How Long For Increased Dose Of Antidepressant To Work

Prim Care Companion J Clin Psychiatry. 2006; eight(5): 269–278.

Effects of the Antidepressant Duloxetine on Body Weight: Analyses of 10 Clinical Studies

Received 2005 Dec xvi; Accustomed 2006 Jan 31.

Abstruse

Objective: To assess the outcome of duloxetine, an inhibitor of serotonin and norepinephrine reup-take, on body weight of patients with major depressive disorder (MDD).

Method: Torso weight information were obtained from all ten phase 2 and III registration studies of duloxetine in the treatment of MDD, every bit defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), performed past Eli Lilly and Company betwixt Feb 1999 and July 2003. Both astute (8–nine weeks) and long-term (26, 34, and 52 weeks) studies were analyzed.

Results: In the acute placebo-controlled studies, duloxetine-treated patients had a mean alter of −0.5 kg compared with a change of 0.2 kg for placebo-treated patients (p < .001); no consequent human relationship between duloxetine dose and weight change was observed. In placebo-controlled studies including an active comparator arm, similar acute hateful weight changes were seen in duloxetine-treated and fluoxetine-treated patients (−0.7 kg vs. −0.six kg) and in duloxetine-treated and paroxetine-treated patients (−0.3 kg vs. −0.2 kg). During longer-term treatment (34 weeks), mean weight change in patients treated with duloxetine 40 mg b.i.d. was not significantly different from that seen in placebo-treated patients (0.seven kg vs. 0.1 kg), while patients treated with the college duloxetine dose of 60 mg b.i.d. or with paroxetine gained significantly (p ≤?.05) more than weight than placebo-treated patients (0.9 kg, 1.0 kg, and 0.one kg, respectively). In a 52-calendar week open up-label study, duloxetine-treated patients had a mean weight gain of 1.i kg at endpoint (p < .001).

Conclusion: Duloxetine-treated patients experienced weight loss after short-term handling, followed by pocket-sized weight gain on longer-term handling. The size of the weight changes observed suggests that the antidepressant duloxetine has minimal furnishings on weight for the majority of patients.

Many antidepressants bear on torso weight. Weight gain, in particular, may lead to patient dissatisfaction, noncompliance, and eventual discontinuation of therapy.¹ The tricyclic antidepressants are commonly associated with weight gain that tin be disturbing to patients and may interfere with patients' willingness to proceed long-term maintenance treatment.² Conversely, the selective serotonin reuptake inhibitors (SSRIs) fluoxetine^{3, iv} and sertraline^five and the dopamine reuptake inhibitor bupropion⁵ are associated with short-term weight loss. In the long term, patients treated with fluoxetine tend to regain their weight afterwards experiencing an initial short-term weight loss.^six Another SSRI, paroxetine, is associated with long-term weight gain,⁷ whereas bupropion may induce long-term weight loss.^viii Sibutramine, a monoamine re-uptake inhibitor of norepinephrine (NE) and serotonin (five-HT)⁹ that was initially studied every bit an antidepressant, is used as an anti-obesity agent to induce weight loss.^{10, 11} Duloxetine hydrochloride (hereafter referred to equally du-loxetine), a dual-reuptake inhibitor of both 5-HT and NE, lacks significant analogousness for muscarinic, histamine₁, α_i-adrenergic, dopamine_two, 5-HT_1A, v-HT_1B, five-HT_1D, v-HT_2A, 5-HT_2C, and opioid receptors.¹² Duloxetine blocks 5-HT and NE reuptake by the inhibition of binding to 5-HT and NE transporters, which has been demonstrated both in vitro and in vivo.^{12, 13}

Duloxetine has demonstrated efficacy in the treatment of major depressive disorder (MDD) in double-blind placebo-controlled studies^14–19 and is licensed in the U.s.a., Europe, and elsewhere for the treatment of MDD. The weight information for patients with MDD treated with duloxetine accept not previously been comprehensively analyzed. Data from astute and long-term treatment clinical studies were therefore analyzed to evaluate whether duloxetine has an effect on weight in patients with MDD.

METHOD

Overview of Studies

Body weight data were obtained from all 10 stage 2 and 3 registration studies of duloxetine in the treatment of MDD, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),²⁰ performed by Eli Lilly and Company betwixt February 1999 and July 2003. In improver to the actual weight data, treatment-emergent weight-related adverse events (ambition decreased, appetite increased, and anorexia) were collected in all the studies. Treatment assignments and relevant details of each written report (studies 1–x) are summarized in Tabular array one; pairs of studies were conducted under a common protocol. Except for study 10 and the acute phase of report 9 (a relapse-prevention study), all studies were randomized, double-blind, and controlled (with placebo, fluoxetine, and/or paroxetine used equally comparators). Both in one case-daily (q.d.) and twice-daily (b.i.d.) dosing were used in these studies. The master outcomes of all the studies (except study 6, which is currently in printing) have been previously published (encounter Table 1 for citations). The appropriate ethical review committees approved all the studies, and the written report participants provided signed informed consent before study participation.

Table ane.

Description of the Major Depressive Disorder Studies Used in the Integrated Analyses

The chief focus of these analyses was on the duloxetine versus placebo comparisons. Comparisons of duloxetine with fluoxetine and paroxetine were used to help put the comparisons with placebo into a clinically relevant context. Because paroxetine and fluoxetine artillery did not coexist in any study, the furnishings of these treatments on body weight were not directly compared. Duloxetine doses spanned the therapeutically relevant dose range, whereas fluoxetine and paroxetine doses were at the lower end of their respective recommended dose ranges. Thus, comparisons between duloxetine and the active comparators should be interpreted in light of the doses used.

Statistical Analyses

Analyses were performed using the intent-to-treat principle, in which all patients were included in the groups to which they were randomly allocated, even if the patient did not accept the assigned treatment, did not receive the correct treatment, or otherwise did not follow the protocol. All treatment hypotheses were tested using a two-sided α = .05. Analyses were performed using SAS statistical software (SAS Institute, Cary, Due north.C.).

For some analyses of astute data, all duloxetine dose groups in the therapeutically relevant range (twoscore–120 mg/24-hour interval) were combined into 1 group. This approach created the largest possible number of patients per group and avoided the confounding of dose with protocol that would have otherwise existed.

Datasets

The following data-pooling strategies were used to match the corresponding hypotheses to be tested:

1. Astute placebo-controlled dataset. Acute (8–9 weeks) data from the duloxetine and placebo arms of studies 1–eight were pooled and compared.

2. Acute fluoxetine-controlled dataset. Information from the duloxetine and fluoxetine artillery of studies 1 and 2 were pooled and compared.

3. Astute paroxetine-controlled dataset. Acute (eight weeks) information from the duloxetine and paroxetine arms of studies 3–6 were pooled and compared.

4. Long-term placebo- and paroxetine-controlled dataset. Long-term (34 weeks) data from the 4 individual handling artillery of the astute and continuation phases combined of studies five and half-dozen were pooled and compared.

In add-on, the following datasets did not involve pooling beyond duloxetine doses or studies:

5. Acute uncontrolled dataset. Acute (12 weeks) du-loxetine data from written report 9.

6. Long-term placebo-controlled dataset. Long-term (26 weeks) data from the duloxetine and placebo arms of study nine.

7. Long-term uncontrolled dataset. Long-term (52 weeks) duloxetine data from study x.

Mean modify analyses

The change in weight from baseline to endpoint (each patient's last ascertainment during the handling menstruum) was compared amongst handling groups using a fixed-furnishings analysis of variance (ANOVA) model. When analyses were performed across protocols, such as the acute placebo- and acute paroxetine-controlled datasets, an ANOVA model with terms for treatment, study, and treatment-by-study interaction was used. Treatment effects were assessed using Type III sums of squares, which weighted each study equally. When 1 study (long-term placebo-controlled dataset) or two studies conducted under a common protocol (acute fluoxetine-controlled and long-term placebo- and paroxetine-controlled datasets) were analyzed, the ANOVA model included the chiselled furnishings of handling and investigator. The assay of the long-term placebo- and paroxe-tine-controlled dataset, in which only efficacy responders continued beyond eight weeks, besides included the baseline weight. There was a significant (p ≤?.10) investigator-by-treatment interaction for the long-term placebo-controlled dataset, so the interaction was retained in the model, using Type II sums of squares for comparing treatments.

Demographic analyses

Continuous demographic information were analyzed using an ANOVA model that independent terms for investigator (the term report was used for the acute placebo-controlled and acute paroxetine-controlled datasets) and treatment. Categorical demographic data were analyzed using Fisher exact test (acute fluoxetine-controlled dataset) or the χ² test (other controlled datasets).

Subgroup analyses

Subgroup analyses of modify in weight for the acute placebo-controlled dataset were performed, with subgroups based on trunk mass index (BMI) (< 25 vs. 25 to < xxx vs. ≥?30 kg/m²), age (< 55 vs. ≥?55 years), gender, and indigenous origin (Caucasian vs. other). An analysis of covariance (ANCOVA) model with terms for treatment, study, baseline, subgroup, and treatment-past-subgroup furnishings was used to obtain the interaction p value, which was tested at the .ten significance level. An ANCOVA model with terms for handling, study, and baseline effects was used for within-subgroup treatment comparisons. In a similar analysis of the long-term placebo-controlled and paroxetine-controlled dataset by BMI subgroup, the term for investigator, rather than study, was used. For the long-term uncontrolled dataset, the change from baseline to endpoint was summarized by each of the 4 subgroup variables.

Repeated measures analyses

A likelihood-based, mixed-effects repeated measures model was also used to analyze change in weight for studies three and 4 (pooled), and 7 and 8 (pooled). Dose titration was not used in these studies, thus preventing the confounding of dose with visit that is present in studies ane and 2, for which investigator-initiated dose titration inside the range of 20–sixty mg b.i.d. could occur at whatsoever fourth dimension during the acute phase. A similar analysis was performed for the long-term placebo-and paroxetine-controlled dataset, for which automated curt-term dose titration (three and 6 days for patients randomly assigned to duloxetine twoscore and 60 mg b.i.d., respectively) was used. The repeated measures model independent fixed categorical effects of handling, investigator, visit, and treatment-past-visit interaction, as well as the fixed continuous covariates of baseline and baseline-by-visit interaction. An unstructured covariance matrix was used to model the within-patient errors. For the long-term uncontrolled dataset, the repeated measures model used stock-still categorical effects of investigator and visit, as well as the fixed continuous covariate of the baseline weight. A compound symmetric matrix was used to model the inside-patient errors.

Potentially clinically significant changes in weight and weight-related adverse events

The frequencies of potentially clinically significant (PCS) measured changes in weight (loss or gain of ≥ 7%) from baseline to endpoint or whatsoever time, every bit well every bit the frequencies of treatment-emergent weight-related adverse events (weight decreased/increased and anorexia), were compared between treatment groups using Fisher exact test, or across protocols, by the Cochran-Mantel-Haenszel test stratified past study.

Association of weight change with HAM-D scores

The association between the alter from baseline to endpoint in the Hamilton Rating Scale for Depression–17 items (HAM-D-17) total score and weight in the long-term uncontrolled dataset was evaluated using Spearman'south Rho correlation coefficient.

RESULTS

Patient Characteristics

Baseline patient characteristics, including gender, age, ethnicity, and weight, are presented in Tabular array 2 for the astute handling studies and Table iii for the long-term treatment studies. Treatment groups did not differ significantly for any of these characteristics except that patients in the duloxetine treatment group of the acute placebo-controlled dataset weighed significantly more than patients in the placebo treatment group (p ≤?.01).

Table 2.

Baseline Patient Characteristics in Acute Studies

Tabular array 3.

Baseline Patient Characteristics in Long-Term Studies

Acute Placebo-Controlled Dataset

Weight change and treatment-emergent weight-related agin events during 8 to nine weeks of acute treatment are summarized in Tabular array 4. Duloxetine-treated patients (pooled doses) lost significantly more weight from baseline to endpoint than did placebo-treated patients, who gained slightly (−0.5 kg vs. 0.ii kg, p < .001). Repeated measures analysis revealed no consequent human relationship between duloxetine dose and weight change (Tabular array 5; Figures 1A, 1B, and ​ 2A [showtime eight weeks]). In studies three and 4 and studies 7 and 8, patients who received duloxetine 40 mg/solar day, sixty mg/24-hour interval, or 80 mg/day lost significantly more weight than did placebo-treated patients (meet Tabular array v for p values), simply the differences in studies 5 and 6 were not significant. The subgroup analysis of change in weight past baseline BMI strata showed that there was a meaning handling-by-BMI interaction (p = .001), with the amount of weight loss in duloxetine-treated patients compared with placebo-treated patients increasing with higher BMI (Table 4). In each BMI stratum, duloxetine-treated patients lost significantly more weight compared with placebo-treated patients, who gained slightly (p < .001). The incidences of PCS weight loss (≥?7%) from baseline to endpoint or any fourth dimension were significantly greater for duloxetine-treated than for placebo-treated patients (p = .035 and p = .010, respectively). The incidences of PCS weight gain (≥?7%) from baseline to endpoint or at any time were not significantly different for duloxetine-treated compared with placebo-treated patients.

Change in Trunk Weight During (A) eight Weeks of Acute Handling With Duloxetine forty mg/day (xx mg b.i.d.), Duloxetine 80 mg/24-hour interval (twoscore mg b.i.d.), Paroxetine xx mg/day (20 mg q.d.), or Placebo (studies 3 and iv; repeated measures analysis) and (B) 9 Weeks of Astute Treatment With Duloxetine 60 mg/day (lx mg q.d.) or Placebo (studies 7 and eight; repeated measures analysis)

Change in Body Weight During (A) 34 Weeks of Long-Term Treatment With Duloxetine eighty mg/day (40 mg b.i.d.), Duloxetine 120 mg/day (lx mg b.i.d.), Paroxetine xx mg/twenty-four hours (20 mg q.d.), or Placebo (studies 5 and 6; repeated measures analysis) and (B) 52 Weeks of Long-Term Treatment With Duloxetine 80 to 120 mg/solar day (40–60 mg b.i.d.) (written report 10; repeated measures analysis)

Tabular array 4.

Trunk Weight Change and Treatment-Emergent Weight-Related Agin Events in Acute Placebo-Controlled Studies (studies 1–8)

Tabular array v.

Outcome of Duloxetine on Alter in Body Weight From Baseline to Final Report Visit of Acute Phase (placebo-controlled, acute studies): Repeated Measures Assay past Dose^a

Duloxetine-treated patients reported the treatment-emergent weight-related adverse events of appetite decreased (p < .001) and anorexia (p = .001) significantly more often than did placebo-treated patients (Table iv). A lower pct of duloxetine-treated patients (1.i%) compared with placebo-treated patients (i.4%) reported appetite increased; however, this difference was non significant. The incidences of weight-related events were similar beyond duloxetine doses. Anorexia was the but weight-related event reported as a reason for treatment discontinuation (duloxetine, 0.one%; placebo, 0.0%). Subgroup analyses of weight alter by age (< 55 vs. ≥?55 years), origin (Caucasian vs. other), and gender institute no significant treatment-by-subgroup interactions.

Acute Fluoxetine-Controlled and Paroxetine-Controlled Datasets

In studies comparing duloxetine with fluoxetine (studies one and two) during 8 weeks of acute handling, the mean change in weight from baseline to endpoint was not significantly different for duloxetine-treated compared with fluoxetine-treated patients (−0.vii kg vs. −0.half dozen kg; Table 6). No significant differences were observed between duloxetine-treated patients and fluoxetine-treated patients with regard to PCS weight proceeds or loss, or incidence of treatment-emergent weight-related adverse events. The treatment-emergent weight-related adverse events of appetite decreased, ambition increased, and anorexia were non reported every bit a reason for discontinuation in these studies.

Table 6.

Body Weight Change and Treatment-Emergent Weight-Related Adverse Events in Acute Active Comparator–Controlled Studies

In studies that compared duloxetine with paroxetine (studies 3–six) during 8 weeks of astute treatment, the mean alter in weight from baseline to endpoint was not significantly different for duloxetine-treated compared with paroxetine-treated patients (−0.3 kg vs. −0.2 kg; Tabular array 6). No meaning differences were observed between duloxetine-treated patients and paroxetine-treated patients with regard to the incidence of PCS weight proceeds or PCS weight loss. Significantly more duloxetine-treated patients reported ambition decreased than did paroxetine-treated patients (4.2% vs. 1.4%; p = .011). Ambition decreased, ambition increased, and anorexia were not reported as a reason for discontinuation in these studies.

Long-Term Treatment Datasets

In studies five and 6, patients whose HAM-D-17 full score was reduced at least by thirty% from baseline to the finish (week 8) of the acute stage were eligible to enter a 26-week continuation phase. These patients continued on the same treatment, even so nether double-bullheaded atmospheric condition. Weight data for these studies were analyzed across the acute and continuation phases combined (34 weeks; Tabular array vii). Pooling the corresponding arms of studies 5 and half dozen, of the patients initially randomly assigned, 129 of the 192 placebo-treated patients, 141 of the 188 duloxetine 40 mg b.i.d.-treated patients, 156 of the 196 duloxetine 60 mg b.i.d.-treated patients, and 140 of the 183 paroxetine 20 mg q.d.-treated patients entered the continuation stage. The mean changes in weight from baseline to the end of the astute phase ranged across the 4 treatment groups from −0.17 to 0.xviii kg for all randomly assigned patients and from −0.06 to 0.xix kg for the patients who entered the continuation phase. These results practice not suggest a selection bias with respect to weight for the patients who entered the continuation phase. For this reason, the long-term placebo- and paroxetine-controlled dataset included all available data for the entire 34 weeks of treatment for all randomized patients.

Tabular array seven.

Body Weight Change and Treatment-Emergent Weight-Related Agin Events in Long-Term Studies

The least squares hateful weight change from baseline to endpoint for patients treated with duloxetine at a dose of forty mg b.i.d. was not significantly unlike from that seen in placebo-treated patients (0.vii kg vs. 0.1 kg; Tabular array 7). Weight changes in duloxetine 60 mg b.i.d.-treated patients (0.nine kg) and paroxetine twenty mg q.d.-treated patients (ane.0 kg) were, however, significantly greater than those seen in placebo-treated patients (0.one kg, p ≤?.05 for each). The least squares hateful weight changes by repeated measures at 34 weeks show similar results; changes during the 34 weeks for each handling group are shown in Figure 2A. No meaning treatment-past-BMI subgroup interaction was observed. The treatment groups did non differ significantly in the rates of PCS weight loss at endpoint or any time, whereas the rates of PCS weight proceeds at endpoint were significantly higher in all agile treatment arms compared with placebo (meet Table 7 for p values). However, the rates of PCS weight gain at any time did not differ significantly between patients receiving duloxetine 40 mg b.i.d. and patients receiving placebo, whereas significantly more patients receiving duloxetine threescore mg b.i.d. and patients receiving paroxetine experienced PCS weight gain at whatever fourth dimension compared with placebo (p ≤?.05 and p ≤?.001, respectively). No pregnant differences between treatment groups were seen in the incidence of treatment-emergent weight-related adverse events. In add-on, no patients discontinued from the studies due to appetite decreased, appetite increased, or anorexia. The comparisons of both duloxetine treatment groups (40 mg b.i.d. and sixty mg b.i.d.) with paroxetine 20 mg q.d. did not reveal any significant differences in weight change from baseline to endpoint or to week 34, PCS weight change at endpoint or any time, or in treatment-emergent weight-related adverse events.

The astute uncontrolled dataset and the long-term placebo-controlled dataset are based on the acute and continuation phases, respectively, of study 9. In the acute uncontrolled dataset, the mean weight change from baseline to endpoint for duloxetine-treated patients was non pregnant (−0.ane kg). The respective hateful change for patients who were subsequently randomly assigned in the 26-calendar week continuation phase was 0.1 kg. In this long-term placebo-controlled dataset, mean changes in weight from baseline to endpoint did non differ significantly between the groups (duloxetine lx mg q.d., 1.0 kg; placebo, 0.9 kg).

In the long-term uncontrolled dataset (study 10), at that place was a significant within-group mean weight modify from baseline to endpoint for duloxetine-treated patients of i.1 kg (p < .001; Table 7). After 52 weeks of duloxetine handling, there was a significant within-group least squares mean weight increment of two.i kg (p < .001) by repeated measures analysis. The rate of weight gain decreased as the elapsing of exposure became greater (Effigy 2B). Anorexia (0.1%) was the but treatment-emergent weight-related adverse outcome reported as a reason for treatment discontinuation. Hateful weight gain decreased with increasing BMI (Table vii), merely mean weight changes from baseline to endpoint in subgroups based on age (< 55 vs. ≥?55 years), gender, and ethnic origin (Cauca-sian vs. other) were like. The incidences of PCS weight gain were numerically greater than those for PCS weight loss. To meliorate understand the group that experienced the PCS weight gain at endpoint, the data were stratified into ii groups (PCS weight gain vs. no PCS weight gain), simply no statistical inferences were fabricated betwixt these groups because they were based on postal service-baseline data. The groups were relatively equally matched with regard to age and ethnic origin. However, the PCS weight gain grouping had a somewhat college percentage of female patients compared with the no PCS weight gain group (79.two% vs. 71.1%). The mean baseline BMI scores were slightly lower in the PCS weight proceeds group compared with the no PCS weight gain grouping (24.9 vs. 26.eight kg/k²), similarly for baseline weight (65.0 vs. 71.ane kg). The mean baseline HAM-D-17 total score was slightly college for the PCS weight gain group compared with the no PCS weight gain group (23.3 vs. 22.2).

The Spearman'southward Rho correlation between the change in the HAM-D-17 total score and change in weight from baseline to endpoint was −0.xx (p < .001). These two variables were farther explored in patient subgroups divers past overall compliance in taking the study medication. The patient was considered compliant if at each visit the patient, in the investigator's stance, was compliant in taking the study medication. In that location were 984 compliant and 257 noncompliant patients. The mean weight gain and comeback in HAM-D-17 total score were greater among the compliant patients than among the non-compliant patients (one.3 vs. 0.one kg and −15.5 vs. −8.7, respectively).

DISCUSSION

During 8 to 9 weeks of acute therapy, duloxetine-treated patients lost weight when compared with placebo-treated patients. Self-reports of treatment-emergent weight-related adverse events were consistent with the observed weight loss, in that patients in the duloxetine treatment group reported appetite decreased and anorexia significantly more often than patients in the placebo treatment grouping, whereas reports of appetite increased were similar. No duloxetine-treated patients reported appetite decreased or appetite increased equally a reason for discontinuation, whereas 0.1% of duloxetine-treated patients discontinued due to anorexia. Patients treated with duloxetine 40 to 120 mg/twenty-four hour period experienced weight loss similar to that seen in patients treated with fluoxetine twenty mg/day or paroxetine 20 mg/day during 8 weeks of therapy. No consistent relationship was observed betwixt duloxetine dose and weight change.

After longer-term handling with duloxetine, paroxetine, or placebo, a different motion-picture show emerged, namely, small weight gain rather than weight loss with duloxetine. Weight gain in patients treated with duloxetine 40 mg b.i.d. did non differ significantly from that seen in placebo-treated patients. Patients treated with the highest dose of duloxetine, 60 mg b.i.d., and at the everyman recommended dose of paroxetine, 20 mg q.d., did, nonetheless, proceeds significantly more weight than did placebo-treated patients. Consistent with this finding, PCS weight gain was also seen more often in patients in these treatment arms. These information suggest a possible relationship between duloxetine dose and weight gain during longer-term handling, but farther study would be needed to ostend this.

In the relapse prevention written report (written report 9), patients treated with duloxetine 60 mg q.d. during the 12-calendar week, open-label, acute stage gained on boilerplate 0.one kg. Responders were and so randomly assigned to duloxetine 60 mg q.d. or placebo for an additional 26 weeks, during which time both duloxetine-treated and placebo-treated patients gained approximately i kg on average. This weight gain with placebo following successful acute treatment with duloxetine is particularly interesting, the about likely explanation perchance existence "normal" weight gain over time in successfully treated patients. The fact that patients who continued on duloxetine during continuation handling gained no more weight than placebo-treated patients during this time suggests that at its recommended dose of sixty mg q.d., duloxetine may non be associated with meaning weight change during longer-term treatment, although this needs further investigation. During the 52-calendar week open up-label study (report 10), duloxetine-treated patients gained a hateful of 1.one kg of weight.

Overall, these information suggest a pattern of acute weight loss with duloxetine, followed past weight proceeds subsequently longer-term treatment that appears modest and possibly dose-related. This design of long-term weight proceeds after astute weight loss has too been observed in studies of fluoxetine and sertraline.^{vi, 7} Of the studies presented here, the 52-week uncontrolled written report best approximates the feel of patients treated in existent clinical practice, and weight changes accompanying long-term treatment with duloxetine are therefore most likely to follow the patterns seen in this written report. Withal, it is unclear to what extent the mean one.1-kg weight gain seen in duloxetine-treated patients in this study is attributable to the issue of duloxetine treatment itself rather than other factors, such as normal weight gain over time. For example, in a review of private-practise patients with depression, the 72% of patients who remitted from depression gained an average of 6.four kg.²⁴ Patients who gained weight did not differ from patients who did non gain weight in terms of age, gender, diagnosis, duration of remission, or use of tricyclic antidepressants, tricyclic-SSRI combination, benzodiazepines, neuroleptics, and mood stabilizers. Benazzi²⁴ suggests that weight gain in remitted patients with depression is, at least in part, an consequence of recovery from depression rather than a pharmacologic upshot of antidepressants. In the 52-calendar week uncontrolled study, the patients who exhibited PCS weight proceeds, on average, weighed less and had lower BMI scores at baseline than those who did not experience PCS weight proceeds. Patients with a baseline BMI of ≤?25 kg/chiliad² experienced the greatest weight gain.

The negative correlation between change in HAM-D-17 full scores and change in weight indicates that patients tended to gain weight every bit their low improved. Although this correlation was highly significant, it was very small. Thus, the change in the HAM-D-17 total score may play but a small function in explaining the modify in weight. The fact that the hateful weight gain and improvement in the HAM-D-17 full score were greater amid the compliant patients than amongst the non-compliant patients suggests that the changes in weight and low symptoms are both, at least to some extent, related to duloxetine.

The analyses presented in this article take a number of limitations that merit consideration. First, the results must be considered in light of the dosing used for the active comparators. Although the 20-mg/day dose of paroxetine used in these studies is approved, commonly prescribed, and effective,²⁵ it is at the low end of the approved dose range. The aforementioned can be said for the 20-mg/twenty-four hour period dose of fluoxetine that was used in these studies. In contrast, the doses of duloxetine spanned its entire dose range. In retrospect, it would have been more than informative to practitioners if the studies had permitted the total dose range of the comparators. Second, because paroxetine and fluoxetine arms did not coexist in any study, the effects of these treatments on body weight could not be directly compared. Third, our ability to examine whether there is a relationship between duloxetine dose and weight alter is limited by the fact that the full dose range was non investigated within whatsoever private study. 4th, despite the large number of subjects overall, comparisons involving relatively rare events undoubtedly lacked acceptable statistical power. By contrast, some analyses of actual weight change had and so much ability that small differences were adamant to be statistically significant. Hence, emphasis should be placed on the number of subjects with particular events. Finally, although analyses of weight change, treatment-emergent adverse events, and adverse events reported as the reason for discontinuation were specified in each protocol, and betwixt-study variability was controlled for in the analyses, the determination to pool these data was not planned at the beginning of this research program.

Many factors may be taken into consideration when choosing the about appropriate antidepressant for a particular patient, including the effect of the drug on body weight. For the patient who is overweight, an antidepressant that induces pregnant weight gain may be less advisable. Furthermore, patient satisfaction, and hence adherence to the treatment regimen, may be negatively impacted past a drug that is associated with meaning weight gain in the short and long term.^ane In fact, patients are reluctant to be treated with a medication that has weight-related side furnishings.⁷

Duloxetine appears to have minimal curt-term and long-term effects on weight for the majority of patients and thus may bear witness to be an adequate therapy when furnishings on weight are a consideration in the selection of an antidepressant medication.

Drug names: bupropion (Wellbutrin and others), duloxetine (Cymbalta), fluoxetine (Prozac and others), paroxetine (Paxil, Pexeva, and others), sertraline (Zoloft and others), sibutramine (Meridia).

Footnotes

This piece of work was sponsored and funded by Eli Lilly and Co., Indianapolis, Ind.

Dr. Wise has consulted for Eli Lilly, Pfizer, and GlaxoSmithKline; has received grant/research support from Eli Lilly; has received honoraria from Eli Lilly, Pfizer, GlaxoSmithKline, and Bristol-Myers Squibb; and has served on the speakers or informational boards of Eli Lilly, Pfizer, GlaxoSmithKline, AstraZeneca, and Bristol-Myers Squibb. Drs. Perahia, Losin, and Wiltse and Ms. Pangallo are employees and stock shareholders of Eli Lilly.

The authors thank the Duloxetine Team, the clinical investigators and staff, and the many patients for their participation in the clinical studies that provided the information for this publication. We likewise thank David J. Goldstein, Yard.D., Ph.D., and Thomas C. Lee, M.A., for their contributions to early drafts of the manuscript; Sharie Sipowicz, B.Due south., for editorial assistance; and Barry Brolley, Chiliad.Due south., and Wenqi Y'all, M.S., for programming aid.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1764530/

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