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1.  Effects of Zinc Supplementation in Patients with Major Depression: A Randomized Clinical Trial 
Iranian Journal of Psychiatry  2013;8(2):73-79.
Major depression is a mood disorder that causes changes in physical activity, appetite, sleep and weight. Regarding the role of zinc in the pathology of depression, the present study was aimed to investigate the effects of zinc supplementation in the treatment of this disease.
This study was a double-blind randomized clinical trial. Forty four patients with major depression were randomly assigned to groups receiving zinc supplementation and placebo. Patients in Zinc group received daily supplementation with 25 mg zinc adjunct to antidepressant; Selective Serotonin Reuptake Inhibitors (SSRIs), while the patients in placebo group received placebo with antidepressants (SSRIs) for twelve weeks. Severity of depression was measured using the Beck Depression Inventory at baseline and was repeated at the sixth and twelfth weeks. ANOVA with repeated measure was used to compare and track the changes during the study.
The mean score of Beck test decreased significantly in the zinc supplement group at the end of week 6 (P < 0.01) and 12 (P < 0.001) compared to the baseline. The mean score of Beck Depression Inventory reduced significantly compared to the placebo group at the end of 12th week (P < 0.05)
The results of the present study indicate that zinc supplementation together with SSRIs antidepressant drug improves major depressive disorders more effectively in patients with placebo plus antidepressants (SSRIs).
PMCID: PMC3796297  PMID: 24130605
Major depressive disorder; Zinc supplement; placebo and Selective Serotonin Reuptake Inhibitors (SSRIs)
2.  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
3.  A randomized, double-blind clinical trial on the efficacy of cortical direct current stimulation for the treatment of major depression 
Preliminary findings suggest that transcranial direct current stimulation (tDCS) can have antidepressant effects. We sought to test this further in a parallel-group, double-blind clinical trial with 40 patients with major depression, medication-free randomized into three groups of treatment: anodal tDCS of the left dorsolateral prefrontal cortex (active group – ‘DLPFC’); anodal tDCS of the occipital cortex (active control group – ‘occipital’) and sham tDCS (placebo control group – ‘sham’). tDCS was applied for 10 sessions during a 2-wk period. Mood was evaluated by a blinded rater using the Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI). The treatment was well tolerated with minimal side-effects that were distributed equally across all treatment groups. We found significantly larger reductions in depression scores after DLPFC tDCS [HDRS reduction of 40.4% (±25.8%)] compared to occipital [HDRS reduction of 21.3% (±12.9%)] and sham tDCS [HDRS reduction of 10.4% (±36.6%)]. The beneficial effects of tDCS in the DLPFC group persisted for 1 month after the end of treatment. Our findings support further investigation on the effects of this novel potential therapeutic approach – tDCS – for the treatment of major depression.
PMCID: PMC3372849  PMID: 17559710
Brain stimulation; electrical stimulation; major depression; prefrontal cortex; transcranial direct current stimulation
4.  Pharmacometabolomics of Response to Sertraline and to Placebo in Major Depressive Disorder – Possible Role for Methoxyindole Pathway 
PLoS ONE  2013;8(7):e68283.
Therapeutic response to selective serotonin (5-HT) reuptake inhibitors in Major Depressive Disorder (MDD) varies considerably among patients, and the onset of antidepressant therapeutic action is delayed until after 2 to 4 weeks of treatment. The objective of this study was to analyze changes within methoxyindole and kynurenine (KYN) branches of tryptophan pathway to determine whether differential regulation within these branches may contribute to mechanism of variation in response to treatment. Metabolomics approach was used to characterize early biochemical changes in tryptophan pathway and correlated biochemical changes with treatment outcome. Outpatients with MDD were randomly assigned to sertraline (n = 35) or placebo (n = 40) in a double-blind 4-week trial; response to treatment was measured using the 17-item Hamilton Rating Scale for Depression (HAMD17). Targeted electrochemistry based metabolomic platform (LCECA) was used to profile serum samples from MDD patients. The response rate was slightly higher for sertraline than for placebo (21/35 [60%] vs. 20/40 [50%], respectively, χ2(1)  = 0.75, p = 0.39). Patients showing a good response to sertraline had higher pretreatment levels of 5-methoxytryptamine (5-MTPM), greater reduction in 5-MTPM levels after treatment, an increase in 5-Methoxytryptophol (5-MTPOL) and Melatonin (MEL) levels, and decreases in the (KYN)/MEL and 3-Hydroxykynurenine (3-OHKY)/MEL ratios post-treatment compared to pretreatment. These changes were not seen in the patients showing poor response to sertraline. In the placebo group, more favorable treatment outcome was associated with increases in 5-MTPOL and MEL levels and significant decreases in the KYN/MEL and 3-OHKY/MEL; changes in 5-MTPM levels were not associated with the 4-week response. These results suggest that recovery from a depressed state due to treatment with drug or with placebo could be associated with preferential utilization of serotonin for production of melatonin and 5-MTPOL.
PMCID: PMC3714282  PMID: 23874572
5.  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
6.  Dense Cranial Electroacupuncture Stimulation for Major Depressive Disorder—A Single-Blind, Randomized, Controlled Study 
PLoS ONE  2012;7(1):e29651.
Previous studies suggest that electroacupuncture possesses therapeutic benefits for depressive disorders. The purpose of this study was to determine whether dense cranial electroacupuncture stimulation (DCEAS) could enhance the antidepressant efficacy in the early phase of selective serotonin reuptake inhibitor (SSRI) treatment of major depressive disorder (MDD).
In this single-blind, randomized, controlled study, patients with MDD were randomly assigned to 9-session DCEAS or noninvasive electroacupuncture (n-EA) control procedure in combination with fluoxetine (FLX) for 3 weeks. Clinical outcomes were measured using the 17-item Hamilton Depression Rating Scale (HAMD-17), Clinical Global Impression-severity (CGI-S), and Self-rating Depression Scale (SDS) as well as the response and remission rates.
Seventy-three patients were randomly assigned to n-EA (n = 35) and DCEAS (n = 38), of whom 34 in n-EA and 36 in DCEAS group were analyzed. DCEAS-treated patients displayed a significantly greater reduction from baseline in HAMD-17 scores at Day 3 through Day 21 and in SDS scores at Day 3 and Day 21 compared to patients receiving n-EA. DCEAS intervention also produced a higher rate of clinically significant response compared to n-EA procedure (19.4% (7/36) vs. 8.8% (3/34)). The incidence of adverse events was similar in the two groups.
DCEAS is a safe and effective intervention that augments the antidepressant efficacy. It can be considered as an additional therapy in the early phase of SSRI treatment of depressed patients.
Trial Registration ISRCTN88008690
PMCID: PMC3253099  PMID: 22238631
7.  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
8.  Use of slow-release melatonin in treatment-resistant depression. 
OBJECTIVE: To examine antidepressant augmentation with and hypnotic effects of slow-release melatonin (SR-melatonin) in patients with treatment-resistant depression. DESIGN: Open-label trial. SETTING: Tertiary care outpatient depression clinic. PATIENTS: Nine outpatients who had failed to respond to 2 or more 8-week trials of antidepressant medication. INTERVENTIONS: Patients received SR-melatonin 5 mg per day for the first 2 weeks and 10 mg per day for the final 2 weeks, in addition to their antidepressant medication. OUTCOME MEASURES: Structured Clinical Interview for DSM-IV, Axis 1 Disorders, Hamilton Rating Scale for Depression (HRSD), Beck Depression Inventory, Response Style Questionnaire, sleep and fatigue measures. RESULTS: One patient was excluded after 1 week because of the development of a mixed affective state. In the remaining 8 patients there was a 20% mean decrease in HRSD scores after 4 weeks of treatment, with no individual achieving an improvement of 50% or more. There was a 36% decrease on the 3-item HRSD related to insomnia, with 4 of 8 patients showing at least a 50% improvement on this measure. The greatest decrease in insomnia occurred during the last 2 weeks of the study, following the increase in dosage to 10 mg per day of SR-melatonin. Patients also reported significantly lower levels of fatigue post-treatment. CONCLUSIONS: SR-melatonin may be a useful adjunct for sleep, but does not substantially augment existing antidepressant therapies in some patients with treatment-resistant depression.
PMCID: PMC1407707  PMID: 10721684
9.  Directly Observed Antidepressant Medication Treatment and HIV Outcomes Among Homeless and Marginally Housed HIV-Positive Adults: A Randomized Controlled Trial 
American journal of public health  2012;103(2):308-315.
We assessed whether directly observed fluoxetine treatment reduced depression symptom severity and improved HIV outcomes among homeless and marginally housed HIV-positive adults in San Francisco, California, in 2002 to 2008.
We conducted a nonblinded, randomized controlled trial of once-weekly fluoxetine, directly observed for 24 weeks, then self-administered for 12 weeks (n|=|137 persons with major or minor depressive disorder or dysthymia). Hamilton Depression Rating Scale score was the primary outcome. Response was a 50% reduction from baseline and remission a score below 8. Secondary measures were Beck Depression Inventory-II (BDI-II) score, antiretroviral uptake, antiretroviral adherence (measured by unannounced pill count), and HIV-1 RNA viral suppression (<|50 copies/mL).
The intervention reduced depression symptom severity (b|=|−1.97; 95% confidence interval [CI]|=|−0.85, −3.08; P|<|.001) and increased response (adjusted odds ratio [AOR]|=|2.40; 95% CI|=|1.86, 3.10; P|<|.001) and remission (AOR|=|2.97; 95% CI|=|1.29, 3.87; P|<|.001). BDI-II results were similar. We observed no statistically significant differences in secondary HIV outcomes.
Directly observed fluoxetine may be an effective depression treatment strategy for HIV-positive homeless and marginally housed adults, a vulnerable population with multiple barriers to adherence.
PMCID: PMC3558777  PMID: 22720766
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.  Pilot Randomized Clinical Trial of an SSRI vs Bupropion: Effects on Suicidal Behavior, Ideation, and Mood in Major Depression 
Neuropsychopharmacology  2011;37(3):697-706.
Randomized controlled trials in depressed patients selected for elevated suicidal risk are rare. The resultant lack of data leaves uncertainty about treatment in this population. This study compared a serotonin reuptake inhibitor with a noradrenergic/dopaminergic antidepressant in major depression with elevated suicidal risk factors. We conducted a double-blind, randomized, clinical pilot trial of paroxetine (N=36) or bupropion (N=38) in DSM IV major depression with a suicide attempt history or current suicidal ideation. The effects during acute (8 weeks) and continuation treatment (up to 16 weeks) were measured. Main outcomes were suicidal behavior and ideation. The secondary outcome was modified 17-item Hamilton Depression Rating Scale score subtracting the suicide item (mHDRS-17). Treatment was not associated with time to a suicidal event and no treatment main effect or treatment × time interaction on suicidal ideation or mHDRS-17 was found. Exploratory model selection showed modest advantages for paroxetine on: (1) mHDRS-17 (p=0.02); and (2) in a separate model adjusted for baseline depression, for suicidal ideation measured with the Beck Scale for Suicidal Ideation (p=0.03), with benefit increasing with baseline severity. Depressed patients with greater baseline suicidal ideation treated with paroxetine compared with bupropion appeared to experience greater acute improvement in suicidal ideation, after adjusting for global depression. Given the lack of evidence-based pharmacotherapy guidelines for suicidal, depressed patients—an important public health population—this preliminary finding merits further study.
PMCID: PMC3260969  PMID: 21993207
suicide; depression; antidepressant; pilot; clinical trial; depression; unipolar; bipolar; psychopharmacology; clinical pharmacology; clinical trials; mood; anxiety; stress disorders; suicidal behavior; suicidal ideation
12.  The Effect of Methylated Vitamin B Complex on Depressive and Anxiety Symptoms and Quality of Life in Adults with Depression 
ISRN Psychiatry  2013;2013:621453.
Depression, the most common type of mental illness, is the second leading cause of disability and is increasing among Americans. The effect of improved nutrition, particularly with dietary supplements, on depression may provide an alternative to standard medical treatment. Some studies have shown that certain nutrients (e.g., inositol and S-adenosyl methionine) are effective at improving depressed mood, although the results are not unequivocal. The current study was a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of a vitamin B complex nutritional supplement (Max Stress B) for improving depressive and anxiety symptoms according to the Beck Depression and Anxiety Inventories (BDI and BAI) in 60 adults diagnosed with major depression or other forms of depressive disorders. Secondary outcomes included quality of life according to the SF-36. Participants were assessed at baseline and 30- and 60-day followups. Max Stress B showed significant and more continuous improvements in depressive and anxiety symptoms, compared to placebo. Additionally, Max Stress B showed significant improvement on the mental health scale of the SF-36 compared to placebo. Thus, we showed modest utility of Max Stress B to improve mood symptoms and mental health quality of life in adults with depression.
PMCID: PMC3658370  PMID: 23738221
13.  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
14.  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
15.  Antidepressant response trajectories and quantitative electroencephalography (QEEG) biomarkers in major depressive disorder 
Individuals with Major Depressive Disorder (MDD) vary regarding the rate, magnitude and stability of symptom changes during antidepressant treatment. Growth mixture modeling (GMM) can be used to identify patterns of change in symptom severity over time. Quantitative electroencephalographic (QEEG) cordance within the first week of treatment has been associated with endpoint clinical outcomes but has not been examined in relation to patterns of symptom change. Ninety-four adults with MDD were randomized to eight weeks of double-blinded treatment with fluoxetine 20 mg or venlafaxine 150 mg (n = 49) or placebo (n = 45). An exploratory random effect GMM was applied to Hamilton Depression Rating Scale (Ham-D17) scores over 11 timepoints. Linear mixed models examined 48-h, and 1-week changes in QEEG midline-and-right-frontal (MRF) cordance for subjects in the GMM trajectory classes. Among medication subjects an estimated 62% of subjects were classified as responders, 21% as non-responders, and 17% as symptomatically volatile—i.e., showing a course of alternating improvement and worsening. MRF cordance showed a significant class-by-time interaction (F(2,41) = 6.82, p = .003); as hypothesized, the responders showed a significantly greater 1-week decrease in cordance as compared to non-responders (mean difference = −.76, Std. Error = .34, df = 73, p = .03) but not volatile subjects. Subjects with a volatile course of symptom change may merit special clinical consideration and, from a research perspective, may confound the interpretation of typical binary endpoint outcomes. Statistical methods such as GMM are needed to identify clinically relevant symptom response trajectories.
PMCID: PMC2925497  PMID: 19631948
Depression; EEG; Cordance; Antidepressants; Statistical models; Growth mixture modeling
16.  Vilazodone in the treatment of major depressive disorder: efficacy across symptoms and severity of depression 
Vilazodone is a potent selective serotonin reuptake inhibitor and serotonin 1A receptor partial agonist approved for the treatment of major depressive disorder in adults. To assess the efficacy of vilazodone across a range of symptoms and severities of depression, data from two phase III, 8-week, randomized, double-blind, placebo-controlled trials were pooled for analysis. Overall improvement in depressive symptoms measured using the Montgomery–Åsberg Depression Rating Scale (MADRS) and the 17-item Hamilton Depression Rating Scale was statistically significant (P<0.05) for vilazodone treatment compared with placebo as early as Week 1 and continued throughout double-blind treatment. Vilazodone treatment compared with placebo showed significant improvement on all 10 individual MADRS symptom items at end of treatment (P<0.01). Rates of response and remission were significantly greater in the vilazodone group relative to the placebo group, with numbers needed to treat ranging from eight to nine for response and 12–17 for remission. Between-group treatment differences in MADRS and the other outcome measures were similar among all depression subgroups, with no consistent pattern associated with depression severity. These findings support the efficacy of vilazodone across a broad range of depressive symptoms and severities for the treatment of major depressive disorder.
PMCID: PMC3901802  PMID: 24247740
antidepressant; major depressive disorder; selective serotonin reuptake inhibitors; serotonin 1A receptor agonists; vilazodone
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.  The Antidepressant Treatment Response (ATR) Index and Treatment Outcomes in a Placebo-controlled Trial of Fluoxetine 
Recent research aims at developing a biomarker to predict antidepressant treatment outcomes in Major Depressive Disorder (MDD). The Antidepressant Treatment Response index (ATRindex) has been correlated with response to antidepressant medication (Leuchter et al., 2009a, 2009b) but has not been assessed in a placebo-controlled trial. EEGs were used to calculate ATR-index for 23 randomized MDD subjects to eight weeks of fluoxetine treatment (FLX) 20 mg (n=12) or placebo (n=11). The 17-item Hamilton Depression Rating Scale (HamD17) assessed symptom severity, while a percent change in HamD17 score, endpoint response (≥ 50% improvement) and remission (HamD17 score ≤ 7) were used to assess ATR-index as a predictor. ATR-index was significantly associated with improvement on FLX (r = .64, p = .01), with a higher mean ATR-index for FLX responders than non-responders (t(10)= −2.07, p=0.03). Receiver Operating Characteristic analysis found a .83 area under the curve (p = .03), for ATR-index as a predictor for FLX, while an optimized ATR-index cutoff of 47.3 yielded 100% sensitivity, 66.7% specificity, 75% PPV and 100% NPV. Importantly, ATR-index did not correlate significantly with placebo outcomes. Results extend ATR-index findings to include predictive validity with fluoxetine, suggesting that this biomarker has specificity for drug effects.
PMCID: PMC3188349  PMID: 21946361
antidepressant medication; placebo response; biomarker; EEG
19.  The combination of triiodothyronine (T3) and sertraline is not superior to sertraline monotherapy in the treatment of major depressive disorder☆ 
Journal of psychiatric research  2012;46(11):1406-1413.
To determine whether the combination of triiodothyronine (T3) plus sertraline at treatment initiation confers greater antidepressant efficacy than sertraline plus placebo in patients with major depressive disorder.
Eight-week, double blind, randomized placebo controlled clinical trial of 153 adult outpatients between 18 and 60 years of age, with DSM-IV defined major depressive disorder. Patients were treated with sertraline flexibly adjusted for tolerability and in a double blind fashion with placebo or T3 (25 μg/day in week 1 and increasing to 50 μg/day in week 2). Response was defined categorically as 50% reduction and total score less than 15 in 21-item Hamilton Rating Scale for Depression (HRSD-21) at week 8 and remission as HRSD-21 less than 8.
There was no difference between treatment groups at final assessment; 65% of placebo and 61.8% of T3 treated subjects achieved response and 50.6% of placebo and 40.8% of T3 treated patients achieved remission. The mean daily dose at final assessment of sertraline and T3, respectively was 144.7 mg (±48.7 mg) and 48.2 μg (±7 μg). Median time to response did not differ between treatment groups. Baseline thyroid function tests did not predict response to sertraline treatment or T3 augmentation.
These results do not support the routine use of T3 to enhance or accelerate onset of antidepressant response in patients with major depressive disorder.
PMCID: PMC3760770  PMID: 22964160
Depression; Triiodothyronine; Augmentation; Response; Remission; Antidepressant
20.  Insomnia Severity is an Indicator of Suicidal Ideation During a Depression Clinical Trial 
Sleep medicine  2010;11(9):822-827.
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.
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.
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.
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.
PMCID: PMC2936685  PMID: 20478741
insomnia; suicide; depression; clinical trial; eszopiclone; placebo
21.  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
22.  A randomized, placebo-controlled trial of risperidone augmentation for patients with difficult-to-treat unipolar, non-psychotic major depression 
Journal of psychiatric research  2008;43(3):205-214.
Patients (30–50%) with non-psychotic major depression will not respond despite an adequate trial of antidepressant medication. This study evaluated risperidone as an augmenting agent for patients who failed or only partially responded to an adequate trial of an antidepressant medication.
Ninety-seven patients with unipolar non-psychotic major depression who were not responsive to antidepressant monotherapy were randomized to risperidone (0.5–3 mg/day) or placebo augmentation in a four-week, double-blind, placebo controlled treatment trial. The primary outcome measure was remission defined by a score of ≤10 on the Montgomery–Asberg Depression Rating Scale (MADRS). Secondary outcomes measures were the Hamilton Rating Scale for Depression, the Clinician Global Impression of Severity scale and the overall satisfaction item of the Quality of Life and Enjoyment Questionnaire.
Subjects in both treatment groups improved significantly over time. The odds of remitting were significantly better for patients in the risperidone vs. placebo arm (OR = 3.33, p = .011). At the end of 4 weeks of treatment 52% of the risperidone augmentation group remitted (MADRS ≤ 10) compared to 24% of the placebo augmentation group (CMH(1) = 6.48, p = .011), but the two groups were converging. Patients in the risperidone group also reported significantly more improvement in quality-of-life than patients in the placebo group. There were no between-group differences in the number of adverse events reported, however, weight gain was significantly higher in the group receiving risperidone.
Augmentation of an antidepressant with risperidone for patients with difficult-to-treat depression leads to more rapid response and a higher remission rate and better quality-of-life.
PMCID: PMC3685867  PMID: 18586273
Antidepressants; Antipsychotic; Clinical drug studies; Mood disorders – unipolar
23.  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
24.  Olanzapine and fluoxetine combination therapy for treatment-resistant depression: review of efficacy, safety, and study design issues 
Treatment-resistant depression (TRD) is a common occurrence in clinical practice. Up to 30% of patients with major depression do not respond to conventional antidepressant treatment, while a significantly greater number of patients experience only partial symptom reduction. Numerous strategies may be applied by the practicing clinician to overcome limitations in the effectiveness of antidepressant monotherapy, including combining drug treatment with evidence-supported psychotherapies, combining antidepressants (combination pharmacotherapy), and combining antidepressants with other non-antidepressant psychotropic medications (augmentation treatment). One such augmentation strategy, the combination of the selective serotonin reuptake inhibitor, fluoxetine (FLX), with the atypical antipsychotic drug, olanzapine (OLZ), is supported by the results of four randomized, double-blind, acute phase studies of patients who had responded inadequately to antidepressant monotherapy. In each study, the FLX/OLZ combination caused rapid reduction in Montgomery-Asberg Depression Rating scale scores, with two of the four studies showing significantly greater improvement than antidepressant monotherapy at study endpoint. Effects of the FLX/OLZ combination were strongest in cases where failure to respond to two antidepressants prior to randomization was established during the current depressive episode. The FLX/OLZ combination was well-tolerated; however, body weight gain and increases in prolactin were greater than that of the antidepressant monotherapy groups, and were comparable to that of OLZ monotherapy. While effective during acute-phase treatment, questions remain regarding the long-term efficacy and safety of FLX/OLZ relative to antidepressant monotherapy and other combination strategies. Efforts aimed at determining the placement of FLX/OLZ among the available options for addressing TRD are limited by lack of comparison and sequential treatment studies. Important aspects of study design and directions for future research are discussed.
PMCID: PMC2706569  PMID: 19590732
olanzapine; fluoxetine; combination therapy; major depression; treatment resistance
25.  Repetitive transcranial magnetic stimulation is as effective as fluoxetine in the treatment of depression in patients with Parkinson's disease 
Methods: 42 patients were enrolled into two groups: group 1, active rTMS (15 Hz rTMS for 10 days) and placebo drug treatment; group 2, sham rTMS and fluoxetine 20 mg/day. A specially designed sham coil was used for sham stimulation. The unified Parkinson's disease rating scale (UPDRS), activities of daily living (ADL), Hamilton rating scale for depression (HRSD), Beck depression inventory (BDI), and mini-mental state examination (MMSE) were assessed by a rater blinded to treatment arm.
Results: HRSD and BDI were improved to the same extent in both groups after two weeks of treatment (38% and 32% for group 1, 41% and 33% for group 2, respectively). At week 8 there was a tendency for worse motor UPDRS scores in group 2 (NS). ADL showed improvement at week 8 only in group 1. MMSE improved in both groups after treatment, but faster in group 1 than in group 2. There were fewer adverse effects in group 1 than in group 2.
Conclusions: rTMS has the same antidepressant efficacy as fluoxetine and may have the additional advantage of some motor improvement and earlier cognitive improvement, with fewer adverse effects.
PMCID: PMC1739189  PMID: 15258224

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