlates of treatment response to fluoxetine or cognitive-behavioral therapy in obsessive–compulsive disorder

Nearly one-third of patients with obsessive–compulsive disorder (OCD) fail to respond to adequate therapeutic approaches such as serotonin reuptake inhibitors and/or cognitive-behavioral therapy (CBT). This study investigated structural magnetic resonance imaging (MRI) correlates as potential pre-treatment brain markers to predict treatment response in treatment-naïve OCD patients randomized between trials of fluoxetine or CBT. Treatment-naïve OCD patients underwent structural MRI scans before randomization to a 12-week clinical trial of either fluoxetine or group-based CBT. Voxel-based morphometry was used to identify correlations between pretreatment regional gray matter volume and changes in symptom severity on the Yale–Brown Obsessive–Compulsive Scale (Y–BOCS). Brain regional correlations of treatment response differed between treatment groups. Notably, symptom improvement in the fluoxetine treatment group (n=14) was significantly correlated with smaller pretreatment gray matter volume within the right middle lateral orbitofrontal cortex (OFC), whereas symptom improvement in the CBT treatment group (n=15) was significantly correlated with larger pretreatment gray matter volume within the right medial prefrontal cortex (mPFC). No significant a priori regional correlations of treatment response were identified as common between the two treatment groups when considering the entire sample (n=29). These findings suggest that pretreatment gray matter volumes of distinct brain regions within the lateral OFC and mPFC were differentially correlated to treatment response to fluoxetine versus CBT in OCD patients. This study further implicates the mPFC in the fear/anxiety extinction process and stresses the importance of lateral portions of the OFC in mediating fluoxetine's effectiveness in OCD. Clinical registration information: http://clinicaltrials.gov-NCT00680602.

Decreased Aggressive and Locomotor Behaviors in Betta Splendens after Exposure to Fluoxetine

The failure of sewage treatment plants to remove pharmaceuticals such as fluoxetine from waste water has become a concern given that these products are being detected in the surface waters of many countries of the world. The effects of fluoxetine in sub-lethal doses on the neural systems and behaviors of aquatic life are worthy of investigation. This study investigated the effects of sub-lethal amounts fluoxetine dissolved in water on the aggressive and locomotor behaviors of 44 male Betta splendens. Fish treated with 705 microg/l of fluoxetine and 350 microg/l of fluoxetine generally demonstrated significant decreases in locomotion and number of aggressive attacks compared to 0 microg/l of fluoxetine (controls) on Days 11 and 19 of drug exposure and persisted for at least 13 days after removal of fluoxetine. Consistent with decreases in the number of aggressive attacks, there was a significant increase in aggression-response time to a perceived intruder for treated males on Days 11 and 19 and persisted for 6 days following removal of fluoxetine. However, the differences in aggressive and locomotor behaviors seen in the fluoxetine-treated groups were indistinguishable from controls three weeks following drug removal.

Effects of Yulangsan polysaccharide on monoamine neurotransmitters, adenylate cyclase activity and brain-derived neurotrophic factor expression in a mouse model of depression induced by unpredictable chronic mild stress.

The present study established a mouse model of depression induced by unpredictable chronic mild stress. The model mice were treated with Yulangsan polysaccharide (YLSPS; 150, 300 and 600 mg/kg) for 21 days, and compared with fluoxetine-treated and normal control groups. Enzyme-linked immunosorbent assay, radioimmunity and immunohistochemical staining showed that following treatment with YLSPS (300 and 600 mg/kg), monoamine neurotransmitter levels, prefrontal cortex adenylate cyclase activity and hippocampal brain-derived neurotrophic factor expression were significantly elevated, and depression-like behaviors were improved. Open-field and novelty-suppressed feeding tests showed that mouse activity levels were increased and feeding latency was shortened following treatment. Our results indicate that YLSPS inhibits depression by upregulating monoamine neurotransmitters, prefrontal cortex adenylate cyclase activity and hippocampal brain-derived neurotrophic factor expression.

Chronic administration of fluoxetine impairs neurogenic and endothelium-dependent relaxation of the rabbit corpus cavernosum smooth muscle

Antidepressants, including selective serotonin reuptake inhibitors (SSRIs), cause erectile dysfunction; however, the mechanism by which they cause erectile function is unclear. We investigated the reactivity of the corpus cavernosum after chronic fluoxetine treatment in rabbits. Twelve rabbits were randomly divided into two groups: control (n=6) or 20mg/kg/day of fluoxetine delivered i.p. (n=6). The reactivity of the corpus cavernosum tissue from the fluoxetine-treated and control groups was studied in organ chambers after 21 days of fluoxetine injection. In the fluoxetine-treated group, endothelium-dependent relaxation of the corpus cavernosum in response to acetylcholine was significantly decreased compared to the control group. However, the sensitivity (i.e., pD(2)) of the fluoxetine-treated cavernosal tissue strips to acetylcholine was not changed with respect to controls. Electrical field stimulation (EFS)-induced neurogenic relaxation was also significantly reduced in the fluoxetine-treated group. Relaxation in response to the nitric oxide (NO) donor sodium nitroprusside was similar between the cavernosal tissues from the two groups. There was also no change in agonist potency between the two groups. Additionally, chronic fluoxetine treatment had no effect on KCl-induced contractile responses. When tissue contraction was produced with phenylephrine to study relaxation in response to various stimuli, the tension induced was similar between the fluoxetine-treated and control groups. This study suggests that chronic fluoxetine treatment causes significant functional changes to the penile erectile tissue of rabbits, and these changes may contribute to the development of impotence.

Gender-dependent effects of fluoxetine on selected biochemical parameters in guinea pigs

Gender-related changes in plasma chemistry values were examined in guinea pigs after taking oral fluoxetine hydrochloride (HCl) as a widely prescribed drug for weight reduction and treatment of depressive disorders. Twenty guinea pigs of both sexes were divided into four groups of five animals. For both of the sexes, one group was treated with oral fluoxetine HCl (20 mg/kg/day) and another was used as a control which administered with distilled water. On the last day of the experiment (35th day), blood samples were collected for determining selected plasma biochemical parameters. For lipid profile, increases in high-density lipoprotein cholesterol, very low-density lipoprotein-cholesterol, and triglycerides were seen in both sexes, along with increases in total cholesterol and low-density lipoprotein cholesterol (LDL-C) in males and decreases of LDL-C in females and atherogenic index in both sexes. The levels of total protein, globulins, urea, and creatinine were increased only in the male guinea pigs that received fluoxetine. Although, the levels of creatine phosphokinase and alanine transaminase decreased in the fluoxetine-treated female guinea pigs compared to control. Other parameters like lactate dehydrogenase, alkaline phosphatase, aspartate transaminase, albumin, total bilirubin, (in)direct bilirubin, fasting blood sugar, calcium, and phosphorus did not alter following intake of fluoxetine in both sexes. For hormonal profile, testosterone and tetraiodothyronine (T4) in males and T3 and thyroid-stimulating hormone in both sexes did not change in fluoxetine-treated guinea pigs. However, the level of T4 decreased in fluoxetine-treated female group compared with the control group. Fluoxetine treatment resulted in gender-dependent effects. The decrease of T4 in female guinea pigs that received fluoxetine supports that this drug would be a possible endocrine disruptor.

Downregulation of osteopontin is associated with fluoxetine amelioration of monocrotaline-induced pulmonary inflammation and vascular remodelling

1. Osteopontin (OPN) has emerged as a key factor in inflammatory activation and cardiovascular remodelling. The aim of the present study was to investigate the involvement of OPN in fluoxetine amelioration of monocrotaline (MCT)-induced pulmonary inflammation and vascular remodelling in rats. 2. Wistar rats were divided into control, MCT and two fluoxetine-treated groups. Pulmonary arterial hypertension (PAH) was induced by a single injection of MCT (60 mg/kg, i.p.). Fluoxetine (2 and 10 mg/kg) was administered via the intragastric route once a day for 21 days. On Day 22, pulmonary haemodynamic measurements were undertaken, followed by ELISA, western blotting and immunohistochemistry. 3. Monocrotaline caused pulmonary inflammation and vascular remodelling and significantly enhanced OPN expression in the plasma, lungs and pulmonary arteries. Fluoxetine decreased pulmonary arterial pressure and ameliorated pulmonary inflammation and pulmonary vascular remodelling. At 10 mg/kg, fluoxetine significantly inhibited MCT-induced increases in the expression of serotonin transporter (SERT) and phosphorylated extracellular signal-regulated kinase 1/2 and downregulated the expression of OPN, macrophage inflammatory protein-1β and matrix metalloproteinase 2/tissue inhibitor of metalloproteinase 2. Although 2 mg/kg fluoxetine tended to ameliorate some MCT-induced changes in the lung, the differences did not always reach statistical significance. Linear regression analysis showed that there was a positive correlation between plasma OPN concentrations and mean pulmonary arterial pressure, as well as percentage medial wall thickness and percentage wall area in the pulmonary artery. 4. In conclusion, the amelioration by fluoxetine of MCT-induced pulmonary inflammation and vascular remodelling is associated with downregulation of OPN expression in rats.

Fluoxetine Alleviates Behavioral Depression while Decreasing Acetylcholine Release in the Nucleus Accumbens Shell

Selective serotonin reuptake inhibitors, such as fluoxetine, have demonstrated the ability to alleviate behavioral depression in the forced swim test; however, the sites and mechanisms of their actions remain to be further elucidated. Previous studies have suggested that behavioral depression in the swim test is mediated in part by acetylcholine (ACh) stimulating the cholinergic M1 receptors in the nucleus accumbens (NAc) shell. The current study tested whether acute, local, and chronic, subcutaneous fluoxetine treatments increase escape motivation during the swim test while simultaneously lowering extracellular ACh in the NAc shell. Experiment 1: Fluoxetine (1.0 mM) infused unilaterally in the NAc shell for 40 min reduced extracellular ACh while simultaneously increasing swimming time. Experiment 2: Fluoxetine (0.2, 0.5, and 0.75 mM) infused bilaterally in the NAc shell on day 3 dose-dependently decreased immobility and increased the total escape attempts (swimming and climbing) compared with Ringer given on day 2. Experiment 3: Fluoxetine (0.5 mM) infused bilaterally in the NAc for 40 min did not affect activities in an open field. Experiment 4: Chronic systemic fluoxetine treatment decreased immobility scores and increased total escape attempt scores compared with control saline treatment. In all, 14 days after the initial swim test, basal extracellular ACh in the shell was still elevated in the saline-treated group, but not in the fluoxetine-treated group. In summary, these data suggest that one of the potential mechanisms by which fluoxetine alleviates behavioral depression in the forced swim test may be to suppress cholinergic activities in the NAc shell.

Effects of fluoxetine and escitalopram on C-reactive protein in patients of depression

Objective:To study the anti-inflammatory activity of fluoxetine and escitalopram in newly diagnosed patients of depression and also to evaluate the association between depression and inflammation.Materials and Methods:Ninety-eight newly diagnosed patients of depression were recruited as cases. From these, 48 had started treatment with fluoxetine (20 mg/day) and 50 had started treatment with escitalopram (20 mg/day). After 2 months of treatment of these patients, Hamilton rating scale for depression (HRSD scale), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and white blood cell (WBC) count were measured and compared to their respective baseline values before starting treatment. One hundred healthy volunteers were recruited as controls and their baseline of CRP, ESR and WBC count were measured and compared with their respective baseline values of cases. Severity of depression was measured by HRSD scale and anti-inflammatory activity was measured by reduction CRP, ESR and WBC count.Results:On baseline comparison between cases and controls, there were significant increases in the levels of CRP (P = 0.014), ESR (P = 0.023) and WBC count (P = 0.020) in cases. In fluoxetine (20 mg/day) treatment group, there was a significant reduction in the levels of CRP (P = 0.046), ESR (P = 0.043) and WBC count (P = 0.021) after 2 months of treatment but no significant reduction in HRSD scale (P = 0.190). Similarly, in escitalopram treatment group, there was a significant reduction in CRP (P = 0.041), ESR (P = 0.030) and WBC count (P = 0.017) after 2 months of treatment but no significant reduction in HRSD scale (P = 0.169).Conclusion:In newly diagnosed patients of depression, inflammatory markers such as CRP, ESR and WBC count were significantly raised and Selective serotonin reuptake inhibitors SSRIs such as fluoxetine and escitalopram reduced them independent of their antidepressant effect. So, SSRIs have some anti-inflammatory activity independent of their antidepressant action.

Fluoxetine reverses the memory impairment and reduction in proliferation and survival of hippocampal cells caused by methotrexate chemotherapy

RationaleAdjuvant cancer chemotherapy can cause long-lasting, cognitive deficits. It is postulated that these impairments are due to these drugs targeting neural precursors within the adult hippocampus, the loss of which has been associated with memory impairment.ObjectivesThe present study investigates the effects of the chemotherapy, methotrexate (MTX) on spatial working memory and the proliferation and survival of the neural precursors involved in hippocampal neurogenesis, and the possible neuroprotective properties of the antidepressant fluoxetine.MethodsMale Lister hooded rats were administered MTX (75 mg/kg, two i.v. doses a week apart) followed by leucovorin rescue (i.p. 18 h after MTX at 6 mg/kg and at 26, 42 and 50 h at 3 mg/kg) and/or fluoxetine (10 mg/kg/day in drinking water for 40 days). Memory was tested using the novel location recognition (NLR) test. Using markers, cell proliferation (Ki67) and survival (bromodeoxyuridine/BrdU), in the dentate gyrus were quantified.ResultsMTX-treated rats showed a cognitive deficit in the NLR task compared with the vehicle and fluoxetine-treated groups. Cognitive ability was restored in the group receiving both MTX and fluoxetine. MTX reduced both the number of proliferating cells in the SGZ and their survival. This was prevented by the co-administration of fluoxetine, which alone increased cell numbers.ConclusionsThese results demonstrate that MTX induces an impairment in spatial working memory and has a negative long-term effect on hippocampal neurogenesis, which is counteracted by the co-administration of fluoxetine. If translatable to patients, this finding has the potential to prevent the chemotherapy-induced cognitive deficits experienced by many cancer survivors.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-010-2122-2) contains supplementary material, which is available to authorized users.

TPH1 is associated with major depressive disorder but not with SSRI/SNRI response in Taiwanese patients

Tryptophan hydroxylase 1 (TPH1), which encodes the rate-limiting enzyme tryptophan hydroxylase in the biosynthesis of serotonin, is a candidate gene in the development and treatment response of major depressive disorder (MDD); however, its actual role is uncertain. We aimed to compare the allele frequencies of TPH1 in MDD patients and healthy controls in Taiwan, and also to investigate the association between TPH1 A218C and treatment response to either fluoxetine or venlafaxine in a Taiwanese population with MDD. One hundred five healthy controls and 115 outpatients diagnosed with MDD were recruited and genotyped for the TPH1 218A/C (rs1800532) polymorphism. Patients were randomized into either the fluoxetine or venlafaxine treatment group. The 21-item Hamilton rating scale for depression (HAM-D) was administered to evaluate depressive symptoms at baseline and bi-weekly over 6weeks of treatment. The TPH1 218A/C allele frequencies differed significantly between healthy controls and MDD patients in Taiwan, with a higher prevalence of the A allele in the patient group (p = 0.025). The odds ratio of the A allele to the C allele was 0.507 for the subjects with MDD. There was no significant correlation between the percentage change in HAM-D score and either TPH1 218A/C genotype or TPH1 allele frequencies. This study indicated that the TPH1 218A/C genotype and allele frequencies differed between the Taiwanese healthy controls and MDD patients but could not be used to predict treatment outcome in Taiwanese MDD patients. Further research with larger sample sizes is needed to confirm the role of TPH1 218A/C.

Effects of long‐term treatment with fluoxetine and venlafaxine on rat isolated vas deferens

Antidepressant therapy is considered as one of the factors leading to male infertility. In this study, the effects of long-term treatment with fluoxetine or venlafaxine were investigated on electrical field stimulation (EFS, 1-64 Hz), noradrenaline (10(-8) to 10(-4) M), serotonin (10(-8) to 10(-4) M), adenosine 5'-triphosphate [ATP (10(-8) to 10(-4) M)] and 80 mM KCl-induced contractile responses in the epididymal and prostatic portions of rat isolated vas deferens strips. Serotonin-induced contractile responses were significantly increased in the epididymal portion of the vas deferens obtained from the fluoxetine-treatment group, whereas in the prostatic portion there was no change. However, venlafaxine treatment had no effect on serotonin responses in the either portion of the vas deferens. Both fluoxetine and venlafaxine treatment significantly inhibited ATP-evoked contractions of the prostatic and epididymal portions of the rat vas deferens, but had no effect on EFS, noradrenaline- and KCl-evoked contractions of the vas deferentia in both portions. In conclusion, these results suggest that chronic treatment with fluoxetine and venlafaxine affects vas deferens motility. Purinoceptors may, at least in part, responsible for the impaired motility in chronic treatment of venlafaxine and fluoxetine.

Personality traits and recovery from major depressive disorder

Objective: To study the correlation of personality traits measured by the Temperament and Character Inventory (TCI) with the prognosis of major depressive disorder in patients treated with either fluoxetine or short-term psychodynamic psychotherapy in a randomized comparative study. Method: 35 patients with DSM IV-defined major depressive disorder of mild or moderate severity were randomized to receive either short-term psychodynamic psychotherapy or fluoxetine treatment for 16 weeks. Prior to beginning of the therapy, patients were assessed with TCI. The Hamilton Depression Rating Scale (HDRS) was used as the outcome measure completed at the baseline and follow-up at 4 months. Results: In the combined group (n=35), Harm Avoidance was associated with the severity of the depression measured by the HDRS at the baseline (P=0.01) and baseline Self-Directedness with the HDRS at 4 months follow-up (P=0.03). In the fluoxetine treatment group, Reward Dependence (P=0.03), Self-Directedness (P=0.01) and Cooperativeness (P=0.02) at the baseline associated with HDRS at 4 months follow-up. No statistically significant associations between personality traits and depression scores at the follow-up were found in the patients treated with psychotherapy. Conclusion: In this whole cohort of depressive patients, baseline high Self-Directedness predicted higher depression scores after 4 months of treatment. In the fluoxetine treatment group, subjects with high baseline Reward Dependence, Self-Directedness or Cooperativeness were likely more severely depressed at the 4 months follow-up. We suggest that associations between personality traits and remaining depressive symptoms after 4 months treatment with fluoxetine could be caused by the potential differences in the placebo effect.

Serotonin (5-hydroxytryptamine) transporter inhibition causes bone loss in adult mice independently of estrogen deficiency

Selective serotonin reuptake inhibitors (SSRIs) treat depression by antagonizing the serotonin (5-hydroxytryptamine) transporter (5-HTT). These drugs may also have skeletal effects given the presence of functional serotonergic pathways in bone and evidence demonstrating detrimental effects of SSRIs on postmenopausal bone changes. This study aimed to explore the influence of an SSRI (fluoxetine hydrochloride) on the bone changes associated with estrogen deficiency in adult mice. Adult, female, Swiss-Webster mice underwent ovariectomy (OVX) or sham OVX and were treated daily for 4 weeks with either fluoxetine hydrochloride (5 or 20 mg/kg) or a vehicle solution (control). In vivo assessments of hindlimb areal and tibial volumetric bone mineral density were performed at baseline and after 4 weeks of intervention. Femurs and lumbar vertebrae were subsequently removed and assessed ex vivo for bone mineral density and trabecular bone architecture and turnover. In vivo and ex vivo skeletal measures found no interactions between OVX (estrogen deficiency) and 5-HTT inhibition, indicating that the skeletal effects of these interventions were independent. 5-HTT inhibition had detrimental skeletal effects, with the fluoxetine-treated groups having reduced bone mineral density and altered trabecular architecture. These changes resulted from both a decrease in bone formation and increase in bone resorption. These data indicate that a commonly prescribed SSRI has a negative influence on the adult skeleton, independent of estrogen deficiency. This finding supports clinical data demonstrating SSRI use to be associated with accelerated bone loss after menopause and highlights a need for further research into the skeletal effects of SSRIs.

Reduced efficacy of fluoxetine following MDMA (“Ecstasy”)-induced serotonin loss in rats

Long-term serotonin (5-HT) neuronal loss is currently a major cause of concern associated with recreational use of the substituted amphetamine 3,4 methylenedioxymethamphetamine (MDMA; “Ecstasy”). Such loss may be problematic considering that psychiatric disorders such as depression and anxiety and responses to first line treatments for these disorders are associated with 5-HT. In this study the effects of prior exposure to MDMA on behavioural and central neurochemical changes induced by the serotonin (5-HT) re-uptake inhibitor and antidepressant fluoxetine were examined in rats. Animals were administered MDMA (10 mg/kg. i.p.) four times daily for two consecutive days. One week later the animals were subjected to treatment with fluoxetine (10 mg/kg, i.p.). Fluoxetine treatment groups received either acute (saline injections for 20 days followed by 3 fluoxetine treatments over 24 h) or chronic (once daily fluoxetine for 21 days) drug administration. Prior exposure to MDMA resulted in an attenuation of fluoxetine-induced swimming behaviour in the modified forced swimming test (FST); a behavioural test of antidepressant action. In parallel MDMA treatment resulted in significant regional depletions of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) accompanied by a reduction in cortical [ 3H] paroxetine binding to nerve terminal 5-HT transporters. MDMA-induced 5-HT loss was enhanced in animals following chronic fluoxetine administration. Elimination of fluoxetine and its metabolite norfluoxetine from the brain abolished this interaction between MDMA and fluoxetine treatment. Fluoxetine administration reduced both 5-HIAA and the 5-HIAA:5-HT metabolism ratio, which was attenuated in animals pre-treated with MDMA. Overall the results show that MDMA induces long-term 5-HT loss in the rodent brain and consequently diminishes behaviour and reductions in 5-HT metabolism induced by the antidepressant fluoxetine. These results have potential clinical relevance, suggesting that 5-HT re-uptake inhibitors such as fluoxetine may be less effective at treating depression in chronic abusers of MDMA.

Differential Role of Galanin Receptors in the Regulation of Depression-Like Behavior and Monoamine/Stress-Related Genes at the Cell Body Level

The present study on rat examined the role of galanin receptor subtypes in regulation of depression-like behavior as well as potential molecular mechanisms involved in the locus coeruleus (LC) and dorsal raphe (DR). The effect of intracerebroventricular (i.c.v.) infusion of galanin or galanin receptor GalR1- and GalR2-selective ligands was studied in the forced swim test, followed by quantitative in situ hybridization studies. Naive control, non-treated (swim control), saline- and fluoxetine-treated rats were used as controls in the behavioral and in situ hybridization studies. Subchronic treatment with fluoxetine reduced immobility and climbing time. Intracerebroventricular infusion of galanin, the GalR1 agonist M617 or the GalR2 antagonist M871 increased, while the GalR2(R3) agonist AR-M1896 decreased, immobility time compared to the aCSF-treated animals. Galanin also decreased the time of climbing. Galanin mRNA levels were upregulated by the combination of injection+swim stress in the saline- and the fluoxetine-treated groups in the LC, but not in the DR. Also tyrosine hydroxylase levels in the LC were increased following injection+swim stress in the saline- and fluoxetine-treated rats. Tryptophan hydroxylase 2 and serotonin transporter mRNAs were not significantly affected by any treatment. 5-HT(1A) mRNA levels were downregulated following i.c.v. galanin, M617 or AR-M1896 infusion. These results indicate a differential role of galanin receptor subtypes in depression-like behavior in rodents: GalR1 subtype may mediate 'prodepressive' and GalR2 'antidepressant' effects of galanin. Galanin has a role in behavioral adaptation to stressful events involving changes of molecules important for noradrenaline and/or serotonin transmission.

Fluoxetine versus sertraline in the treatment of patients with undifferentiated somatoform disorder: A randomized, open-label, 12-week, parallel-group trial

The present study was conducted to compare the effectiveness and tolerability of fluoxetine and sertraline in the treatment of undifferentiated somatoform disorder (USD), using the Patient Health Questionnaire (PHQ-15), which was specifically designed for assessing the severity of somatic symptoms. A randomized, 12-week, open-label trial of fluoxetine (10–60 mg/d) and sertraline (25–350 mg/d) in patients with USD was conducted. Six visits, at baseline and weeks 1, 2, 4, 8, and 12, were scheduled. Assessments for effectiveness and tolerability were conducted at each visit. The primary effectiveness measure was the mean change in PHQ-15 total score, from baseline to the end of treatment. Secondary effectiveness measures were the mean changes in total scores on the Beck Depression Inventory (BDI) and the 12-item General Health Questionnaire (GHQ-12), from baseline to the end of treatment. A total of 45 subjects were enrolled; of them, 28 were randomly assigned to receive fluoxetine and 17 to receive sertraline. The total score on the PHQ-15 from baseline to the end of treatment significantly decreased in the fluoxetine (− 10.7, p < 0.0001) and sertraline (− 10.3, p < 0.0001) treatment groups, with no between-group difference ( F = 0.0701, p = 0.7924). Overall, both treatments were well tolerated and no serious adverse event was reported. This study suggests that both agents may have a potential role in the treatment of USD. A double-blind, placebo-controlled trial and/or head-to-head comparison study with larger samples are required to draw more definite conclusions.