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1.  Fluoxetine and suicide: a meta-analysis of controlled trials of treatment for depression. 
BMJ : British Medical Journal  1991;303(6804):685-692.
OBJECTIVE--A comprehensive meta-analysis of clinical trial data was performed to assess the possible association of fluoxetine and suicidality (suicidal acts and ideation). DESIGN--Retrospective analysis of pooled data from 17 double blind clinical trials in patients with major depressive disorder comparing fluoxetine (n = 1765) with a tricyclic antidepressant (n = 731) or placebo (n = 569), or both. MAIN OUTCOME MEASURES--Multiple data sources were searched to identify patients with suicidal acts. Suicidal ideation was assessed with item 3 of the Hamilton depression rating scale, which systematically rates suicidality. Emergence of substantial suicidal ideation was defined as a change in the rating of this item from 0 or 1 at baseline to 3 or 4 during double blind treatment; worsening was defined as any increase from baseline; improvement was defined as a decrease from baseline at the last visit during the treatment. RESULTS--Suicidal acts did not differ significantly in comparisons of fluoxetine with placebo (0.2% v 0.2%, p = 0.494, Mantel-Haenszel adjusted incidence difference) and with tricyclic antidepressants (0.7% v 0.4%, p = 0.419). The pooled incidence of suicidal acts was 0.3% for fluoxetine, 0.2% for placebo, and 0.4% for tricyclic antidepressants, and fluoxetine did not differ significantly from either placebo (p = 0.533, Pearson's chi 2) or tricyclic antidepressants (p = 0.789). Suicidal ideation emerged marginally significantly less often with fluoxetine than with placebo (0.9% v 2.6%, p = 0.094) and numerically less often than with tricyclic antidepressants (1.7% v 3.6%, p = 0.102). The pooled incidence of emergence of substantial suicidal ideation was 1.2% for fluoxetine, 2.6% for placebo, and 3.6% for tricyclic antidepressants. The incidence was significantly lower with fluoxetine than with placebo (p = 0.042) and tricyclic antidepressants (p = 0.001). Any degree of worsening of suicidal ideation was similar with fluoxetine and placebo (15.4% v 17.9%, p = 0.196) and with fluoxetine and tricyclic antidepressants (15.6% v 16.3%, p = 0.793). The pooled incidence of worsening of suicidal ideation was 15.3% for fluoxetine, 17.9% for placebo, and 16.3% for tricyclic antidepressants. The incidence did not differ significantly with fluoxetine and placebo (p = 0.141) or tricyclic antidepressants (p = 0.542). Suicidal ideation improved significantly more with fluoxetine than with placebo (72.0% v 54.8%, p less than 0.001) and was similar to the improvement with tricyclic antidepressants (72.5% v 69.8%, p = 0.294). The pooled incidence of improvement of suicidal ideation was 72.2% for fluoxetine, 54.8% for placebo, and 69.8% for tricyclic antidepressants. The incidence with fluoxetine was significantly greater than with placebo (p less than 0.001) and did not differ from that with tricyclic antidepressants (p = 0.296). CONCLUSIONS--Data from these trials do not show that fluoxetine is associated with an increased risk of suicidal acts or emergence of substantial suicidal thoughts among depressed patients.
PMCID: PMC1670974  PMID: 1833012
2.  Adjunctive Atypical Antipsychotic Treatment for Major Depressive Disorder: A Meta-Analysis of Depression, Quality of Life, and Safety Outcomes 
PLoS Medicine  2013;10(3):e1001403.
In a systematic review and meta-analysis, Glen Spielmans and colleagues find that adjunctive atypical antipsychotic medications are associated with small-to-moderate improvements in depressive symptoms in patients with depression, but there is little evidence for improvement on measures of quality of life, and these medications are linked to adverse events such as weight gain.
Atypical antipsychotic medications are widely prescribed for the adjunctive treatment of depression, yet their total risk–benefit profile is not well understood. We thus conducted a systematic review of the efficacy and safety profiles of atypical antipsychotic medications used for the adjunctive treatment of depression.
Methods and Findings
We included randomized trials comparing adjunctive antipsychotic medication to placebo for treatment-resistant depression in adults. Our literature search (conducted in December 2011 and updated on December 14, 2012) identified 14 short-term trials of aripiprazole, olanzapine/fluoxetine combination (OFC), quetiapine, and risperidone. When possible, we supplemented published literature with data from manufacturers' clinical trial registries and US Food and Drug Administration New Drug Applications. Study duration ranged from 4 to 12 wk. All four drugs had statistically significant effects on remission, as follows: aripiprazole (odds ratio [OR], 2.01; 95% CI, 1.48–2.73), OFC (OR, 1.42; 95% CI, 1.01–2.0), quetiapine (OR, 1.79; 95% CI, 1.33–2.42), and risperidone (OR, 2.37; 95% CI, 1.31–4.30).
The number needed to treat (NNT) was 19 for OFC and nine for each other drug. All drugs with the exception of OFC also had statistically significant effects on response rates, as follows: aripiprazole (OR, 2.07; 95% CI, 1.58–2.72; NNT, 7), OFC (OR, 1.30, 95% CI, 0.87–1.93), quetiapine (OR, 1.53, 95% CI, 1.17–2.0; NNT, 10), and risperidone (OR, 1.83, 95% CI, 1.16–2.88; NNT, 8). All four drugs showed statistically significant effects on clinician-rated depression severity measures (Hedges' g ranged from 0.26 to 0.48; mean difference of 2.69 points on the Montgomery–Asberg Depression Rating Scale across drugs). On measures of functioning and quality of life, these medications produced either no benefit or a very small benefit, except for risperidone, which had a small-to-moderate effect on quality of life (g = 0.49).
Treatment was linked to several adverse events, including akathisia (aripiprazole), sedation (quetiapine, OFC, and aripiprazole), abnormal metabolic laboratory results (quetiapine and OFC), and weight gain (all four drugs, especially OFC). Shortcomings in study design and data reporting, as well as use of post hoc analyses, may have inflated the apparent benefits of treatment and reduced the apparent incidence of adverse events.
Atypical antipsychotic medications for the adjunctive treatment of depression are efficacious in reducing observer-rated depressive symptoms, but clinicians should interpret these findings cautiously in light of (1) the small-to-moderate-sized benefits, (2) the lack of benefit with regards to quality of life or functional impairment, and (3) the abundant evidence of potential treatment-related harm.
Please see later in the article for the Editors' Summary
Editors' Summary
Everyone feels miserable occasionally. But for people who are clinically depressed, feelings of sadness and hopelessness and physical symptoms such as sleeping badly can last for months or years and can make them feel life is no longer worth living. Depression affects one in six people at some time during their life. Clinicians diagnose depression by asking their patients a series of questions about their feelings and symptoms. The answer to each question is given a score, and the total score from the questionnaire (“depression rating scale”) indicates the severity of depression. Treatment of depression often involves talking treatments (psychotherapy) such as cognitive behavioral therapy, which helps people change negative ways of thinking and behaving and antidepressant drugs, most commonly “selective serotonin reuptake inhibitors” such as fluoxetine and paroxetine.
Why Was This Study Done?
Atypical antipsychotic medications (for example, aripiprazole, olanzapine/fluoxetine combination [OFC], quetiapine, and risperidone) are also widely prescribed for the treatment of depression. These drugs, which were developed to treat mental illnesses that are characterized by a loss of contact with reality, are used as adjunctive therapy for depression. That is, they are used in addition to antidepressant drugs. Clinicians wrote nearly four million prescriptions for adjunctive treatment of depression with atypical antipsychotic medications in 2007–2008 in the US alone. However, it is not known whether the benefits of using these drugs to treat depression outweigh their side effects, which include weight gain, sedation, and akathisia (a feeling of inner restlessness resulting in an urge to move, which may or may not be accompanied by increased movement). Here, the researchers undertake a systematic review and meta-analysis of the efficacy and safety profiles of atypical antipsychotic medications used for the adjunctive treatment of depression. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical approach that combines the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 14 short-term randomized controlled trials (duration 4–12 weeks) that compared adjunctive antipsychotic medications (aripiprazole, OFC, quetiapine, or risperidone) to placebo (dummy drug) in the treatment of depression that had not responded to antidepressant medication alone. All four drugs had statistically significant effects (effects unlikely to have happened by chance) on remission, which was most commonly defined as a score of less than eight at the study end point on the Montgomery–Asberg Depression Rating Scale. The researchers calculated the number of patients that would have to be treated for one patient to achieve remission (number needed to treat, or NNT). For OFC, the NNT was 19; for all the other drugs it was nine. All the drugs except OFC also significantly improved response rates (defined as a 50% improvement in depression rating score). However, the medications provided little or no benefit in terms of functioning and quality of life, except for risperidone, which had a small-to-moderate effect on quality of life. Finally, treatment with atypical antipsychotic medications was linked to several adverse effects, including weight gain (all four drugs) and akathisia (aripiprazole).
What Do These Findings Mean?
These results suggest that atypical antipsychotic medications for the adjunctive treatment of depression are efficacious in reducing observer-rated depressive symptoms. However, clinicians should interpret this conclusion cautiously for several reasons. First, adjunctive treatment with atypical antipsychotics provided only small-to-moderate benefits. Moreover, shortcomings in study design and data reporting methods may have inflated the apparent benefits of treatment and reduced the apparent incidence of adverse events. Second, this study provides little evidence that adjunctive treatment with atypical antipsychotics improves patients' quality of life or reduces their functional impairment. Finally, this study highlights abundant evidence of potential treatment-related harm. This evaluation of the safety and efficacy of adjunctive treatments for clinical depression provides critical insights that should help clinicians better understand the risk–benefit profiles of this approach to the treatment of major depressive disorder.
Additional Information
Please access these websites via the online version of this summary at
The US National Institute of Mental Health provides information on all aspects of depression (in English and Spanish); it has a webpage on mental health medications that includes information about atypical antipsychotics
The UK National Health Service Choices website also provides detailed information about depression and includes personal stories about depression
More personal stories about depression are available from
The UK charity Mind provides information on depression and on antipsychotic drugs; Mind also includes personal stories about depression on its website
MedlinePlus provides links to other resources about depression (in English and Spanish)
Healthy Skepticism is an international nonprofit membership association that aims to improve health by reducing harm from misleading health information
PMCID: PMC3595214  PMID: 23554581
3.  Repetitive Transcranial Magnetic Stimulation for the Treatment of Major Depressive Disorder 
Executive Summary
This review was conducted to assess the effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder (MDD).
The Technology
rTMS is a noninvasive way to stimulate nerve cells in areas of the brain. During rTMS, an electrical current passes through a wire coil placed over the scalp. The current induces a magnetic field that produces an electrical field in the brain that then causes nerve cells to depolarize, resulting in the stimulation or disruption of brain activity.
Researchers have investigated rTMS as an option to treat MDD, as an add-on to drug therapy, and, in particular, as an alternative to electroconvulsive therapy (ECT) for patients with treatment-resistant depression.
The advantages of rTMS over ECT for patients with severe refractory depression are that general anesthesia is not needed, it is an outpatient procedure, it requires less energy, the simulation is specific and targeted, and convulsion is not required. The advantages of rTMS as an add-on treatment to drug therapy may include hastening of the clinical response when used with antidepressant drugs.
Review Strategy
The Medical Advisory Secretariat used its standard search strategy to locate international health technology assessments and English-language journal articles published from January 1996 to March 2004.
Summary of Findings
Some early meta-analyses suggested rTMS might be effective for the treatment of MDD (for treatment-resistant MDD and as an add-on treatment to drug therapy for patients not specifically defined as treatment resistant). There were, however, several crucial methodological limitations in the included studies that were not critically assessed. These are discussed below.
Recent meta-analyses (including 2 international health technology assessments) have done evidence-based critical analyses of studies that have assessed rTMS for MDD. The 2 most recent health technology assessments (from the Oxford Cochrane Collaboration and the Norwegian Centre for Health Technology Assessment) concluded that there is no evidence that rTMS is effective for the treatment of MDD, either as compared with a placebo for patients with treatment-resistant or nontreatment-resistant MDD, or as an alternative to ECT for patients with treatment-resistant MDD. This mainly due to the poor quality of the studies.
The major methodological limitations were identified in older meta-analyses, recent health technology assessments, and the most recently published trials (Level 2–4 evidence) on the effectiveness of rTMS for MDD are discussed below.
Small sample size was a limitation acknowledged by many of the authors. There was also a lack of a priori sample size calculation or justification.
Biased randomization may have been a problem. Generally, the published reports lacked detailed information on the method of allocation concealment used. This is important because it is impossible to determine if there was a possible influence (direct or indirect) in the allocation of the patients to different treatment groups.
The trials were single blind, evaluated by external blinded assessors, rather than double blind. Double blinding is more robust, because neither the participants nor the investigators know which participants are receiving the active treatment and which are getting a placebo. Those administering rTMS, however, cannot be blinded to whether they are administering the active treatment or a placebo.
There was patient variability among the studies. In some studies, the authors said that patients were “medication resistant,” but the definitions of resistant, if provided, were inconsistent or unclear. For example, some described “medication resistant” as failing at least one trial of drugs during the current depressive episode. Furthermore, it was unclear if the term “medication resistant” referred to antidepressants only or to combinations of antidepressants and other drug augmentation strategies (such as neuroleptics, benzodiazepine, carbamazepine, and lithium). Also variable was the type of depression (i.e., unipolar and/or bipolar), if patients were inpatients or outpatients, if they had psychotic symptoms or no psychotic symptoms, and the chronicity of depression.
Dropouts or withdrawals were a concern. Some studies reported that patients dropped out, but provided no further details. Intent-to-treat analysis was not done in any of the trials. This is important, because ignoring patients who drop out of a trial can bias the results, usually in favour of the treatment. This is because patients who withdraw from trials are less likely to have had the treatment, more likely to have missed their interim checkups, and more likely to have experienced adverse effects when taking the treatment, compared with patients who do not withdraw. (1)
Measurement of treatment outcomes using scales or inventories makes interpreting results and drawing conclusions difficult. The most common scale, the Hamilton Depression Rating Scale (HDRS) is based on a semistructured interview. Some authors (2) reported that rating scales based on semistructured interviews are more susceptible to observation bias than are self-administered questionnaires such as the Beck Depression Inventory (BDI). Martin et al. (3) argued that the lack of consistency in effect as determined by the 2 scales (a positive result after 2 weeks of treatment as measured by the HDRS and a negative result for the BDI) makes definitive conclusions about the nature of the change in mood of patients impossible. It was suggested that because of difficulties interpreting results from psychometric scales, (4) and the subjective or unstable character of MDD, other, more objective, outcome measures such as readmission to hospital, time to hospital discharge, time to adjunctive treatment, and time off work should be used to assess rTMS for the treatment of depression.
A placebo effect could have influenced the results. Many studies reported response rates for patients who received placebo treatment. For example, Klein et al. (5) reported a control group response rate as high as 25%. Patients receiving placebo rTMS may receive a small dose of magnetic energy that may alter their depression.
Short-term studies were the most common. Patients received rTMS treatment for 1 to 2 weeks. Most studies followed-up patients for 2 to 4 weeks post-treatment. Dannon et al. (6) followed-up patients who responded to a course of ECT or rTMS for up to 6 months; however, the assessment procedure was not blinded, the medication regimen during follow-up was not controlled, and initial baseline data for the patient groups were not reported. The long-term effectiveness of rTMS for the treatment of depression is unknown, as is the long-term use, if any, of maintenance therapy. The cost-effectiveness of rTMS for the treatment of depression is also unknown. A lack of long-term studies makes cost-effectiveness analysis difficult.
The complexity of possible combinations for administering rTMS makes comparing like with like difficult. Wasserman and Lisanby (7) have said that the method for precisely targeting the stimulation in this area is unreliable. It is unknown if the left dorsolateral prefrontal cortex is the optimal location for treatment. Further, differences in rTMS administration include number of trains per session, duration of each train, and motor threshold.
Clinical versus statistical significance. Several meta-analyses and studies have found that the degree of therapeutic change associated with rTMS across studies is relatively modest; that is, results may be statistically, but not necessarily clinically, significant. (8-11). Conventionally, a 50% reduction in the HDRS scores is commonly accepted as a clinically important reduction in depression. Although some studies have observed a statistically significant reduction in the depression rating, many have not shows the clinically significant reduction of 50% on the HDRS. (11-13) Therefore, few patients in these studies would meet the standard criteria for response. (9)
Clinical/methodological diversity and statistical heterogeneity. In the Norwegian health technology assessment, Aarre et al. (14) said that a formal meta-analysis was not feasible because the designs of the studies varied too much, particularly in how rTMS was administered and in the characteristics of the patients. They noted that the quality of the study designs was poor. The 12 studies that comprised the assessment had small samples, and highly variable inclusion criteria and study designs. The patients’ previous histories, diagnoses, treatment histories, and treatment settings were often insufficiently characterized. Furthermore, many studies reported that patients had treatment-resistant MDD, yet did not listclear criteria for the designation. Without this information, Aarre and colleagues suggested that the interpretation of the results is difficult and the generalizability of results is questionable. They concluded that rTMS cannot be recommended as a standard treatment for depression: “More, larger and more carefully designed studies are needed to demonstrate convincingly a clinically relevant effect of rTMS.”
In the Cochrane Collaboration systematic review, Martin et al. (3;15) said that the complexity of possible combinations for administering rTMS makes comparison of like versus like difficult. A statistical test for heterogeneity (chi-square test) examines if the observed treatment effects are more different from each other than one would expect due to random error (or chance) alone. (16) However, this statistical test must be interpreted with caution because it has low power in the (common) situation of a meta-analysis when the trials have small sample sizes or are few. This means that while a statistically significant result may indicate a problem with heterogeneity, a nonsignificant result must not be taken as evidence of no heterogeneity.
Despite not finding statistically significant heterogeneity, Martin et al. reported that the overall mean baseline depression values for the severity of depression were higher in the treatment group than in the placebo group. (3;15) Although these differences were not significant at the level of each study, they may have introduced potential bias into the meta-analysis of pooled data by accentuating the tendency for regression to the mean of the more extreme values. Individual patient data from all the studies were not available; therefore, an appropriate adjustment according to baseline severity was not possible. Martin et al. concluded that the findings from the systematic review and meta-analysis provided insufficient evidence to suggest that rTMS is effective in the treatment of depression. Moreover, there were several confounding factors (e.g., definition of treatment resistance) in the studies, thus the authors concluded, “The rTMS technique needs more high quality trials to show its effectiveness for therapeutic use.”
Due to several serious methodological limitations in the studies that have examined the effectiveness of rTMS in patients with MDD, it is not possible to conclude that rTMS either is or is not effective as a treatment for MDD (in treatment-resistant depression or in nontreatment-resistant depression).
PMCID: PMC3387754  PMID: 23074457
4.  Individualized Homeopathic Treatment and Fluoxetine for Moderate to Severe Depression in Peri- and Postmenopausal Women (HOMDEP-MENOP Study): A Randomized, Double-Dummy, Double-Blind, Placebo-Controlled Trial 
PLoS ONE  2015;10(3):e0118440.
Perimenopausal period refers to the interval when women's menstrual cycles become irregular and is characterized by an increased risk of depression. Use of homeopathy to treat depression is widespread but there is a lack of clinical trials about its efficacy in depression in peri- and postmenopausal women. The aim of this study was to assess efficacy and safety of individualized homeopathic treatment versus placebo and fluoxetine versus placebo in peri- and postmenopausal women with moderate to severe depression.
A randomized, placebo-controlled, double-blind, double-dummy, superiority, three-arm trial with a 6 week follow-up study was conducted. The study was performed in a public research hospital in Mexico City in the outpatient service of homeopathy. One hundred thirty-three peri- and postmenopausal women diagnosed with major depression according to DSM-IV (moderate to severe intensity) were included. The outcomes were: change in the mean total score among groups on the 17-item Hamilton Rating Scale for Depression, Beck Depression Inventory and Greene Scale, after 6 weeks of treatment, response and remission rates, and safety. Efficacy data were analyzed in the intention-to-treat population (ANOVA with Bonferroni post-hoc test).
After a 6-week treatment, homeopathic group was more effective than placebo by 5 points in Hamilton Scale. Response rate was 54.5% and remission rate, 15.9%. There was a significant difference among groups in response rate definition only, but not in remission rate. Fluoxetine-placebo difference was 3.2 points. No differences were observed among groups in the Beck Depression Inventory. Homeopathic group was superior to placebo in Greene Climacteric Scale (8.6 points). Fluoxetine was not different from placebo in Greene Climacteric Scale.
Homeopathy and fluoxetine are effective and safe antidepressants for climacteric women. Homeopathy and fluoxetine were significantly different from placebo in response definition only. Homeopathy, but not fluoxetine, improves menopausal symptoms scored by Greene Climacteric Scale.
Trial Registration NCT01635218
Protocol Publication
PMCID: PMC4359147  PMID: 25768800
5.  The short-term safety and efficacy of fluoxetine in depressed adolescents with alcohol and cannabis use disorders: a pilot randomized placebo-controlled trial 
The objective of this study was to examine whether fluoxetine was superior to placebo in the acute amelioration of depressive symptomatology in adolescents with depressive illness and a comorbid substance use disorder.
Eligible subjects ages 12–17 years with either a current major depressive disorder (MDD) or a depressive disorder that were also suffering from a comorbid substance-related disorder were randomized to receive either fluoxetine or placebo in this single site, 8-week double-blind, placebo-controlled study. The primary outcome analysis was a random effects mixed model for repeated measurements of Children's Depression Rating Scale-Revised (CDRS-R) scores compared between treatment groups across time.
An interim analysis was performed after 34 patients were randomized. Based on the results of a futility analysis, study enrollment was halted. Twenty-nine males and 5 females were randomized to receive fluoxetine (n = 18) or placebo (n = 16). Their mean age was 16.5 (1.1) years. Overall, patients who received fluoxetine and placebo had a reduction in CDRS-R scores. However, there was no significant difference in mean change in CDRS-R total score in those subjects treated with fluoxetine and those who received placebo (treatment difference = 0.19, S.E. = 0.58, F = 0.14, p = .74). Furthermore, there was not a significant difference in rates of positive urine drug toxicology results between treatment groups at any post-randomization visit (F = 0.22, df = 1, p = 0.65). The main limitation of this study is its modest sample size and resulting low statistical power. Other significant limitations to this study include, but are not limited to, the brevity of the trial, high placebo response rate, limited dose range of fluoxetine, and the inclusion of youth who met criteria for depressive disorders other than MDD.
Fluoxetine was not superior to placebo in alleviating depressive symptoms or in decreasing rates of positive drug screens in the acute treatment of adolescents with depression and a concomitant substance use disorder.
PMCID: PMC2666637  PMID: 19298659
6.  12-Month Follow-up of Fluoxetine and Cognitive Behavioral Therapy for Binge Eating Disorder 
The longer-term efficacy of medication treatments for binge eating disorder (BED) remains unknown. This study examined the longer-term effects of fluoxetine and cognitive-behavioral therapy (CBT) either with fluoxetine (CBT+fluoxetine) or with placebo (CBT+placebo) for BED through 12-month follow-up after completing treatments.
81 overweight patients with BED within a randomized double-blind placebo-controlled acute treatment trial allocated to fluoxetine-only, CBT+fluoxetine, and CBT+placebo were assessed before, during, post-treatment, and 6- and 12-months after completing treatments. Outcome variables comprised remission from binge-eating (zero binge-eating episodes for 28 days) and continuous measures of binge-eating frequency, eating disorder psychopathology, depression, and weight.
Intent-to-treat remission rates (missing data coded as non-remission) differed significantly across treatments at post-treatment and at 6- and 12-month follow-ups. At 12-month follow-up remission rates were: 3.7% for fluoxetine-only, 26.9% for CBT+fluoxetine, and 35.7% for CBT+placebo. Mixed-effects models of all available continuous data (without imputation) at post-treatment, 6-month, and 12-month follow-ups (controlling for baseline scores) revealed the treatments differed on all clinical outcome variables, except for weight, across time. CBT+fluoxetine and CBT+placebo did not differ and both were significantly superior to fluoxetine-only on the majority of clinical outcomes.
This represents the first report from any randomized placebo-controlled trial for BED that has reported follow-up data after completing a course of medication-only treatment. CBT+placebo was superior to fluoxetine-only and adding fluoxetine to CBT did not enhance findings compared to adding placebo to CBT. The findings document the longer-term effectiveness of CBT, but not fluoxetine, through 12-months after treatment completion.
PMCID: PMC3514647  PMID: 22985205
7.  Insomnia Moderates Outcome of Serotonin-Selective Reuptake Inhibitor Treatment in Depressed Youth 
Insomnia is evident in the majority of youth with depression, and is associated with poorer outcomes. There are limited data on the impact of insomnia in response to acute treatment, which is particularly relevant with serotonin-selective reuptake inhibitors, given their tendency to worsen sleep architecture.
Three hundred nine children and adolescents (ages 7–18 years) were randomized to fluoxetine (n=157) or placebo (n=152) for 8–9 weeks (Emslie et al.1997, 2002). Substantial insomnia at baseline was defined as a child's depression rating scale-revised [CDRS-R] sleep item ≥4. Outcome measures were CDRS-R, response, and remission.
Insomnia was reported in 172/309 (55.7%) youth, and was associated with higher depression severity and greater fatigue, suicidal ideation, physical complaints, and decreased concentration. While response rates were similar in those with or without insomnia overall (51.7% vs. 55.7%), there is a significant difference by age group. Among adolescents, those with insomnia were less likely to respond to fluoxetine (39.2%; 20/51) than those without (65.9%; 27/41; p=0.013), while in children on fluoxetine, those with insomnia were more likely to respond to fluoxetine (69.4%; 25/36) than those without insomnia (41.4%; 12/29; p=0.027). Insomnia did not impact the response to placebo in either age group. Within adolescents, the overall least squares means for CDRS-R total score (across the 8 weeks of treatment) were significantly different between those who had insomnia versus those who did not within the fluoxetine group (43.65 [SE=1.31] vs. 36.58[SE=1.45], F=12.69, df=1, 169, p=0.0005; d=0.82), but not within the placebo group (44.91[SE=1.34] vs. 43.75[SE=1.68], F=0.29, df=1, 179, p=0.591; d=0.15).
While adolescents reporting substantial insomnia were less likely to respond to antidepressant treatment than those without insomnia, children were more responsive to fluoxetine when they had insomnia. Additional intervention targeting sleep disturbance may be warranted in adolescents.
PMCID: PMC3281293  PMID: 22257126
8.  Fluoxetine: a review on evidence based medicine 
Fluoxetine was the first molecule of a new generation of antidepressants, the Selective Serotonin Re-uptake Inhibitors (SSRIs). It is recurrently the paradigm for the development of any new therapy in the treatment of depression. Many controlled studies and meta-analyses were performed on Fluoxetine, to improve the understanding of its real impact in the psychiatric area. The main objective of this review is to assess the quality and the results reported in the meta-analyses published on Fluoxetine.
Published articles on Medline, Embase and Cochrane databases reporting meta-analyses were used as data sources for this review.
Articles found in the searches were reviewed by 2 independent authors, to assess if these were original meta-analyses. Only data belonging to the most recent and comprehensive meta-analytic studies were included in this review.
Data, based on a group of 9087 patients, who were included in 87 different randomized clinical trials, confirms that fluoxetine is safe and effective in the treatment of depression from the first week of therapy. Fluoxetine's main advantage over previously available antidepressants (TCAs) was its favorable safety profile, that reduced the incidence of early drop-outs and improved patient's compliance, associated with a comparable efficacy on depressive symptoms. In these patients, Fluoxetine has proven to be more effective than placebo from the first week of therapy.
Fluoxetine has shown to be safe and effective in the elderly population, as well as during pregnancy. Furthermore, it was not associated with an increased risk of suicide in the overall evaluation of controlled clinical trials.
The meta-analysis available on the use of Fluoxetine in the treatment of bulimia nervosa shows that the drug is as effective as other agents with fewer patients dropping out of treatment.
Fluoxetine has demonstrated to be as effective as chlomipramine in the treatment of Obsessive-Compulsive-Disorder (OCD).
Fluoxetine can be considered a drug successfully used in several diseases for its favorable safety/efficacy ratio. As the response rate of mentally ill patients is strictly related to each patient's personal characteristics, any new drug in this area, will have to be developed under these considerations.
PMCID: PMC356924  PMID: 14962351
9.  Efficacy and Safety of Long-Term Fluoxetine Versus Lithium Monotherapy of Bipolar II Disorder: A Randomized, Double-Blind, Placebo-Substitution Study 
The American journal of psychiatry  2010;167(7):792-800.
The authors examined the safety and efficacy of long-term fluoxetine monotherapy, lithium monotherapy, and placebo therapy in preventing relapse and recurrence of bipolar type II major depressive episode. The authors hypothesized that fluoxetine monotherapy would be superior to lithium monotherapy with a similar hypomanic mood conversion rate.
Patients at least 18 years old who recovered from their major depressive episode during initial open-label fluoxetine monotherapy were randomly assigned to receive 50 weeks of double-blind monotherapy with fluoxetine at 10–40 mg/day, lithium at 300–1200 mg/day, or placebo. The primary outcome measure was time to relapse or recurrence. Secondary outcome measures included the proportion of patients remaining well and the frequency of hypomanic symptoms.
There were no significant differences in clinical or demographic characteristics among the fluoxetine (N=28), lithium (N=26), and placebo (N=27) groups. The mean time to relapse was 249.9 days for the fluoxetine group, 156.4 days for the lithium group, and 186.9 days for the placebo group. The hazard of relapse was significantly lower with fluoxetine compared with lithium, and the estimated hazard of relapse with lithium was 2.5 times greater than with fluoxetine. There were no statistically significant or clinically meaningful differences in hypomanic symptoms among treatment groups over time. One patient taking fluoxetine and one patient taking placebo discontinued treatment because of hypomania.
These findings suggest that long-term fluoxetine monotherapy may provide superior relapse-prevention benefit relative to lithium monotherapy after recovery from bipolar II major depressive episode without an increase in hypomanic mood conversion episodes.
PMCID: PMC2896440  PMID: 20360317
10.  Influence of fluoxetine on positive and negative affect in a clinic-based smoking cessation trial 
Psychopharmacology  2004;173(1-2):153-159.
Fluoxetine improves affect in clinical syndromes such as depression and premenstrual dysphoric disorder. Little is known about fluoxetine’s influence on mood changes after quitting smoking, which often resemble sub-clinical depression.
The present study, a re-analysis of previously published data (Niaura et al. 2002), examined fluoxetine’s effect on changes in negative and positive affect following quitting smoking.
Adult smokers (n=175) without clinically significant depression were randomized on a double-blind basis to receive fluoxetine hydrochloride (30 or 60 mg daily) or placebo for 10 weeks in combination with cognitive-behavioral therapy (CBT) for smoking cessation. We postulated that fluoxetine would beneficially influence post-cessation changes in positive and negative affect.
Mood change across treatment was analyzed using mixed linear modeling controlling for initial level of nicotine dependence, plasma fluoxetine metabolites, and change in cotinine (a nicotine metabolite) at each visit. Relative to placebo, those on 60 mg fluoxetine experienced an elevation in positive affect that increased across time [t(526)=2.50, P=0.01], and a reduction in negative affect that returned to baseline across time [t(524)=2.26, P=0.02]. There were no differences between 30 mg and placebo on changes in positive or negative affect.
Results indicate that 60 mg of fluoxetine improves both positive and negative mood states after quitting smoking and that diminished positive affect may be an overlooked affective response to smoking cessation.
PMCID: PMC1847574  PMID: 14727000
Fluoxetine; Smoking cessation; Positive affect; Negative affect
11.  Dissection of the Factors Driving the Placebo Effect in Hypnotic Treatment of Depressed Insomniacs 
Sleep medicine  2011;12(6):557-564.
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 9 weeks. Patients were further randomized 1:1 to receive either masked eszopiclone 3 mg 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.
PMCID: PMC3110560  PMID: 21601519
placebo effect; insomnia; depression; clinical trial; regression to the mean; expectancy; social desirability; eszopiclone
12.  Residual sleep disturbance and risk of relapse during the continuation/maintenance phase treatment of major depressive disorder with the selective serotonin reuptake inhibitor fluoxetine 
Relapse of major depressive disorder (MDD) is a common clinical problem. This study was designed to determine whether residual sleep disturbance (insomnia and hypersomnia) predict risk of relapse during the continuation and maintenance treatment of MDD.
A total of 570 patients with MDD were treated with open-label, flexible dose fluoxetine (range 20 to 60 mg; mean dose = 45.8 mg/day; SD = 15.1) for 12 weeks. Under double blind conditions, 262 patients who achieved clinical response were randomly assigned to continue fluoxetine or to switch to placebo for 52 weeks or until relapse. Residual sleep disturbance during the baseline visit of the double-blind phase was assessed using items 4, 5, 6 (insomnia) and 22, 23, 24 (hypersomnia) of the Hamilton Depression Rating Scale (HDRS). Survival analysis was utilized to determine the effect of residual sleep disturbance on risk of relapse.
The severities of early (P > 0.05), middle (P > 0.05), late (P > 0.05), or total (P > 0.05) residual insomnia were not found to significantly predict risk of relapse during continuation and maintenance-phase treatment. Similarly, the severities of early bedtime (P > 0.05), oversleeping (P > 0.05), napping (P > 0.05), or total (P > 0.05) residual hypersomnia were not found to significantly predict risk of relapse during continuation and maintenance-phase treatment.
The present study did not identify the severity of residual sleep disturbance among fluoxetine responders to predict risk of MDD relapse. The size of our sample may have precluded us from identifying more modest effects of residual sleep disturbance on the risk of relapse in MDD patients. Future studies are needed to further explore the relationship between residual sleep disturbance and relapse in MDD.
Trial Registration Identifier: NCT00427128
PMCID: PMC2837657  PMID: 20187924
This study compared the acute phase (12-week) and the long-term (1 year) efficacy of fluoxetine versus placebo for the treatment of the depressive symptoms and the cannabis use of youth with comorbid major depressive disorder (MDD) and an cannabis use disorder (CUD)(cannabis dependence or cannabis abuse). We hypothesized that fluoxetine would demonstrate efficacy in the acute phase trial and at the 1-year follow-up evaluation. Data is also provided regarding the prevalence of risky sexual behaviors in our study sample.
We recently completed the first double-blind placebo-controlled study of fluoxetine in adolescents and young adults with comorbid MDD/CUD. A total of 70 persons participated in the acute phase trial, and 68 of those persons (97%) also participated in the 1-year follow-up evaluation. Results of the acute phase study have already been presented (Cornelius, Bukstein, et al., 2010), but the results of the 1 year follow-up assessment have not been published previously. All participants in both treatment groups also received manual-based cognitive behavioral therapy (CBT) and motivation enhancement therapy (MET) during the 12-week course of the study. The 1-year follow-up evaluation was conducted to assess whether the clinical improvements noted during the acute phase trial persisted long term.
During the acute phase trial, subjects in both the fluoxetine group and the placebo group showed significant within-group improvement in depressive symptoms and in cannabis-related symptoms. However, no significant difference was noted between the floxetine group and the placebo group on any treatment outcome variable during the acute phase trial. End of study levels of depressive symptoms were low in both the fluoxetine group and the placebo group. Most of the clinical improvements in depressive symptoms and for cannabis-related symptoms persisted at the 1-year follow-up evaluation.
Fluoxetine did not demonstrate greater efficacy than placebo for treating either the depressive symptoms or the cannabis-related symptoms of our study sample during the acute phase study or at the 1-year follow-up assessment. The lack of a significant treatment effect for fluoxetine may at least in part reflect efficacy of the CBT/MET psychotherapy. A persistence of the efficacy of the acute phase treatment was noted at the 1-year follow-up evaluation, suggesting long-term effectiveness for the CBT/MET psychotherapy.
PMCID: PMC4200540  PMID: 25328373
14.  Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration 
PLoS Medicine  2008;5(2):e45.
Meta-analyses of antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance. Yet, the efficacy of the antidepressants may also depend on the severity of initial depression scores. The purpose of this analysis is to establish the relation of baseline severity and antidepressant efficacy using a relevant dataset of published and unpublished clinical trials.
Methods and Findings
We obtained data on all clinical trials submitted to the US Food and Drug Administration (FDA) for the licensing of the four new-generation antidepressants for which full datasets were available. We then used meta-analytic techniques to assess linear and quadratic effects of initial severity on improvement scores for drug and placebo groups and on drug–placebo difference scores. Drug–placebo differences increased as a function of initial severity, rising from virtually no difference at moderate levels of initial depression to a relatively small difference for patients with very severe depression, reaching conventional criteria for clinical significance only for patients at the upper end of the very severely depressed category. Meta-regression analyses indicated that the relation of baseline severity and improvement was curvilinear in drug groups and showed a strong, negative linear component in placebo groups.
Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.
Kirsch and colleagues show that, in antidepressant trials, there is a greater difference in efficacy between drug and placebo amongst more severely depressed patients. However, this difference seems to result from a poorer response to placebo amongst more depressed patients.
Editors' Summary
Everyone feels miserable occasionally. But for some people—those with depression—these sad feelings last for months or years and interfere with daily life. Depression is a serious medical illness caused by imbalances in the brain chemicals that regulate mood. It affects one in six people at some time during their life, making them feel hopeless, worthless, unmotivated, even suicidal. Doctors measure the severity of depression using the “Hamilton Rating Scale of Depression” (HRSD), a 17–21 item questionnaire. The answers to each question are given a score and a total score for the questionnaire of more than 18 indicates severe depression. Mild depression is often treated with psychotherapy or talk therapy (for example, cognitive–behavioral therapy helps people to change negative ways of thinking and behaving). For more severe depression, current treatment is usually a combination of psychotherapy and an antidepressant drug, which is hypothesized to normalize the brain chemicals that affect mood. Antidepressants include “tricyclics,” “monoamine oxidases,” and “selective serotonin reuptake inhibitors” (SSRIs). SSRIs are the newest antidepressants and include fluoxetine, venlafaxine, nefazodone, and paroxetine.
Why Was This Study Done?
Although the US Food and Drug Administration (FDA), the UK National Institute for Health and Clinical Excellence (NICE), and other licensing authorities have approved SSRIs for the treatment of depression, some doubts remain about their clinical efficacy. Before an antidepressant is approved for use in patients, it must undergo clinical trials that compare its ability to improve the HRSD scores of patients with that of a placebo, a dummy tablet that contains no drug. Each individual trial provides some information about the new drug's effectiveness but additional information can be gained by combining the results of all the trials in a “meta-analysis,” a statistical method for combining the results of many studies. A previously published meta-analysis of the published and unpublished trials on SSRIs submitted to the FDA during licensing has indicated that these drugs have only a marginal clinical benefit. On average, the SSRIs improved the HRSD score of patients by 1.8 points more than the placebo, whereas NICE has defined a significant clinical benefit for antidepressants as a drug–placebo difference in the improvement of the HRSD score of 3 points. However, average improvement scores may obscure beneficial effects between different groups of patient, so in the meta-analysis in this paper, the researchers investigated whether the baseline severity of depression affects antidepressant efficacy.
What Did the Researchers Do and Find?
The researchers obtained data on all the clinical trials submitted to the FDA for the licensing of fluoxetine, venlafaxine, nefazodone, and paroxetine. They then used meta-analytic techniques to investigate whether the initial severity of depression affected the HRSD improvement scores for the drug and placebo groups in these trials. They confirmed first that the overall effect of these new generation of antidepressants was below the recommended criteria for clinical significance. Then they showed that there was virtually no difference in the improvement scores for drug and placebo in patients with moderate depression and only a small and clinically insignificant difference among patients with very severe depression. The difference in improvement between the antidepressant and placebo reached clinical significance, however, in patients with initial HRSD scores of more than 28—that is, in the most severely depressed patients. Additional analyses indicated that the apparent clinical effectiveness of the antidepressants among these most severely depressed patients reflected a decreased responsiveness to placebo rather than an increased responsiveness to antidepressants.
What Do These Findings Mean?
These findings suggest that, compared with placebo, the new-generation antidepressants do not produce clinically significant improvements in depression in patients who initially have moderate or even very severe depression, but show significant effects only in the most severely depressed patients. The findings also show that the effect for these patients seems to be due to decreased responsiveness to placebo, rather than increased responsiveness to medication. Given these results, the researchers conclude that there is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective. In addition, the finding that extremely depressed patients are less responsive to placebo than less severely depressed patients but have similar responses to antidepressants is a potentially important insight into how patients with depression respond to antidepressants and placebos that should be investigated further.
Additional Information.
Please access these Web sites via the online version of this summary at
The MedlinePlus encyclopedia contains a page on depression (in English and Spanish)
Detailed information for patients and caregivers is available on all aspects of depression (including symptoms and treatment) from the US National Institute of Medical Health and from the UK National Health Service Direct Health Encyclopedia
MedlinePlus provides a list of links to further information on depression
Clinical Guidance for professionals, patients, caregivers and the public is provided by the UK National Institute for Health and Clinical Excellence
PMCID: PMC2253608  PMID: 18303940
15.  Nortriptyline versus fluoxetine in the treatment of major depressive disorder: a six-month, double-blind clinical trial 
Depression is a common psychiatric disorder worldwide, including in Iran, and is estimated to affect 10%–15% of the population. Antidepressant drugs can have multiple side effects, so a good choice of drug is important for successful treatment. This study compared the efficacy of nortriptyline with that of fluoxetine in the treatment of patients with major depressive disorder and assessed related factors, including age, gender, and level of education.
The study was a double-blind, randomized clinical trial with a six-month follow-up period. Participants were 120 patients aged 15–60 years with a diagnosis of major depressive disorder based on a psychiatry interview and the Beck depression rating scale, which were performed at the beginning, middle, and end of the study. The patients were treated with nortriptyline or fluoxetine. The paired t-test, independent t-test, and the k chi-square test were used to analyze the data.
Twenty-three patients dropped out and 97 remained in the trial. Before intervention, the mean depression score was 32.85 ± 6.23 in the nortriptyline group and 33.12 ± 6.50 in the fluoxetine group. The results of the independent t-test showed a significant difference between depression score means before and after treatment in both groups. Changes at the end of the trial compared with baseline scores were 13.4 ± 4.68 and 16.96 ± 4.96 for nortriptyline and fluoxetine, respectively. Paired t-testing showed a significant difference in the mean depression score for both the nortriptyline and fluoxetine groups. Age, gender, and level of education had no significant effects on the outcome of treatment in the two groups.
The present study suggests that both nortriptyline and fluoxetine were effective in the treatment of depression, but that fluoxetine was more effective than nortriptyline after 3 and 6 months of treatment.
Video abstract
PMCID: PMC3284259  PMID: 22359466
major depressive disorder; nortriptyline; fluoxetine; treatment
16.  Double-Blind Fluoxetine Trial in Comorbid MDD-CUD Youth and Young Adults 
Drug and alcohol dependence  2010;112(1-2):39-45.
This study compared the acute phase (12-week) efficacy of fluoxetine versus placebo for the treatment of the depressive symptoms and the cannabis use of adolescents and young adults with comorbid major depression (MDD) and an cannabis use disorder (CUD)(cannabis dependence or cannabis abuse). We hypothesized that fluoxetine would demonstrate efficacy versus placebo for the treatment of the depressive symptoms and the cannabis use of adolescents and young adults with comorbid MDD/CUD.
We conducted the first double-blind placebo-controlled study of fluoxetine in adolescents and young adults with comorbid MDD/CUD. All participants in both treatment groups also received manual-based cognitive behavioral therapy (CBT) and motivation enhancement therapy (MET) during the 12-week course of the study.
Fluoxetine was well tolerated in this treatment population. No significant group-by-time interactions were noted for any depression-related or cannabis-use related outcome variable over the 12-week study. Subjects in both the fluoxetine group and the placebo group showed significant within-group improvement in depressive symptoms and in number of DSM diagnostic criteria for a CUD. Large magnitude decreases in depressive symptoms were noted in both treatment groups, and end-of-study levels of depressive symptoms were low in both treatment groups.
Fluoxetine did not demonstrate greater efficacy than placebo for treating either the depressive symptoms or the cannabis-related symptoms of our study sample of comorbid adolescents and young adults. The lack of a significant between-group difference in these symptoms may reflect limited medication efficacy, or may result from efficacy of the CBT/MET psychotherapy or from limited sample size.
PMCID: PMC2946416  PMID: 20576364
Cannabis Use Disorder; Major Depressive Disorder; Fluoxetine; Cognitive Behavioral Therapy; Motivation Enhancement Therapy
17.  Moclobemide versus fluoxetine in the treatment of major depressive disorder in adults. 
The objective of the present study was to compare the safety and efficacy of moclobemide versus fluoxetine in adult patients with major depressive disorder. The design of the study was a multicenter, double-blind, comparative, and randomized trial. A 1- to 2-week single-blind placebo washout phase was followed by 6 weeks of double-blind treatment with moclobemide or fluoxetine. A total of 150 patients were enrolled in the study. There were 128 patients eligible to be randomized, with 66 patients receiving moclobemide and 62 patients receiving fluoxetine. At the termination of the study, patients in the moclobemide group were receiving a mean dose of 440 mg +/- 123 mg, while the mean dose in the fluoxetine group was 35 mg +/- 8 mg. No significant treatment differences were found for any of the efficacy parameters. Headache and nausea were the most frequently reported adverse events in both treatment groups. Headache and blurred vision were reported significantly more often (P < 0.05) in the fluoxetine group, whereas significantly more dry mouth was reported (P < 0.05) in the moclobemide group. These results provide supporting evidence of the comparable efficacy of moclobemide and fluoxetine and the better tolerability of moclobemide when used in the treatment of major depressive disorder.
PMCID: PMC1188834  PMID: 9074306
18.  Suicidal Thoughts and Behavior With Antidepressant Treatment 
Archives of general psychiatry  2012;69(6):580-587.
The US Food and Drug Administration issued a black box warning for antidepressants and suicidal thoughts and behavior in children and young adults.
To determine the short-term safety of anti-depressants by standard assessments of suicidal thoughts and behavior in youth, adult, and geriatric populations and the mediating effect of changes in depressive symptoms.
Data Sources
All intent-to-treat person-level longitudinal data of major depressive disorder from 12 adult, 4 geriatric, and 4 youth randomized controlled trials of fluoxetine hydrochloride and 21 adult trials of venlafaxine hydrochloride.
Study Selection
All sponsor-conducted randomized controlled trials of fluoxetine and venlafaxine.
Data Extraction
The suicide items from the Children’s Depression Rating Scale–Revised and the Hamilton Depression Rating Scale as well as adverse event reports of suicide attempts and suicide during active treatment were analyzed in 9185 patients (fluoxetine: 2635 adults, 960 geriatric patients, 708 youths; venlafaxine: 2421 adults with immediate-release venlafaxine and 2461 adults with extended-release venlafaxine) for a total of 53 260 person-week observations.
Data Synthesis
Suicidal thoughts and behavior decreased over time for adult and geriatric patients randomized to fluoxetine or venlafaxine compared with placebo, but no differences were found for youths. In adults, reduction in suicide ideation and attempts occurred through a reduction in depressive symptoms. In all age groups, severity of depression improved with medication and was significantly related to suicide ideation or behavior.
Fluoxetine and venlafaxine decreased suicidal thoughts and behavior for adult and geriatric patients. This protective effect is mediated by decreases in depressive symptoms with treatment. For youths, no significant effects of treatment on suicidal thoughts and behavior were found, although depression responded to treatment. No evidence of increased suicide risk was observed in youths receiving active medication. To our knowledge, this is the first research synthesis of suicidal thoughts and behavior in depressed patients treated with antidepressants that examined the mediating role of depressive symptoms using complete longitudinal person-level data from a large set of published and unpublished studies.
PMCID: PMC3367101  PMID: 22309973
19.  Fluoxetine Increases Suicide Ideation Less than Placebo During Treatment of Adults with Minor Depressive Disorder 
Journal of psychiatric research  2013;47(9):1199-1203.
Some reports suggest an increase in suicide ideations and behaviors in patients treated with antidepressants. This is an analysis of the impact of fluoxetine on suicide ideations in outpatients with Minor Depressive Disorder.
Research subjects were adult outpatients with Minor Depressive Disorder (N=162), who received fluoxetine or placebo in a prospective, 12-week, double blind randomized trial. The research participants were evaluated weekly with standard rating scales that included 4 suicide-related items; item 3 of the Hamilton Rating Scale for Depression (HRSD), item 18 of Inventory of Depressive Symptomatology (IDS-C), and items 15 and 59 of the Hopkins Symptom Checklist (SCL-90). Clinically significant intensification of suicide ideation was defined as an increase of ≥2 on any of these items.
Overall 60/162 subjects (37%) had an increase of ≥1 point during treatment and 17/162 (10.5%) of ≥2 points on at least one suicide item, with 12/81 (14.8%) placebo and 5/81 (6.2%) fluoxetine treated subjects having a ≥2 point gain. Of the study participants with baseline suicide ideation, 9/22 (40.9%) placebo and 3/24 (12.5%) fluoxetine treated had ≥2 point increase (p=0.04). Survival analysis revealed that subjects on placebo were significantly more likely (p=0.050) to experience a ≥2 point increase on one or more item, a difference that emerged early and continued throughout the 12-week trial.
Compared to placebo, fluoxetine was not associated with a clinically significant increase in suicide ideation among adults with Minor Depressive Disorder during 12 weeks of treatment.
PMCID: PMC3729337  PMID: 23786912
Minor Depressive Disorder; fluoxetine; antidepressant; treatment emergent suicide ideation
20.  Efficacy of vitamin C as an adjunct to fluoxetine therapy in pediatric major depressive disorder: a randomized, double-blind, placebo-controlled pilot study 
Nutrition Journal  2013;12:31.
Current antidepressants used to treat pediatric patients have the disadvantage of limited efficacy and potentially serious side effects. The purpose of this study was to assess the efficacy of vitamin C as an adjuvant agent in the treatment of pediatric major depressive disorder in a six-month, double-blind, placebo-controlled pilot trial.
The study group (n=12) was given fluoxetine (10–20 mg/day) plus vitamin C (1000 mg/day) and control group (n=12) administered fluoxetine (10–20 mg/day) plus placebo. The data were analyzed by ANOVA and t-test for independent samples.
Both groups demonstrated significantly improved scores on the Children’s Depression Rating Scale (CDRS), the Children’s Depression Inventory (CDI), and the Clinical Global Impression (CGI). ANOVA was significantly different on all clinical measurements (group effect, time effect, and interaction), with the exception of group effect and interaction for CGI. Patients treated for six months with fluoxetine and vitamin C showed a significant decrease in depressive symptoms in comparison to the fluoxetine plus placebo group as measured by the CDRS (t=11.36, P<0.0001) and CDI (t=12.27, P<0.0001), but not CGI (t=0.13, P=0.90). No serious adverse effects were observed.
These preliminary results suggest that vitamin C may be an effective adjuvant agent in the treatment of MDD in pediatric patients.
PMCID: PMC3599706  PMID: 23510529
21.  Olanzapine and fluoxetine combination in severe or resistant depression 
Indian Journal of Psychiatry  2003;45(4):234-238.
Objective :
The purpose of this study was to investigate the efficacy and safety of Fixed Dose Combination (FDC) of olanzapine 5 mg and fluoxetine 20 mg in Indian patients with severe or treatment resistant depression.
Design :
This was an open, non-comparative study of seven weeks duration with an initial placebo run in period of one week.
Method :
One hundred and fifty three patients were enrolled. One hundred and forty-four patients completed the study as per protocol and 151 patients were safety evaluable. One hundred and eleven patients (77%) received one tablet of FDC of olanzapine 5 mg / fluoxetine 20 mg once daily for 6 weeks, in patients (14%), the dose was stepped up at the end of 2 weeks to 2 tablets of FDC of olanzapine 5 mg/ fluoxetine 20 mg once daily for a further 4 weeks and 13 patients (9%) required dose to be stepped up at the end of 4 weeks to 3 tablets of FDC of olanzapine 5 mg and fluoxetine 20 mg once daily for last 2 weeks.
Results :
One hundred and thirty four patients (93%) responded to FDC of olanzapine and fluoxetine therapy (a responder was defined as a patient with 50 % reduction over baseline in HDRS total score at the end of therapy).Statistically significant (p < 0.0001) reductions in HDRS total score, MADRS total score and CGI severity scores were seen with olanzapine/ fluoxetine combination. One hundred and four patients (72%) were remitters (HDRS total score of <7) after 6 weeks of therapy.
Adverse experiences were reported by thirty one patients (20.5%). Majority of them were mild in intensity. No serious adverse event was recorded with study therapy. Three patients were withdrawn from the therapy due to adverse event.
Conclusion :
Treatment with FDC of olanzapine 5 mg / fluoxetine 20 mg was highly effective and well tolerated in Indian patients with severe or treatment resistant depression.
PMCID: PMC2952370  PMID: 21206864
Olanzapine; Fluoxetine; Severe depression
22.  Necessity of Hippocampal Neurogenesis for the Therapeutic Action of Antidepressants in Adult Nonhuman Primates 
PLoS ONE  2011;6(4):e17600.
Rodent studies show that neurogenesis is necessary for mediating the salutary effects of antidepressants. Nonhuman primate (NHP) studies may bridge important rodent findings to the clinical realm since NHP-depression shares significant homology with human depression and kinetics of primate neurogenesis differ from those in rodents. After demonstrating that antidepressants can stimulate neurogenesis in NHPs, our present study examines whether neurogenesis is required for antidepressant efficacy in NHPs.
Adult female bonnets were randomized to three social pens (N = 6 each). Pen-1 subjects were exposed to control-conditions for 15 weeks with half receiving the antidepressant fluoxetine and the rest receiving saline-placebo. Pen-2 subjects were exposed to 15 weeks of separation-stress with half receiving fluoxetine and half receiving placebo. Pen-3 subjects 2 weeks of irradiation (N = 4) or sham-irradiation (N = 2) and then exposed to 15 weeks of stress and fluoxetine. Dependent measures were weekly behavioral observations and postmortem neurogenesis levels.
Exposing NHPs to repeated separation stress resulted in depression-like behaviors (anhedonia and subordinance) accompanied by reduced hippocampal neurogenesis. Treatment with fluoxetine stimulated neurogenesis and prevented the emergence of depression-like behaviors. Ablation of neurogenesis with irradiation abolished the therapeutic effects of fluoxetine. Non-stressed controls had normative behaviors although the fluoxetine-treated controls had higher neurogenesis rates. Across all groups, depression-like behaviors were associated with decreased rates of neurogenesis but this inverse correlation was only significant for new neurons in the anterior dentate gyrus that were at the threshold of completing maturation.
We provide evidence that induction of neurogenesis is integral to the therapeutic effects of fluoxetine in NHPs. Given the similarity between monkeys and humans, hippocampal neurogenesis likely plays a similar role in the treatment of clinical depression. Future studies will examine several outstanding questions such as whether neuro-suppression is sufficient for producing depression and whether therapeutic neuroplastic effects of fluoxetine are specific to antidepressants.
PMCID: PMC3078107  PMID: 21525974
23.  Who Benefits from Antidepressants? 
Archives of general psychiatry  2012;69(6):572-579.
Some meta-analyses suggest that efficacy of antidepressants for major depression is over-stated and limited to severe depression.
To determine short-term efficacy of antidepressants for treating major depression in youth, adults and geriatric populations.
Reanalysis of all intent-to-treat person-level longitudinal data during the first 6 weeks of treatment of major depressive disorder from 12 adult, 4 geriatric and 4 youth RCTs of fluoxetine and 21 adult trials of venlafaxine.
All sponsor conducted RCTs of fluoxetine and venlafaxine.
Main Outcome Measures
Children’s Depression Rating Scale (youth), the Hamilton Depression Rating Scale (adult and geriatric) and estimated response and remission rates at 6 weeks.
Fluoxetine – 2635 adult, 960 geriatric and 708 youth. Venlafaxine - 2421 IR and 2461 ER adult.
Patients in all age and drug groups had significantly greater improvement relative to placebo controls. Differential rate of improvement was largest for adult fluoxetine patients (35% greater than placebo). Youth had the largest treated versus control difference in response rates (24.1%) and remission rates (30.1%), with adult differences generally in the 15%–22% range. Geriatric patients had the smallest drug-placebo differences, 19% greater rate of improvement, 10% for response and 7% for remission. Venlafaxine IR produced larger effects than ER. Baseline severity could not be shown to affect symptom reduction.
This is the first research synthesis in this area to use complete longitudinal person-level data from a large set of published and unpublished studies. The results do not support previous findings that antidepressants show little benefit except for severe depression. The antidepressants fluoxetine and venlafaxine are efficacious for major depression, in all age groups although more so in youth and adults compared with geriatric patients. Baseline severity was not significantly related to degree of treatment advantage over placebo.
PMCID: PMC3371295  PMID: 22393205
24.  Effects of Electroacupuncture on Depression and the Production of Glial Cell Line–Derived Neurotrophic Factor Compared with Fluoxetine: A Randomized Controlled Pilot Study 
Background and Objective
Postmortem studies indicate that the number and density of glial cells are reduced in different brain regions of patients with depression. Glial cell line–derived neurotrophic factor (GDNF) plays an important role in the pathogenesis of depressive disorder (DD) and might be a biomarker for damage to nerve cells. In this study, we compared the therapeutic effects of electroacupuncture (EA) and fluoxetine, a serotonin reuptake inhibitor, on DD patients, focusing on the serum level of GDNF.
This was a prospective, randomized clinical trial.
Seventy-five patients with DD from the Department of Acupuncture, Beijing Hospital of Traditional Chinese Medicine, were recruited.
Twenty patients were treated with acupuncture for 6 weeks on the acupoints of Baihui (DU20) and Zusanli (ST36). Sixteen patients were treated with acupuncture for 6 weeks on the acupoints of Taichong (LR3), Sanyinjiao (SP6), Neiguan (PC6), and Shenmen (HT7), and constituted the electroacupuncture control group. The patients received acupuncture treatment five times per week. Twenty-five patients were treated with oral fluoxetine (20 mg/day) for 6 weeks.
Outcome measures
All subjects were evaluated by the Hamilton Depression Rating Scale at four time points (0 [baseline], 2, 4, and 6 weeks after treatment). Serum GDNF was quantified in duplicate by enzyme-linked immunosorbent assay (ELISA).
EA and fluoxetine had similar curative effects on DD patients. EA had a faster onset of action, better response rate, and better improvement rate than fluoxetine. Both fluoxetine and EA treatment restored the normal concentration of GDNF in the serum of DD patients.
EA treatment for depression is as effective as a recommended dose of fluoxetine. However, EA demonstrates an advantage in the regulation of the production of GDNF compared with fluoxetine.
PMCID: PMC3768227  PMID: 23647408
25.  Comparison Among Clomipramine, Fluoxetine, and Placebo for the Treatment of Anxiety Disorders in Children and Adolescents 
Objective: The purpose of this study was to test the efficacy of clomipramine and fluoxetine, controlled by placebo, and compare their action in children and adolescents with anxiety disorders.
Method: Thirty subjects (ages 7–17 years), who were diagnosed with generalized anxiety disorder and/or separation anxiety disorder and/or social phobia, were submitted to a 12 week double-blind, randomized, placebo-controlled trial of clomipramine and fluoxetine. The instruments included: the Schedule for Affective Disorders and Schizophrenia, the Multidimensional Anxiety Scale for Children, the Children's Depression Inventory, the Clinical Global Impressions, and the Children's Global Assessment Scale.
Results: All groups (clomipramine [n=9], fluoxetine [n=10], placebo [n=11]) showed a significant improvement after 12 weeks of treatment. There were significant differences between the fluoxetine and placebo groups in some ratings of anxiety severity and impairment. No significant differences were observed between clomipramine and placebo groups or between fluoxetine and clomipramine groups.
Conclusions: Treatment with placebo showed an unusual high response rate. Clomipramine showed similar efficacy compared with fluoxetine, although it was not superior to placebo.
PMCID: PMC3870579  PMID: 24350814

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