Weeks Of Fluoxetine Research Articles

The effects of fluoxetine in improving the neurocognitive functioning of children with attention deficit hyperactivity disorder attending the psychiatric clinic of the University Teaching Hospital, Lusaka, Zambia

Introduction: Stimulants are medicines approved to treat attention deficit hyperactivity disorder (ADHD) in children and adolescents and are considered the first-line pharmacological agents in ADHD management. These medicines are highly controlled and are usually unavailable in Zambia. Therefore, it is important to seek some supplementary therapy that may substitute stimulants. Fluoxetine has been used for its purpose in Zambia. Objective: The main aim of this study was to find out the effects of fluoxetine in improving the neurocognitive functioning of children with ADHD attending our local psychiatric clinic. Two specific objectives guided the study: to identify the effects of fluoxetine in improving attention and executive functioning in children with ADHD and to find out the effects of fluoxetine in improving memory in children with ADHD. Methodology: The study used a causal-comparative study design and a purposive sampling method. 10 patients (aged 7-11) meeting DSM-5 criteria for ADHD were required in this study. The participants were assessed before they started their treatment with fluoxetine and 4 weeks after the therapy started. The research participants' memory, attention, and executive functioning were specifically considered in this study. Results: The analysis of the results for test 2 using ANOVA were as follows; α = 0.05, the critical value for an F with d. f. (4, 40) being 2.61, the F ratio is 9.96 and total mean square is 272.18, and the total sum of squares is 13337. Since α = .05 and d. f. = 4, 40, (we reject H0 since F4,40 ≤2.61). The computed value of the F statistic is 9.96. The null hypothesis was rejected in the second assessment, and the alternative hypothesis was accepted. Conclusion: There was a significant difference in the neurocognitive functioning performance of children with ADHD before and after taking fluoxetine. The results of this study indicated that the executive functioning, attention, and memory of ADHD children showed improvement after commencing 4-week fluoxetine therapy.

Impact of ACE2 genetic variant on antidepressant efficacy of SSRIs.

Identification of a new axis of angiotensin-converting enzyme 2 (ACE2)/angiotensin (1-7)/Mas receptor, in the renin-angiotensin system (RAS), has opened a new insight regarding the role of RAS and angiotensin in higher brain functions. ACE2 catabolizes angiotensin II and produces angiotensin (1-7), an agonist of Mas receptor. Mice lacking the Mas receptor (angiotensin 1-7 receptor) exhibit anxiety-like behaviours. The present study was conducted to test the hypothesis of the involvement of ACE2 genetic variant (G8790A) on response to selective serotonin reuptake inhibitors (SSRIs). In a randomised control trial, 200 newly diagnosed Iranian patients with major depressive disorder completed 6 weeks of fluoxetine or sertraline treatment. Patients with a reduction of 50% or more in the Hamilton Rating Scale for Depression score were considered responsive to treatment. G8790A polymorphism was determined in extracted DNAs using restriction fragment length polymerase chain reaction method. Our results show that the A allele and AA and GA genotypes were significantly associated with better response to SSRIs (p = 0.008; OR = 3.4; 95% CI = 1.4-8.5 and p = 0.027; OR = 3.3, 95% CI = 1.2-9.2, respectively). Moreover, patients with GA and AA genotypes responded significantly better to sertraline (p = 0.0002; OR = 9.1; 95% CI = 2.4-33.7). The A allele was significantly associated with better response to sertraline (p = 0.0001; OR = 7.6; 95% CI = 2.5-23.3). In conclusion, our results confirm the role of G8790A in response to some SSRIs.

The impact of chronic fluoxetine on conditioned fear expression and hippocampal FGF2 in rats: Short- and long-term effects.

Phenotypic differences in conditioned fear expression may be a marker of vulnerability to the development of anxiety disorders. Hippocampal FGF2 correlates negatively with conditioned fear expression, and antidepressants, the first-line pharmacological treatment for anxiety, increase hippocampal FGF2. In the present study, we assessed whether treatment with the selective serotonin reuptake inhibitor fluoxetine reduces conditioned fear expression in rats that naturally express lower (Low fear) or higher (High fear) levels of fear following a single-trial conditioning session. Experiment 1 demonstrated that phenotypic differences in fear expression were highly stable over a two-week interval. Experiment 2 demonstrated that two weeks of fluoxetine treatment (administered via drinking water) reduced conditioned fear expression in both Low and High fear rats. Experiment 3 demonstrated that two weeks of fluoxetine reduced conditioned fear expression even when treatment commenced two weeks after fear conditioning, but not when conditioned fear was assessed following a two-week drug-free washout period. Additionally, fluoxetine increased hippocampal FGF2 levels relative to vehicle-treated rats, but only when measured immediately after fluoxetine treatment, and not two weeks after treatment termination. Together, these results provide further indirect evidence that endogenous hippocampal FGF2 may mediate individual differences in conditioned fear expression. They also suggest that fluoxetine may be effective in reducing conditioned fear expression in both vulnerable and resilient populations when administered immediately, or sometime after, aversive experiences, but these effects do not persist once treatment is terminated.

Relationships between circadian measures, depression, and response to antidepressant treatment: A preliminary investigation

Few studies have examined relationships between circadian rhythms and unipolar major depressive disorder. Further, no study to date has examined circadian markers as predictors of response to depression treatment. In the present study, we examined associations between circadian timing and its alignment with sleep and depression severity in 30 adults with major depressive disorder who completed a randomized controlled trial of two weeks of time in bed (TIB) restriction administered adjunctive to fluoxetine, with a focus on sex differences. Thirty adults with major depressive disorder received 8 weeks of fluoxetine 20–40 mgs and were randomized to 8h TIB or 6h TIB for the first 2 weeks. Participants in the 6h TIB condition were further randomized to a delayed bedtime or advanced risetime group. Circadian measures included dim light melatonin onset (DLMO) and the difference between DLMO and midsleep point (i.e., phase angle difference). Depression was assessed using the Hamilton Rating Scale for Depression. For females, a phase delay after 2 weeks of fluoxetine and the experimental TIB manipulation was associated with a poorer response to fluoxetine, and depression severity was negatively correlated with phase angle difference, whereas males showed a positive correlation between depression severity and phase angle difference.

Insomnia as a Moderator of Response to Time in Bed Restriction for Augmenting Antidepressant Treatment: A Preliminary Investigation

ABSTRACTBackground: There are complex, bidirectional associations between major depressive disorder and insomnia. In the present study, we evaluated insomnia as a moderator of response to antidepressant therapy in the context of a sleep manipulation (time in bed restriction) for major depressive disorder. Methods: Fifty-eight adults with major depressive disorder received 8 weeks of fluoxetine 20–40 mgs and were randomized to 8 hr time in bed (8h TIB) or 6 hr time in bed (6h TIB) for the first 2 weeks (participants in the 6h TIB condition were further randomized to a delayed bedtime (Late Bedtime) or advanced rise time (Early Rise Time) group). Insomnia was assessed at baseline using the Insomnia Severity Index. Depression symptom severity was determined by the clinician-rated 17-item Hamilton Rating Scale for Depression (HAMD-17), completed weekly. Results: A group by time interaction was observed whereby HAMD-17 scores were higher for participants assigned to the 6h TIB group (without insomnia, weeks 3 through 7; with insomnia from week 3 through 6, ps < .05) relative to participants without insomnia assigned to the 8h TIB group. There were no differences in HAMD-17 scores for participants with insomnia in the 6h TIB group relative to the 8h TIB group. Conclusion: These preliminary findings suggest that response to fluoxetine may be hindered by TIB restriction in individuals without insomnia. Individuals with insomnia respond similarly to fluoxetine regardless of whether their TIB is restricted. Limitations include exclusive use of self-report measures to categorize insomnia, and small sample sizes in several of the subgroups.

Using genomics to predict antidepressant response in suicidal depressed children

BackgroundDepression and anxiety disorders are among the most common childhood psychiatric disorders. Selective serotonin reuptake inhibitors (SSRIs) are generally considered first-line treatment for both depression and anxiety in this age group. However, it has been reported that 30%–40% of all patients who receive a sufficient dose and duration of treatment fail to respond. Moreover, SSRI use is frequently associated with serious adverse events (SAE), including activation symptoms, manic switch and increased suicidal behavior. These are particularly relevant in pediatric populations because of concerns about the suicide threat of SSRIs, resulting in a black-box warning. Currently there is no way of knowing in advance who of the patients will respond. Identification of biomarkers that would be early predictors of response and of the occurrence of SAE could help to maximize the benefit–risk ratio for the use of SSRIs, and speed up the matching of treatment to patient. The main objective of this project is therefore to identify and validate biomarkers predicting response and SAE in depressed children and adolescents, thus improving treatment, enabling the development of novel diagnostic tests and suggest novel therapeutic targets for future related drug development.MethodsAs a preliminary pilot, we already obtained blood samples from 80 depressed and anxious children and adolescents over the last year before, during and after eight weeks of fluoxetine (FLU) therapy. Genetic and epigenetic samples were collected from all participants. The patients were treated with FLU 20–40 mg/day for 8 weeks. Clinical response was measured with several scales including the Children's Depression Rating Scale–Revised (CDRS-R), the Beck Depression Inventory (BDI) and the Screen for Child Anxiety Related Emotional Disorders (SCARED).ResultsThe participant's age ranged from 6 to 18 (14.12 ± 2.30) years. The overall response rate was 56%. Ten percent responded with SAE. Regarding Pharmacogenetics, The 5-HTTLPR ss genotype was associated with a poorer clinical response with regard to depressive symptoms as well with fewer reports of agitation compared to the ll genotype. Regarding immune measures, we analyzed cytokine levels from 41 children. Plasma concentrations of TNF-α, IL-6 and IL-1β were measured by enzyme linked immunosorbent assays (ELISA) before and after FLU treatment. Antidepressant treatment significantly reduced TNF-α levels (P = 0.037), with no significant changes in the levels of IL-6 and IL-1β. All three pro-inflammatory cytokines were significantly (P &lt; 0.05) higher in SSRI-refractory than SSRI-responsive patients, i.e.: higher levels of TNF-α, IL-6 and IL-1β might predict non-response to fluoxetine treatment in children.Future plansOut of the study sample we selected 13 remitters and 13 non-responders and 10 children with SAE (activation symptoms, manic/hypomanic switch, increased suicidality), and analyzed expression profiles in peripheral blood at admission and after 8 weeks of treatment using illumine Truseq technique. Hopefully, we shall find significant differences in miRNA profiles between the different groups which may serve as biomarkers indicating AD treatment response and SAE. The differentially regulated miRNA's can be studied in depth in the future in animal models in order to support the hypothesis that they may be involved in the AD mechanism.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Glutamate transporter 1-mediated antidepressant-like effect in a rat model of chronic unpredictable stress.

In recent years, more attention has been paid to the role of the glutamate transporter 1 (GLT-1, EAAT2) in major depressive disorder (MDD). However, experimental data on brain GLT-1 levels are, to some extent, inconsistent in human postmortem and animal studies. These discrepancies imply that the role of GLT-1 in the pathophysiology of MDD and the action of antidepressants remain obscure. This work was designed to study the impact of chronic unpredictable stress (CUS) for 2 sessions per day for 35 days and four weeks of fluoxetine (FLX) on depressive-like behaviors in rats, as well as the concomitant expression of the GLT-1 protein in the hippocampus. Behavioral changes were assessed by the sucrose preference and open field tests. GLT-1 levels were detected by immunohistchemistry and Western blot analysis. Our study demonstrated that the animals exposed to CUS showed depressive-like behaviors and exhibited a significant decrease in GLT-1 expression in the hippocampus. Chronic FLX treatment reversed the behavioral deficits and the CUS-induced decrease in GLT-1 levels. Taken together, our results support the reduction of GLT-1 in human postmortem studies in MDD and suggest that GLT-1 may be involved in the antidepressant activity of FLX. Our studies further support the notion that GLT-1 is an attractive candidate molecule associated with the fundamental processes of MDD and may be a potential, and novel pharmacological target for the treatment of MDD.

Obsessive–compulsive-like behaviors in house mice are attenuated by a probiotic (Lactobacillus rhamnosus GG)

Two experiments examined probiotic pretreatment (Lactobacillus rhamnosus GG) on obsessive-compulsive disorder (OCD)-like behavior induction by RU 24969 in BALB/cJ house mice. In the first experiment, two groups were defined by their daily pretreatment by oral gavage of either (a) L. rhamnosus (1×10⁹ CFU/day) or (b) the saline vehicle. Both a 2- and 4-week probiotic pretreatment attenuated OCD-like behavior induction (increased perseverative open-field locomotion, stereotypic turning, and marble burying) relative to saline pretreatment. Experiment 2 re-examined the 2-week probiotic pretreatment while also comparing it to a 4-week fluoxetine pretreatment. Again, groups were defined by daily pretreatment of either (a) L. rhamnosus for 2 weeks, (b) the saline vehicle for 2 weeks, or (c) fluoxetine (10 mg/kg) for 4 weeks. Pretreatment by either L. rhamnosus or fluoxetine blocked the induction of OCD-like behavior compared with saline pretreatment. Thus the 2-week probiotic pretreatment was again effective. Although side effects of fluoxetine or L. rhamnosus on androgen-dependent behaviors could not be demonstrated, L. rhamnosus treatment appeared comparable to fluoxetine treatment in attenuating mouse OCD-like behaviors.

Neural response to emotional stimuli associated with successful antidepressant treatment and behavioural activation

BackgroundMajor Depressive Disorder (MDD) is a leading cause of disability globally. Currently available treatments have limited efficacy and combination strategies are frequently used. Several lines of research have demonstrated that MDD patients experience impairments in various components of affective processing, including regulation of affective states. AimTo identify baseline and 1-week neuroimaging predictors of response to a 6-week trial of fluoxetine/ olanzapine combination treatment during an affective processing task. MethodsTweny-one MDD patients and 18 healthy controls were enrolled in the study. MDD patients were treated with 6 weeks of fluoxetine (40–60mg/day) and olanzapine (5–12.5mg/day). All participants viewed images from the International Affective Picture Rating System during a functional magnetic resonance (fMRI) scan at baseline and 1 week. ResultsThere was a 57% response rate (defined as a 50% decrease in Hamilton Rating Scale for Depression-17 item) at 6 weeks. At baseline, responders had increased premotor activity while viewing negative images compared to non-responders and healthy controls. Higher baseline premotor activity was also predictive of greater percent change on the HAMD-17 and improvement in negative disposition and behavioural drive. Non-responders exhibited increased insular activity at baseline compared to responders. Higher activity in the posterior cingulate cortex was also predictive of greater percent change on the HAMD-17. Change from baseline to 1 week did not produce any significant predictive findings. ConclusionsTreatment with fluoxetine/ olanzapine demonstrated similar biomarkers of response to monotherapeutic strategies. In particular, posterior cingulate cortex, anterior insula, and premotor cortex may show predictive differences in their response affective images prior to treatment. Further research needs to be conducted to determine the utility of early changes in emotion circuitry in predicting antidepressant response.

The change of insulin levels after six weeks antidepressant use in drug-naïve major depressive patients

BackgroundA reciprocal relationship between diabetes risk and depression has been reported. There are few studies investigating glucose–insulin homeostasis before and after short-term antidepressant treatment in drug-naïve major depressive disorder (MDD) patients. MethodsThis study included 104 healthy controls and 50 drug-naïve MDD patients diagnosed according to the DSM-IV criteria. These MDD patients were randomly assigned to receive fluoxetine or venlafaxine for six weeks. Depressive symptoms, body mass index, fasting plasma levels of glucose and insulin were measured. ResultsCompared to the healthy controls, the fasting plasma insulin and the homeostasis model of assessment for pancreatic β-cell secretory function (HOMA-β) was significantly lower in the MDD patients before antidepressant treatment (7.7±4.8μIU/mL vs. 5.1±4.2μIU/mL, p=0.006; 114.2±72.3% vs. 74.8±52.0%, p=0.005, respectively). However, these indices were not correlated with depression severity. After 6 weeks of fluoxetine or venlafaxine treatment, the level of HOMA-β borderline significantly increased (108.1±75.5%, p=0.059). LimitationsThe study was limited by the follow-up duration and lack of a placebo group. ConclusionsAntidepressants might affect insulin secretion independently of the therapeutic effects on MDD. Further studies are needed to investigate the long-term effects of antidepressants on insulin regulation in MDD patients.

Neurogenesis-Independent Antidepressant-Like Effects on Behavior and Stress Axis Response of a Dual Orexin Receptor Antagonist in a Rodent Model of Depression

Growing evidence indicates that an increase of orexin (or hypocretin) signaling is involved in the pathophysiology of major depression, but little is known regarding the causal link between the orexinergic system and depressive-like states. Here we blocked orexin receptors in mice subjected to unpredictable chronic mild stress (UCMS) to investigate putative antidepressant-like effects of this treatment, as well as the underlying mechanisms. BALB/c mice were exposed to 9 weeks of UCMS and from the third week onward treated daily with fluoxetine (20 mg/kg per day, per os) or with the dual orexin receptor antagonist almorexant (100 mg/kg per day, per os). The effects of UCMS regimen and pharmacological treatments were assessed by physical measures and behavioral testing. The dexamethasone suppression test was performed to examine the integrity of the negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, and immunohistochemical markers were used to assess cell proliferation (Ki-67), immature newborn neurons (doublecortin), and mature newborn neurons (5-bromo-2'-deoxyuridine/NeuN) in the dorsal and ventral parts of the hippocampus. Our results show that 7 weeks of fluoxetine or almorexant treatments counteract the UCMS-induced physical and behavioral alterations. Both treatments prevented the HPA axis dysregulation caused by UCMS, but only fluoxetine reversed the UCMS-induced decrease of hippocampal cell proliferation and neurogenesis, while chronic almorexant treatment decreased cell proliferation and neurogenesis specifically in the ventral hippocampus. Taken together, this is the first evidence that pharmacological blockade of the orexinergic system induces a robust antidepressant-like effect and the restoration of stress-related HPA axis defect independently from a neurogenic action.

LPS inhibits the effects of fluoxetine on depression-like behavior and hippocampal neurogenesis in rats

Depressed patients with increased inflammatory cytokines in peripheral blood have been reported to be more likely to exhibit treatment resistance. However, it is unknown whether the inflammation influences the action of antidepressant drugs. Here, we investigated the influence of lipopolysaccharide (LPS) on the antidepressant action of fluoxetine in depressive rats induced by chronic unpredictable mild stress (CUMS). In this study, we first modified the CUMS paradigm by administration of LPS daily before the stressor, and then investigated the influence of inflammation on the antidepressant action of fluoxetine. The effects of stress exposure and antidepressant treatment were assessed by behavioral testing (sucrose preference test, forced swimming test, novelty suppressed feeding test) and hippocampal BrdU labeling. The CUMS-induced behavioral changes can be reversed by 4-week fluoxetine treatment. Fluoxetine also increased the hippocampal neurogenesis in the depressive rats. Pretreatment with LPS, to mimic inflammation, had no significant effect on depressive behavior but attenuated the antidepressant action of fluoxetine significantly. Thus, our results suggest that the inflammation might play a certain role in the pathophysiology of antidepressant treatment resistance.

Acetylsalicylic acid as an augmentation agent in fluoxetine treatment resistant depressive rats

Clinical studies have reported that adjunctive acetylsalicylic acid (aspirin) therapy is beneficial for patients with treatment resistant depression (TRD). However, there still exist negative epidemiological data on the link between aspirin and depression. Therefore, this study aimed to further investigate whether aspirin can be used as an augmentation agent in fluoxetine treatment resistant depressive rats induced by chronic unpredictable mild stress (CUMS). In this study, the effects of CUMS regimen and antidepressant treatment were assessed by behavioral testing, hippocampal expression of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2). 4-week fluoxetine treatment reversed the behavioral changes in approximately 70–80% depressive rats. That is, 20–30% depressive rats were resistant to fluoxetine. In the hippocampus of fluoxetine treatment resistant depressive rats, a significant upregulation of COX-2 level and PGE2 concentration was observed. However, in these rats adjunctive aspirin treatment significantly improved the depressive behaviors and downregulated the COX-2 level and PGE2 concentration in the hippocampus. Thus, our results suggest that aspirin can be served as an effective adjunctive agent in the treatment resistant depression mediated by inhibition of the COX-2 level and PGE2 concentration.

Dissection of the factors driving the placebo effect in hypnotic treatment of depressed insomniacs.

Our prior work has shown that there is improvement in self-reported sleep in persons receiving placebo in hypnotic clinical trials. We examined the components of the "placebo response" in a hypnotic clinical trial. This was an exploratory analysis of a randomized, double-blind clinical trial of eszopiclone versus placebo in the treatment of persons with depression and insomnia who were also receiving fluoxetine at a clinic of a teaching hospital. Sixty adults with both depression and insomnia symptoms, who were free of significant primary sleep disorders, received open-label fluoxetine for 9weeks. Patients were further randomized 1:1 to receive either masked eszopiclone 3mg or placebo at bedtime after the first week of fluoxetine. We examined the respective contributions of three factors associated with the "placebo effect": (1) regression to the mean, (2) expectancy, and (3) social desirability. There was evidence for regression to the mean for the continuous measurement of the Insomnia Severity Index (ISI) and the Hamilton Depression Rating Scale. There was evidence for expectancy in self-reported Wake After Sleep Onset, continuous measurement of ISI, and dichotomous remission/non-remitter measurement of ISI. There was evidence of social desirability affecting self-reported Total Sleep Time. Factors that have been associated with the "placebo effect" are operating in hypnotic clinical trials. However, the role of each factor differs depending upon which self-reported variable is being considered. The findings have implications for clinical trial design in insomnia.

Mesolimbic effects of the antidepressant fluoxetine in Holtzman rats, a genetic strain with increased vulnerability to stress

This is the first metabolic mapping study of the effects of fluoxetine after learned helplessness training. Antidepressants are the most commonly prescribed medications, but the regions underlying treatment effects in affectively disordered brains are poorly understood. We hypothesized the antidepressant action of fluoxetine would produce adaptations in mesolimbic regions after 2 weeks of treatment. We used Holtzman rats, a genetic strain showing susceptibility to novelty-evoked hyperactivity and stress-evoked helplessness, to map regional brain metabolic effects caused by fluoxetine treatment. Animals underwent learned helplessness, and subsequently immobility time was scored in the forced swim test (FST). On the next day, animals began receiving 2 weeks of fluoxetine (5 mg/kg/day) or vehicle and were retested in the FST at the end of drug treatment. Antidepressant behavioral effects of fluoxetine were analyzed using a ratio of immobility during pre- and post-treatment FST sessions. Brains were analyzed for regional metabolic activity using quantitative cytochrome oxidase histochemistry as in our previous study using congenitally helpless rats. Fluoxetine exerted a protective effect against FST-induced immobility behavior in Holtzman rats. Fluoxetine also caused a significant reduction in the mean regional metabolism of the nucleus accumbens shell and the ventral hippocampus as compared to vehicle-treated subjects. Additional networks affected by fluoxetine treatment included the prefrontal–cingulate cortex and brainstem nuclei linked to depression (e.g., habenula, dorsal raphe and interpeduncular nucleus). We concluded that corticolimbic regions such as the prefrontal–cingulate cortex, nucleus accumbens, ventral hippocampus and key brainstem nuclei represent important contributors to the neural network mediating fluoxetine antidepressant action.

Chronic treatment with fluoxetine for more than 6 weeks decreases neurogenesis in the subventricular zone of adult mice

BackgroundRecent studies indicate that chronic treatment with serotonergic antidepressants upregulates adult neurogenesis of the dentate gyrus (DG). In contrast, some studies claimed that there was very little alteration of neurogenesis in the subventricular zone (SVZ) by the antidepressants. Since almost all of those studies treated animals with drugs for 2 to 4 weeks as chronic treatment models of antidepressants, it is possible that antidepressant treatments for longer periods would affect adult neurogenesis in the SVZ.ResultsIn the present study, we examined the effects of long-term (up to 9 weeks) administration of fluoxetine (FLX), a selective serotonin reuptake inhibitor, on cell proliferation and survival in the DG and the SVZ of adult mice. As reported previously, in the DG of mice treated with FLX for 3, 6, or 9 weeks that were also injected with 5-bromodeoxyuridine (BrdU) in the last 3 days before perfusion, the numbers of Ki67- and BrdU-positive cells, which are cell proliferation markers, were significantly upregulated even at 3 weeks after the onset of the FLX treatments, and these increases were sustained in mice treated with FLX for 9 weeks. On the other hand, in the SVZ, we found a small, insignificant decrease in the numbers of Ki67- and BrdU-positive cells at 3 weeks, followed by highly significant decreases in the numbers of Ki67- and BrdU-positive cells at both 6 and 9 weeks. Furthermore, among olfactory newly generated cells that survived for 3 weeks after BrdU injection, the number of new cells was decreased at 9 weeks of FLX treatment.ConclusionsThese results demonstrate that long-term (more than 6 weeks) treatment with FLX has the opposite effect on neurogenesis in the SVZ than it does in the DG. The results also suggest that the decrease in neurogenesis in the SVZ might be involved in some aspects of the drugs' therapeutic effects on depression. In addition, our findings raise the possibility that some of the side effects of antidepressants might be mediated by decreased adult neurogenesis in the SVZ.

Treatment of Insomnia in Depressed Insomniacs: Effects on Health-related Quality of Life, Objective and Self-Reported Sleep, and Depression

Insomnia is associated with poor health related quality of life (HRQOL) in depressed patients. Prior clinical trials of hypnotic treatment of insomnia in depressed patients have shown improvement in HRQOL, but in these studies HRQOL was relegated to a secondary outcome, and objective measures of sleep were not undertaken. Double-blind, randomized, placebo-controlled clinical trial. Outpatient clinic and sleep laboratory. 60 depressed, insomniac outpatients. One week of open-label fluoxetine (FLX), followed by 8 more weeks of FLX combined with either eszopiclone (ESZ) 3 mg or placebo at bedtime. The primary HRQOL measure was the daily living and role functioning subscale (DLRF) of the Basis-32. Other measures included the Q-LES-Q, self-reported sleep, PSG, actigraphy, depression severity (HRSD). At the end of randomized treatment, patients receiving ESZ had lower (better) DLRF scores (0.81 +/- 0.64) than those receiving placebo (1.2 +/- 0.72), p = 0.01. The effect size for DLRF was 0.62, indicating a moderate effect. An advantage for ESZ was also seen in other measures of HRQOL, and most assessments of antidepressant efficacy and sleep. Women reported better end of treatment HRQOL scores than men. ESZ treatment of insomnia in depressed patients is associated with multiple favorable outcomes, including superior improvement in HRQOL, depression severity, and sleep.

The role of clinical variables, neuropsychological performance and SLC6A4 and COMT gene polymorphisms on the prediction of early response to fluoxetine in major depressive disorder

Introduction Major depressive disorder (MDD) is treated with antidepressants, but only between 50% and 70% of the patients respond to the initial treatment. Several authors suggested different factors that could predict antidepressant response, including clinical, psychophysiological, neuropsychological, neuroimaging, and genetic variables. However, these different predictors present poor prognostic sensitivity and specificity by themselves. The aim of our work is to study the possible role of clinical variables, neuropsychological performance, and the 5HTTLPR, rs25531, and val108/58Met COMT polymorphisms in the prediction of the response to fluoxetine after 4 weeks of treatment in a sample of patient with MDD. Methods 64 patients with MDD were genotyped according to the above-mentioned polymorphisms, and were clinically and neuropsychologically assessed before a 4-week fluoxetine treatment. Fluoxetine response was assessed by using the Hamilton Depression Rating Scale. We carried out a binary logistic regression model for the potential predictive variables. Results Out of the clinical variables studied, only the number of anxiety disorders comorbid with MDD have predicted a poor response to the treatment. A combination of a good performance in variables of attention and low performance in planning could predict a good response to fluoxetine in patients with MDD. None of the genetic variables studied had predictive value in our model. Limitations The possible placebo effect has not been controlled. Our study is focused on response prediction but not in remission prediction. Conclusions Our work suggests that the combination of the number of comorbid anxiety disorders, an attentional variable, and two planning variables makes it possible to correctly classify 82% of the depressed patients who responded to the treatment with fluoxetine, and 74% of the patients who did not respond to that treatment.

Anxious depression and early changes in the HAMD-17 anxiety-somatization factor items and antidepressant treatment outcome

The objective of this study was to assess the relationship between early changes in anxiety/somatization symptoms and treatment outcome among major depressive disorder patients during a 12-week trial of fluoxetine. We also examined the relationship between anxious depression and treatment response. Five hundred and ten major depressive disorder patients received 12 weeks of fluoxetine with flexible dosing [target dosages: 10 mg/day (week 1), 20 mg/day (weeks 2-4), 40 mg/day (weeks 4-8), and 60 mg/day (weeks 5-12)]. We assessed the relationship between early changes in 17-item Hamilton Rating Scale for Depression (HAMD-17)-anxiety/somatization factor items and depressive remission, as well as whether anxious depression at baseline predicted remission at study endpoint. Baseline HAMD-17 scores were considered as covariates and the Bonferroni correction (P < or = 0.008) was used for multiple comparisons. Adjusting for baseline HAMD-17 scores, patients who experienced greater early improvement in somatic symptoms (gastrointestinal) were significantly more likely to attain remission (HAMD-17 <8) at endpoint than those without early improvement (P=0.006). Early changes in the remaining items did not predict remission, nor did anxious depression at baseline. In conclusion, among the anxiety/somatization factor items, only early changes in somatic symptoms (gastrointestinal) predicted remission. Future studies are warranted to further investigate this relationship as well as that between anxious depression and treatment outcome.

Insomnia severity is an indicator of suicidal ideation during a depression clinical trial

Objective Insomnia has been linked to suicidal ideas and suicide death in cross-sectional and longitudinal population-based studies. A link between insomnia and suicide has not been previously examined in the setting of a clinical trial. Herein we describe the relationship between insomnia and suicidal thinking during the course of a clinical trial for depression with insomnia. Methods Sixty patients aged 41.5 ± 12.5 years (2/3 women) with major depressive episode and symptoms of insomnia received open-label fluoxetine for 9 weeks and also received blinded, randomized eszopiclone 3 mg or placebo at bedtime after the first week of fluoxetine. Insomnia symptoms were assessed with the Insomnia Severity Index (ISI), and suicidal ideation was assessed with The Scale for Suicide Ideation (SSI). Depression symptoms were assessed with the depressed mood item and the anhedonia item from the Hamilton Rating Scale for Depression-24 (HRSD24), as well as a sum score for all non-sleep and non-suicide items from the HRSD (HRSD20). Measurements were taken at baseline and weeks 1, 2, 4, 6, and 8. SSI was examined by generalized linear mixed models for repeated measures as the outcome of interest for all 60 participants with ISI and various mood symptoms as independent variables, with adjustment for age, gender, treatment assignment, and baseline SSI. Results Higher levels of insomnia corresponded to significantly greater intensity of suicidal thinking ( p < 0.01). The depressed mood item of the HRSD, and the sum of the HRSD20, both corresponded to greater suicidal thinking ( p < 0.001). The anhedonia item did not correspond with suicidal thinking. When both ISI and the depressed mood item, or ISI and the anhedonia item, were included together in the same model, the ISI remained an independent predictor of suicidal thinking. Conclusions The results support the concept that insomnia may be a useful indicator for suicidal ideation and now extend this idea into clinical trials. Insomnia remains an independent indicator of suicidal ideation, even taking into account the core symptoms of depression such as depressed mood and anhedonia. The complaint of insomnia during a depression clinical trial might indicate that more direct questioning about suicide is warranted.