A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain.

BACKGROUND: Serotonin (5-HT) and norepinephrine (NE) are involved in pain modulation via descending inhibitory pathways in the brain and spinal cord. OBJECTIVE: To assess the efficacy of duloxetine, a dual reuptake inhibitor of 5-HT and NE, on the reduction of pain severity, as well as secondary outcome measures in patients with diabetic peripheral neuropathic pain (DPNP). METHODS: In this double-blind study, patients with DPNP and without comorbid depression were randomly assigned to treatment with duloxetine 60 mg once daily (QD), duloxetine 60 mg twice daily (BID), or placebo for 12 weeks. The primary outcome measure was the weekly mean score of 24-hour average pain severity on the 11-point Likert scale. Secondary measures and health outcome measures were also assessed. RESULTS: Duloxetine 60 mg QD and 60 mg BID demonstrated improvement in the management of DPNP and showed rapid onset of action, with separation from placebo beginning at week 1 on the 24-hour average pain severity score. For all secondary measures for pain (except allodynia), mean changes showed an advantage of duloxetine over placebo, with no significant difference between 60 mg QD and 60 mg BID. Clinical Global Impression of Severity and Patient's Global Impression of Improvement evaluation demonstrated greater improvement on duloxetine- vs placebo-treated patients. Duloxetine showed no notable interference on diabetic controls, and both doses were safely administered. CONCLUSIONS: This study confirms previous findings that duloxetine at 60 mg QD and 60 mg BID is effective and safe in the management of diabetic peripheral neuropathic pain.

Duloxetine versus routine care in the long-term management of diabetic peripheral neuropathic pain.

INTRODUCTION: Duloxetine hydrochloride is a dual reuptake inhibitor of both serotonin and norepinephrine. In the present open-label study, the safety of duloxetine at a fixed-dose of 60 mg twice daily (BID) for up to 52 weeks was evaluated and compared to routine care in the therapy of patients diagnosed with diabetic peripheral neuropathic pain (DPNP). METHODS: Patients who completed a 13-week, double-blind, duloxetine and placebo acute therapy period were rerandomly assigned in a 2:1 ratio to therapy with duloxetine 60 mg BID (N=161) or routine care (N=76) for an additional 52 weeks. Routine care consisted primarily of gabapentin, amitriptyline, and venlafaxine. The study included male or female outpatients 18 years of age or older with a diagnosis of DPNP caused by type 1 or type 2 diabetes. RESULTS: A higher percentage of routine care-treated patients experienced 1 or more serious adverse events. No statistically significant therapy-group difference was observed in the overall incidence of treatment-emergent adverse events (TEAEs). The TEAEs reported by 10% or more of duloxetine 60 mg BID-treated patients were nausea, and by the routine care-treated patients were peripheral edema, pain in the extremity, somnolence, and dizziness. Duloxetine did not appear to adversely affect glycemic control, lipid profiles, nerve function, or the course of DPNP. There were no statistically significant therapy-group differences observed in the 36-item Short-Form Health Survey subscales or in the EuroQol 5-Dimension Questionnaire. CONCLUSIONS: In this study, duloxetine was safe and well tolerated compared to routine care in the long-term management of patients with DPNP.

Fibromyalgia syndrome.

The objectives of the first OMERACT Fibromyalgia Syndrome (FM) Workshop were to identify and prioritize symptom domains that should be consistently evaluated in FM clinical trials, and to identify aspects of domains and outcome measures that should be part of a concerted research agenda of FM researchers. Such an effort will help standardize and improve the quality of outcomes research in FM. A principal assumption in this workshop has been that there exists a clinical syndrome, generally known as FM, characterized by chronic widespread pain typically associated with fatigue, sleep disturbance, mood disturbance, and other symptoms and signs, and considered to be related to central neuromodulatory dysregulation. FM can be diagnosed using 1990 American College of Rheumatology criteria. In preparation for the workshop a Delphi exercise involving 23 FM researchers was conducted to establish a preliminary prioritization of domains of inquiry. At the OMERACT meeting, the workshop included presentation of the Delphi results; a review of placebo-controlled trials of FM treatment, with a focus on the outcome measures used and their performance; a panel discussion of the key issues in FM trials, from both an investigator and regulatory agency perspective; and a voting process by the workshop attendees. The results of the workshop were presented in the plenary session on the final day of the meeting. A prioritized list of domains of FM to be investigated was thus developed, key issues and controversies in the field were debated, and consensus on a research agenda on outcome measure development was reached.

Efficacy and safety of atomoxetine in childhood attention-deficit/hyperactivity disorder with comorbid oppositional defiant disorder.

OBJECTIVE: To compare the safety and efficacy of atomoxetine, a selective inhibitor of the norepinephrine transporter, versus placebo in Attention-Deficit/Hyperactivity Disorder (ADHD) patients with comorbid Oppositional Defiant Disorder (ODD). METHODS: A subset analysis of 98 children from two identical, multi-site, double-blind, randomized, placebo-controlled trials involving 9 weeks of treatment with atomoxetine or placebo was conducted. Patients met DSM-IV ADHD criteria. ODD was diagnosed with the Diagnostic Interview for Children and Adolescents-IV (DICA-IV; Reich, Weiner, and Herjanic, 1997). ADHD severity was assessed with the ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHD-RS-IV-Parent:lnv; DuPaul, Power, Anastopoulos, and Reid, 1998); the short version of the Conners' Parent Rating Scales-Revised (CPRS-R:S; Conners, 2000); and the Clinical Global Impressions of ADHD Severity (CGI-ADHD-S; Guy, 1976). Clinical response was defined as a > or = 25% reduction in ADHD-RS-IV-Parent:lnv total score. RESULTS: ADHD-RS-IV-Parent:lnv, CGI-ADHD-S, and three CPRS-R:S subscale scores improved markedly with atomoxetine treatment. However, a decrease in the CPRS-R:S Oppositional subscore for atomoxetine-treated patients was not significantly greater than scores for placebo-treated patients. Clinical response rates were 65.4% in the atomoxetine group, and 36.4% in the placebo group (p = .007). CONCLUSION: Atomoxetine was effective for the treatment of ADHD in patients with comorbid ODD. It did not significantly reduce the severity of ODD symptoms, and was well tolerated by the patients.

Safety profile of atomoxetine in the treatment of children and adolescents with ADHD.

Atomoxetine is a selective norepinephrine reuptake inhibitor that is being developed for the treatment of attention-deficit/hyperactivity disorder (ADHD). Atomoxetine will be the first nonstimulant medication approved by the U.S. Food and Drug Administration (FDA) for the treatment of ADHD. Throughout the testing phases, more than 2000 children and adolescents have been exposed to atomoxetine in clinical trials, with both the number of exposures and the length of exposure time increasing. Serious adverse events have not been clearly associated with the drug, and there have been few discontinuations due to adverse events. The most common drug-related event reported in trials has been decreased appetite and an initial period of weight loss followed by an apparently normal rate of weight gain. These events tend to appear early in the course of treatment with atomoxetine and then decline. Atomoxetine has also been associated with mild increases in blood pressure and pulse that plateau during treatment and resolve upon discontinuation. There have been no effects seen on the QT interval, and the cytochrome P450 2D6 metabolism of patients seems to have little effect on safety or tolerability of the drug. This article will review the data from completed and ongoing clinical trials available at the time the New Drug Application was submitted to the FDA. Described are serious adverse events, discontinuations, and treatment-emergent adverse events. Specifically, cardiac effects and effects on weight, height, and metabolism that are related to treatment of ADHD with atomoxetine in children and adolescents are discussed.

A noradrenergic and serotonergic hypothesis of the linkage between epilepsy and affective disorders.

Noradrenergic and/or serotonergic deficits, as well as other abnormalities, may contribute to predisposition to some epilepsies and depressions. Evidence for this hypothesis stems from several sources. Epidemiological investigations are intriguing but incomplete. Pharmacological studies show that noradrenergic and/or serotonergic transmission are both anticonvulsant and antidepressant. Therapeutically pertinent investigations show that antidepressant drugs have anticonvulsant properties, whereas antiepileptic drugs are effective in the management of affective disorders. Additional investigations demonstrate that seizures, whether spontaneously occurring or therapeutically induced, protect against depression. Through studies of innate pathophysiology, noradrenergic and serotonergic deficits have been identified in individuals with depression and in animal models of epilepsy, as well as in some humans with epilepsy. Vagal nerve stimulation, a treatment already known to be effective in the epilepsies, is presently under investigation for effectiveness in affective disorder. New evidence suggests that vagal nerve stimulation exerts at least some of its therapeutic effects through its capacity to increase noradrenergic and serotonergic transmission. Finally, emerging evidence supports the concept that some genetic mammalian models of the human epilepsies exhibit analogous manifestations of depression.

Fluoxetine and concomitant centrally acting medication use during clinical trials of depression: the absence of an effect related to agitation and suicidal behavior.

Concomitant use of psychoactive medications is a common practice in most clinical trials of antidepressant medications. However, the relative therapeutic impact of such use on trial results has not been the subject of much attention. We conducted a meta-analysis to determine whether concomitant use of psychoactive medications confounded the efficacy or safety results of a series of fluoxetine trials. Data were evaluated from 25 randomized, double-blind clinical trials comparing fluoxetine with placebo or a tricyclic antidepressant (TCA) in 4,016 patients with major depression. We compared incidence rates of concomitant use of anxiolytics, sedatives, and antipsychotics between treatments. In addition, we compared the change in total score for the 21-Item Hamilton Depression Rating Scale (HAMD21): incidence rates of any worsening, emergence, or improvement in psychomotor agitation; and incidence of suicidal acts and any worsening, emergence, or improvement in suicidal ideation between treatment groups among patients taking/not taking a sedative. Anxiolytic and antipsychotic drug use was uncommon (8.3% and 0.9% overall use, respectively) and did not substantially increase over time. Sedative drugs were used most often (29.6% overall), but only 29.8% of the fluoxetine-treated patients took one or more doses. Regarding efficacy, fluoxetine was superior to placebo in decreasing HAMD21 total scores among patients taking/not taking sedatives. Effects on safety were assessed by examining agitation and suicidal ideation. Use of sedatives did not affect the change in the HAMD agitation score; scores were similar in patients receiving fluoxetine, placebo, and TCAs. In all treatment groups, anxiolytic use tended to increase as the HAMD anxiety score increased. Fluoxetine was superior to placebo in treating suicidal ideation, and the concomitant use of sedatives did not influence this effect. Overall, concomitant use of psychotropic medications in the fluoxetine depression clinical trials was uncommon. Our meta-analysis demonstrated that the clinical efficacy and safety of fluoxetine were not confounded by the concomitant use of medications.

Vagus nerve stimulation for the treatment of medically intractable seizures. Results of a 1-year open-extension trial. Vagus Nerve Stimulation Study Group.

BACKGROUND: Chronic vagus nerve stimulation (VNS) continues to be evaluated as an adjunctive treatment for medically intractable seizures. A previous randomized controlled trial of 114 patients demonstrated a significant decrease in seizure frequency during 3 months of VNS at effective stimulation levels. OBJECTIVE: To evaluate the efficacy of 1 year of VNS therapy for the treatment of medically refractory partial seizures and the relationship between initial and long-term response. PATIENTS AND METHODS: All patients exiting the randomized controlled study of VNS for treatment of medically refractory partial seizures were offered indefinite treatment extension as part of an open-label trial. One hundred (88%) of 114 patients completed 12 months of VNS treatment at effective stimulation levels. Fourteen patients discontinued VNS treatment prior to 1 year, principally because of the treatment's lack of efficacy. These 14 patients were retained in the present analysis using an intent-to-treat approach. Antiepileptic drug use was monitored throughout the trial. Seizure frequency was analyzed in 4 sequential 3-month treatment periods. RESULTS: Compared with pretreatment baseline, there was a significant decrease in seizure frequency during each of the 3-month treatment periods. Seizure frequency was reduced by a median of 20% during the first 3 months of VNS treatment and by 32% during stimulation months 10 through 12. Response during the first 3 months of VNS treatment was a statistically significant predictor of response at months 10 through 12. The observed reduction in seizure frequency was not explained by overall changes in antiepileptic drug use. CONCLUSIONS: The results indicate that VNS remains an effective adjunctive therapy for medically refractory partial seizures over a period of at least 1 year. Response during the first 3 months of treatment is predictive of long-term response.

Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizures.

Electrical stimulation of the vagus nerve (VNS) is a new method for the treatment of patients with medically intractable epilepsy. Sixteen patients, ten of whom participated in a larger multicenter double-blind trial on the efficacy of VNS in epilepsy, and six who participated in pilot studies, consented to participate in the present study. Ten patients received HIGH stimulation and six patients LOW stimulation for the 3-month trial. Cerebrospinal fluid (CSF) samples (16 ml) were collected both before and after 3 months of VNS. Amino acid and neurotransmitter metabolites were analyzed. Four patients responded to VS with more than a 25% seizure reduction after 3 months. Mean and median concentrations of phosphoethanolamine (PEA) increased in responders and decreased in nonresponders. Free GABA increased in both groups but more so in the nonresponders. After 9 months of VS (6-9 months on HIGH stimulation) 4 of 15 patients had more than 40% seizure reduction. There were significant correlations between seizure reduction and increases in asparagine, phenylalanine, PEA, alanine and tryptophan concentrations. Comparison between patients with HIGH or LOW stimulation showed a significant increase in ethanolamine (EA) in the HIGH group and a decrease in glutamine in the LOW group. All patients regardless of response or stimulation intensity showed significantly increased total and free GABA levels. A decrease in CSF aspartate was marginally significant. Other trends were decreases in glutamate and increases in 5-hydroxyindoleacetic acid. Chronic VNS appears to have an effect on various amino acids pools in the brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Safety and tolerability of the implantable recurrent laryngeal nerve stimulator.

The recurrent laryngeal nerve (RLN) stimulator has been implanted on a limited basis since 1988 for control of spasmodic dysphonia. A similar vagus nerve stimulator has been implanted in a larger series of patients to control epilepsy. The safety and tolerability of these two stimulators were evaluated. In 113 patients implanted with the vagus nerve stimulator, the complication rate was 0.9%. All patients were monitored for vital signs, electrocardiographic changes, and adverse effects. The absence of changes in vital signs and electrocardiograms during vagal stimulation establishes the safety of this treatment. Since placement of the electrode around the vagus nerve is an easier surgical technique than placement deep to the RLN, it seems reasonable to change the technique to implant the stimulator on the vagus in patients with spasmodic dysphonia.

Vagus nerve stimulation for treatment of partial seizures: 1. A controlled study of effect on seizures. First International Vagus Nerve Stimulation Study Group.

Vagus nerve stimulation (VNS) was shown to reduce seizure frequency in refractory epilepsy patients in two pilot studies. Based on these results, a multicenter, prospectively randomized, parallel, double-blind study of patients with refractory partial seizures was initiated. After a 12-week baseline period, identical vagus nerve stimulators were implanted and patients randomized to either a high or low 14-week VNS treatment paradigm. The primary objective was to demonstrate that high VNS (therapeutic parameters) was more effective in reducing partial seizure frequency than was low VNS (less or noneffective parameters). Patients continued receiving antiepileptic drugs (AEDs) with plasma concentrations held constant throughout the study. We report results of the first 67 patients to exit the 14-week acute phase. After 14 weeks of VNS, 31 patients receiving high VNS experienced a mean seizure frequency percentage reduction of 30.9%, which was statistically significant as compared with the mean seizure frequency percentage reduction of 11.3% in 36 patients receiving low VNS (p = 0.029, t test; p = 0.036, Wilcoxon rank-sum test). In addition to the significant intragroup p-values, mean seizure frequency percentage change reached statistical significance for high VNS (p < 0.001) but not low VNS (p = 0.072) as compared with baseline. Twelve of 31 (38.7%) patients receiving high VNS achieved at least 50% reduction in seizure frequency whereas 7 of 36 (19.4%) patients receiving low VNS experienced at least 50% reduction after 14 weeks. The implant procedure and VNS therapy were well tolerated. Our study confirmed the effectiveness of VNS as treatment for epilepsy patients with refractory partial seizures.

Vagus nerve stimulation for treatment of partial seizures: 2. Safety, side effects, and tolerability. First International Vagus Nerve Stimulation Study Group.

Vagus nerve stimulation (VNS) significantly reduces the frequency of partial seizures in refractory epilepsy patients. We examined the serious adverse events, side effects, and tolerability as they relate to the surgical implant procedure and the stimulating device. We also reviewed potential drug interactions, device output complications, and impact of the therapy on overall health status. We analyzed the first 67 patients to exist the acute phase of the EO3 VNS trial comparing high (therapeutic) VNS to low (less or noneffective) VNS. Data were collected from case report forms used at each of the four visits during the 12-week baseline and at each of the four visits during the 14-week randomized phase of the trial. No significant complications were reported as a result of the implant procedure. Serious adverse events included 1 patient who experienced direct current to the vagus nerve owing to generator malfunction resulting in left vocal cord paralysis and withdrawal of the patient from the study. No clinically significant effects on vital signs, cardiac function, or gastric function were detected. Side effects associated with VNS in the high group were hoarseness (35.5%), coughing (13.9%), and throat pain (12.9%). In the low group, only hoarseness (13.9%) and throat pain (13.9%) were associated with VNS. These effects generally wrre not considered clinically significant and occurred primarily during the stimulation pulses. No patients discontinued VNS therapy during the acute phase because of side effects associated with normal stimulation. Except for the one instance of a short circuit in the system resulting in a direct current, stimulating system complications were minor, limited to programming, unscheduled stimulation, and high lead impedance. Patients, investigators, and patient companions rated patients receiving high stimulation as more "improved" than those receiving low stimulation in regards to overall health status. Antiepileptic drug (AED) plasma concentrations were not affected by VNS. The implant procedure, stimulating system, and therapy proved safe and tolerable during the study. The high percentage (67 of 68) of patients completing the study reflects patient acceptance and tolerability of this mode of therapy.

Vagus nerve stimulation for treatment of partial seizures: 3. Long-term follow-up on first 67 patients exiting a controlled study. First International Vagus Nerve Stimulation Study Group.

Vagus nerve stimulation (VNS) has demonstrated a significant anticonvulsant effect in preclinical studies, in pilot studies in humans, and in the acute phase of a multicenter, double-blinded, randomized study. After completion of a 14-week, blinded, randomized study, with 31 receiving high (therapeutic) VNS and 36 receiving low (less or noneffective) VNS, 67 patients elected to continue in an open extension phase. During the extension phase, all 67 patients received high VNS. Seizure frequency during the 3-month treatment blocks was compared with a 12-week baseline. For both groups, all periods of high VNS demonstrated a significant decrease in seizure frequency (p < 0.01 level) as compared with baseline. For the 16-18-month period of VNS, data were available for 26 of the 31 patients randomized to high VNS. This group achieved a 52.0% mean seizure frequency percentage reduction as compared with baseline. For those converted from low to high VNS, data were available for 24 of the 36 patients at the 16-18-month time period. This group reported a mean seizure frequency percentage reduction of 38.1% as compared with baseline. No significant change in the safety/side effect profile was reported during long-term follow-up. The previously reported side effects of hoarseness/voice change, coughing, and paresthesia (sensation in neck and jaw) continued to occur during VNS. These side effects were well tolerated. During the follow-up period, 1 patient died of thrombotic thrombocytopenic purpura (TTP) and 5 patients discontinued treatment because of unsatisfactory efficacy.

Treatment of epilepsy by stimulation of the vagus nerve.

We treated 14 patients with medically refractory partial seizures by stimulation of the vagus nerve in two single-blind pilot studies. Patients received stimulation through an implantable, programmable NeuroCybernetic Prosthesis, consisting of a pulse generator and a lead-electrode assembly. The mean reduction in seizure frequency after 14 to 35 months of vagal stimulation was 46.6%. Of the 14 patients, five (35.7%) had a 50% or greater reduction in seizure frequency. Two patients, one of whom had had 10 to 100 seizures per day before stimulation, have been seizure-free for over 1 year. Adverse events were primarily limited to initial hoarseness and a tingling sensation at the electrode site in the neck when the device was activated. Most patients tolerated the device and stimulation well. There were no permanent adverse events. Some cases of medically refractory partial seizures are improved by vagal stimulation.

Clinical experience with a helical bipolar stimulating lead.

Over 100 patients have been treated for partial epilepsy using a NeuroCybernetic Prosthesis System (NCP). The NCP System is comprised of an implantable pulse generator, an implantable bipolar stimulating lead, and an external communication system. The lead delivers electrical impulses from the NCP Generator to the vagus nerve, and includes a connector end that plugs into the generator, a silicone insulated lead body, and the helical electrode array that attaches to the nerve. The surgical implantation technique has a significant impact on lead reliability and performance. The lead electrode has performed well to date. Modifications to further improve reliability have been implemented. Clinical experience, case history examples, and voltage measurements are examined. The lead electrode is an important component of the overall system and plays a significant part in the success of vagus nerve stimulation therapy.

Treatment of refractory partial seizures: preliminary results of a controlled study.

Vagus nerve stimulation for the treatment of epilepsy has been studied in medically refractory patients with partial seizures in a randomized, blinded, parallel study. After a 3-month baseline period, the patients were implanted with the Neurocybernetic Prosthesis (NCP) system consisting of the NCP Generator and the Bipolar Vagal Stimulation Lead. Two stimulation paradigms were used, HIGH, which delivers what is considered to be optimal stimulation parameters and LOW, which is considered to be less or noneffective. The system and vagus nerve stimulation were well tolerated and few adverse events have been attributed to either. One patient experienced a period of direct current to the nerve due to a generator malfunction. This results in paralysis of the left vocal cord. Efficacy analysis on the first 37 patients to complete the controlled portion of the study has shown that the patients in the HIGH group experienced a mean reduction in seizure frequency of 33.3% and patients in the LOW group experienced a mean reduction in seizure frequency of 8.4%. The difference between the groups is statistically significant with a P value of 0.025. Analysis of seizure duration and intensity does not show any significant change. Ratings of the patient's overall condition by the patient, investigator, and companion as a measurement of "quality of life" also show improvement in the HIGH group. The results of this interim study demonstrate that vagus nerve stimulation is a safe and effective method of treating partial epileptic seizures.

High-dose fluoxetine: efficacy and activating-sedating effects in agitated and retarded depression.

The effects of high-dose fluoxetine (median 80 mg/day), standard-dose imipramine (median 200 mg/day), and placebo were studied in 706 outpatients meeting DSM-III criteria for major depressive disorder. Baseline psychomotor activity of each patient was prospectively categorized as agitated, retarded, or neither. Rates of occurrence of total and significant (leading to discontinuation) activating adverse events (insomnia, agitation, anxiety, nervousness) and sedating events (somnolence, asthenia) were compared between treatments on an overall basis and within categories of baseline psychomotor activity. Additionally, these rates were compared across baseline psychomotor activity for each treatment. Efficacy was evaluated on an overall basis and with respect to baseline psychomotor activity. There was more total activation with fluoxetine than placebo (p = 0.008), but total activation with fluoxetine (28%) showed only a trend (p = 0.092) for being greater than with imipramine (21%). Discontinuations for activation with fluoxetine (5%) did not differ from imipramine (5%). Sedation and discontinuations for sedation with both fluoxetine and imipramine significantly exceeded placebo. The only drug-drug difference in discontinuations was for sedation where imipramine (11%) exceeded fluoxetine (5%; p = 0.008). Only for the occurrence of sedation with imipramine (47% among patients retarded at baseline) was there a significant association with baseline psychomotor activity (p = 0.021). Both fluoxetine and imipramine were superior to placebo and equal in efficacy in decreasing total Hamilton Rating Scale for Depression (HAM-D), the sleep disturbance HAM-D factor, and the anxiety/somatization HAM-D factor scores. These improvements were independent of baseline psychomotor activity.

Approaches for the development of oral drug therapies for erectile dysfunction.

Currently, there are no effective oral drug therapies for the treatment of sexual dysfunction. The intent of this review was to outline the new research strategies that have emanated from experimental and clinical observations. These strategies include pharmacologic modification of cellular responses within the ventral diencephalon, brain stem, spinal cord, and penis, which represent segments of the erectile response systems. Although it is theoretically possible to treat sexual dysfunction by targeting any one of these segments, a single approach would most likely benefit only a subgroup of patients. Erectile dysfunction patients may have characteristics of several disorders, in which case combined drug therapies may be more useful. The goal of the current research is to define the regulation of sexual function at each segment of the response loop and to apply this knowledge to the treatment of the diverse disorders that contribute to erectile dysfunction.

Pattern analysis shows beneficial effect of fluoxetine treatment in mild depression.

In a multicentered study, 372 patients with mild major depressive disorder with a Hamilton Rating Scale for Depression (HAM-D) score of 15 to 19 were randomly assigned to 6 weeks of treatment with placebo or 20 mg, 40 mg, or 60 mg/day of fluoxetine. Patients were rated weekly for improvement and the appearance of side effects. Pattern analysis of treatment response showed more patients in the active drug treatment groups having a persistent or a delayed persistent response, the types of response specifically associated with active treatment. Analyses of mean changes in treatment measures showed little difference among treatment groups. This may be explained in part by different distributions in outcome, placebo patients having had a higher frequency of mild improvement with fewer negative and very positive outcomes. Response rate analyses favor the active treatments numerically, but only one of the comparisons is statistically significant. These findings suggest a specific role for fluoxetine treatment in mildly depressed patients who do not respond promptly or who respond inconsistently to nonspecific treatment.

Fluoxetine: relationships among dose, response, adverse events, and plasma concentrations in the treatment of depression.

Data from two large, fixed-dose trials support the efficacy of a fixed 20 mg/day dose of fluoxetine in the treatment of depression. Data pooled from these two studies suggest a dose relationship for adverse events during fluoxetine therapy. At a fixed 20 mg/day dose, only nausea and insomnia were reported by a significantly greater percentage of patients (p less than .05) than those treated with placebo. However, at 60 mg/day, nausea, anxiety, dizziness, and insomnia were reported by a significantly greater percentage of patients (p less than .05) than those treated with placebo. The potential relationship of response rate [Hamilton Rating Scale for Depression (HAM-D) total decrease greater than or equal to 50%] to plasma concentrations of fluoxetine, norfluoxetine, and fluoxetine plus norfluoxetine was evaluated in one study which excluded early responders (less than or equal to 3 weeks of therapy). No significant relationship was found. Furthermore, adverse events were not related to plasma concentrations.