Two Phase III randomised double-blind studies of fixed-dose TC-5214 (dexmecamylamine) adjunct to ongoing antidepressant therapy in patients with major depressive disorder and an inadequate response to prior antidepressant therapy.

OBJECTIVES: To evaluate the neuronal nicotinic channel modulator TC-5214 (dexmecamylamine) as adjunct therapy in patients with major depressive disorder (MDD) and inadequate response to prior antidepressant treatment. METHODS: Study 004 (D4130C00004) and Study 005 (D4130C00005) comprised an 8-week open-label antidepressant (SSRI/SNRI) treatment period followed by an 8-week randomised, active treatment with twice-daily TC-5214 (0.5, 2 or 4 mg in Study 004; 0.1, 1 or 4 mg in Study 005) or placebo, adjunct to ongoing SSRI/SNRI. Primary efficacy endpoint was change in MADRS total score from randomisation (Week 8) to treatment end (Week 16). Secondary endpoints included MADRS response and remission, and changes in SDS and HAM-D-17-item scores. Safety and tolerability were monitored throughout. RESULTS: Studies 004 and 005 randomised 640 and 696 patients, respectively, to TC-5214 or placebo. No statistically significant improvements in MADRS total score or any secondary endpoints were seen with TC-5214 versus placebo in either study at treatment end. The most commonly reported adverse events (> 10%) with TC-5214 were constipation, dizziness and dry mouth. CONCLUSIONS: TC-5214 adjunct to antidepressant was generally well tolerated. However, the studies were not supportive of an antidepressant effect for TC-5214 in patients with MDD and inadequate response to prior antidepressant therapy.

Efficacy and tolerability of flexibly-dosed adjunct TC-5214 (dexmecamylamine) in patients with major depressive disorder and inadequate response to prior antidepressant.

This paper reports the efficacy and tolerability of the nicotinic channel modulator TC-5214 (dexmecamylamine) as adjunct therapy for patients with major depressive disorder who have an inadequate response to initial antidepressant treatment in 2 Phase III studies. These double-blind, placebo-controlled studies (NCT01157078, D4130C00002 [Study 002] conducted in the US and India; NCT01180400, D4130C00003 [Study 003] conducted in Europe) comprised 8 weeks of open-label antidepressant treatment followed by 8 weeks of active treatment during which patients were randomized to flexibly-dosed TC-5214 1-4 mg twice daily (BID) or placebo as an adjunct to ongoing therapy with SSRI/SNRI. The primary efficacy endpoint in both studies was change in Montgomery Åsberg Depression Rating Scale (MADRS) total score from randomization (week 8) to treatment end (week 16). Secondary endpoints included change in Sheehan Disability Scale and Hamilton Depression Rating Scale 17-item scores. Study 002 randomized 319 patients and Study 003 randomized 295 patients to TC-5214 or placebo. At treatment end, no significant differences were seen for change in MADRS total score with TC-5214 versus placebo. Furthermore, there were no significant differences in any of the secondary endpoints. The most commonly reported (≥ 10%) adverse events with TC-5214 in these studies were constipation and headache. In these 2 flexibly-dosed studies, no specific therapeutic effects were observed for TC-5214 (1-4 mg BID) adjunct to antidepressant in the primary endpoint or any secondary endpoint; however, TC-5214 was generally well tolerated. In conclusion, no antidepressant effect of TC-5214 was observed in these studies.

A randomised, placebo-controlled 52-week trial of continued quetiapine treatment in recently depressed patients with bipolar I and bipolar II disorder.

OBJECTIVES: To examine the longer-term efficacy of quetiapine monotherapy in bipolar depression in a preplanned pooling of data from the EMBOLDEN I and II studies. METHODS: Patients (N = 584) with bipolar I or II disorder (most recent episode: depressed) who achieved remission after 8 weeks of treatment with quetiapine (300 or 600 mg/day) were randomised to the same quetiapine dose or placebo for 26-52 weeks or until mood event recurrence. RESULTS: The risk for recurrence of a mood event was significantly lower with quetiapine than placebo (HR 0.51 (95% CI: 0.38-0.69); < 0.001). Quetiapine was associated with a lower risk for recurrence of depressive events (HR 0.43 (95% CI: 0.30-0.62); P < 0.001) but recurrence of manic/hypomanic events was not significantly reduced (HR 0.75 (95% CI: 0.45-1.24; P = 0.263). There was a lower risk of recurrence of mood events in bipolar I (HR 0.58 (95% CI: 0.41-0.82), P = 0.002) and bipolar II patients (HR 0.33 (95% CI: 0.18-0.60), P < 0.001). Discontinuation rates due to adverse events were 4.3, 4.0 and 1.7% for quetiapine 300 mg/day, 600 mg/day and placebo, respectively. Safety data, including changes in lipid and glucose parameters, were consistent with the recognized profile of quetiapine. CONCLUSIONS: The efficacy of quetiapine monotherapy in bipolar depression is maintained during continued treatment for 26-52 weeks. Quetiapine was generally well tolerated.

Efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) monotherapy in patients with generalised anxiety disorder: an analysis of pooled data from three 8-week placebo-controlled studies.

OBJECTIVE: Prospectively planned pooled analysis evaluating efficacy and tolerability of acute quetiapine XR monotherapy in generalised anxiety disorder. METHODS: Data from three 10-week, randomised, double-blind, placebo-controlled studies of similar design were analysed. RESULTS: At Week 8, Hamilton Anxiety Rating Scale (HAM-A) total score significantly improved with quetiapine XR: least squares means change -13.31, p < 0.001 (50 mg/day, n = 452), -14.39, p < 0.001 (150 mg/day, n = 673) and -12.50, p < 0.05 (300 mg/day, n = 444) versus -11.30 placebo; significant (p < 0.001, n = 665) improvements versus placebo were observed with each dose at Week 1. Significant improvements versus placebo at Week 8 are as follows: HAM-A psychic symptom subscale, Montgomery-Åsberg Depression Rating Scale total, Pittsburgh Sleep Quality Index global scores for all quetiapine XR doses; HAM-A response and remission rates, HAM-A somatic symptom subscale score, Clinical Global Impression-Severity of Illness total score, % patients with Clinical Global Impression-Improvement score ≤2 with quetiapine XR 50 and 150 mg/day; and Quality of Life Enjoyment and Satisfaction Questionnaire short form % maximum total score with quetiapine XR 150 mg/day. In the quetiapine XR 50, 150 and 300 mg/day and placebo groups, 13.2%, 16.5%, 24.0% and 5.4% of patients discontinued because of an adverse event, and 1.9%, 1.4%, 3.7% and 1.8% of patients experienced clinically significant changes in glucose. The most common adverse events with quetiapine XR included dry mouth, somnolence, sedation and constipation. CONCLUSION: Quetiapine XR monotherapy reduced the symptoms of generalised anxiety disorder, with improvement from Week 1. Adverse events were consistent with the known tolerability profile of quetiapine.

Extended release quetiapine fumarate (quetiapine XR) monotherapy as maintenance treatment for generalized anxiety disorder: a long-term, randomized, placebo-controlled trial.

The objective of this study was to evaluate the efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) as maintenance monotherapy for patients with generalized anxiety disorder (GAD). Time-to-event (anxiety symptom recurrence; maximum 52 weeks) multicenter, randomized-withdrawal, parallel-group, double-blind, placebo-controlled study of quetiapine XR (50-300 mg/day) following open-label run-in (4-8 weeks) and open-label stabilization (≥ 12 weeks). Primary variable: time from randomization to anxiety event. Secondary variables included: Hamilton Anxiety Rating Scale (HAM-A) total, HAM-A psychic/somatic anxiety factors, Clinical Global Impression-Severity of Illness (CGI-S), and Quality of Life, Enjoyment and Satisfaction Questionnaire (Q-LES-Q) scores; adverse events (AE) reporting. Four hundred and thirty-two patients, stabilized on quetiapine XR, were randomized to continue quetiapine XR (N=216) or switch to placebo (N=216). Risk of anxiety symptom recurrence was significantly reduced by 81% for quetiapine XR versus placebo: hazard ratio=0.19 (95% confidence interval 0.12-0.31; P<0.001). Fewer patients receiving quetiapine XR (N=22, 10.2%) than placebo (N=84, 38.9%) experienced anxiety symptom recurrence. Significant differences were observed between quetiapine XR and placebo in: HAM-A total, psychic/somatic, CGI-S (all P<0.001) and Q-LES-Q (P<0.05) scores. AEs (>10%) during open-label treatment were dry mouth, sedation, somnolence, dizziness, fatigue, and constipation. During randomized treatment, the most common AEs for quetiapine XR were headache and nasopharyngitis. Quetiapine XR monotherapy reduced the risk of anxiety symptom recurrence in patients with GAD stabilized on quetiapine XR, with tolerability results consistent with the known profile of quetiapine.

A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II).

OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of quetiapine and paroxetine monotherapy for major depression in bipolar disorder. METHOD: 740 patients (478 bipolar I, 262 bipolar II) with major depressive episodes (DSM-IV) were randomly assigned to quetiapine 300 mg/d (n = 245), quetiapine 600 mg/d (n = 247), paroxetine 20 mg/d (n = 122), or placebo (n = 126) for 8 weeks. The primary end point was the change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score. The study was conducted from May 2005 to May 2007. RESULTS: Mean MADRS score change from baseline at 8 weeks was -16.19 for quetiapine 300 mg, -16.31 for quetiapine 600 mg, -13.76 for paroxetine, and -12.60 for placebo (P < .001 for both quetiapine doses, P = .313 for paroxetine, vs placebo). Quetiapine-treated (both doses), but not paroxetine-treated, patients showed significantly greater improvements (P < or = .05) in most secondary outcomes measures at week 8 versus the placebo group. Paroxetine significantly improved Hamilton Anxiety Rating Scale scores versus placebo (P < .05) but not MADRS or Hamilton Depression Rating Scale (HDRS) scores. Both quetiapine doses were associated with greater improvements than paroxetine for MADRS and HDRS scores. The most common adverse events were dry mouth, somnolence, sedation, and dizziness with quetiapine (both doses) and dry mouth, sedation, headache, insomnia, and nausea with paroxetine. The incidence of treatment-emergent mania/hypomania was lower with quetiapine compared with paroxetine and placebo. CONCLUSIONS: Quetiapine (300 or 600 mg/d), but not paroxetine, was more effective than placebo for treating acute depressive episodes in bipolar I and II disorder. Quetiapine treatment was generally well tolerated. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00119652.

A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I).

OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of quetiapine and lithium monotherapy with that of placebo for a major depressive episode in bipolar disorder. METHOD: 802 patients with DSM-IV-defined bipolar disorder (499 bipolar I, 303 bipolar II) were randomly allocated to quetiapine 300 mg/d (n = 265), quetiapine 600 mg/d (n = 268), lithium 600 to 1800 mg/d (n = 136), or placebo (n = 133) for 8 weeks. Primary endpoint was the change in Montgomery-Asberg Depression Rating Scale (MADRS) total score. The study was conducted from August 2005 to May 2007. RESULTS: Mean MADRS total score change from baseline at week 8 was -15.4 for quetiapine 300 mg/d, -16.1 for quetiapine 600 mg/d, -13.6 for lithium, and -11.8 for placebo (P < .001 for both quetiapine doses, P = .123 for lithium, vs placebo). Quetiapine 600 mg/d was significantly more effective than lithium in improving MADRS total score at week 8 (P = .013). Quetiapine-treated (both doses), but not lithium-treated, patients showed significant improvements (P < .05) in MADRS response and remission rates, Hamilton Depression Rating Scale (HDRS), Clinical Global Impressions-Bipolar-Severity of Illness and -Change, and Hamilton Anxiety Rating Scale (HARS) scores at week 8 versus placebo. Both quetiapine doses were more effective than lithium at week 8 on the HDRS and HARS. The most common adverse events were somnolence, dry mouth, and dizziness with quetiapine (both doses) and nausea with lithium. CONCLUSIONS: Quetiapine (300 or 600 mg/d) was more effective than placebo for the treatment of episodes of acute depression in bipolar disorder. Lithium did not significantly differ from placebo on the main measures of efficacy. Both treatments were generally well tolerated. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00206141.

Nocifensive behaviors components evoked by brief laser pulses are mediated by C fibers.

Nocifensive behavior involves several response elements that have been used to assess neuropharmacological effects in different animal models of pain. Our previous analysis of laser-evoked nocifensive behaviors suggested that hierarchically organized responses in the nocifensive motor system are recruited in varying degrees by noxious stimuli of different intensities. Nocifensive behaviors can be differentially elicited and mediated by different classes of nociceptors. Thus, the aim of this study was to test the hypothesis that nocifensive behavioral elements elicited by brief laser pulse stimuli are mediated by C nociceptors. Laser-evoked cortical potentials and nocifensive behavior elements were recorded concurrently. As stimulus energy increased, rats exhibited a larger number of different responses and a greater frequency of each response element. Applying the neurotoxin, capsaicin, which selectively inhibits C fibers, to the sciatic nerves of rats, differentially blocked nocifensive behavioral components of flinch, withdrawal and licking but not non-nocifensive responses, namely movement and head turning. Based on these results we suggest that flinch, withdrawal and licking are mediated by C fibers, which are temporally associated with the nocifensive motor system as well as spinal and cortical evoked potentials. These results link hierarchically organized nocifensive responses and the afferent C fibers in the nocifensive motor system.

Sympathetic nerve activity after acupuncture in humans.

The aim of the present study was to determine if acupuncture stimulation inhibits sympathetic nerve activity in humans. Multiunit efferent postganglionic sympathetic activity was recorded with a tungsten microelectrode inserted in a muscle fascicle of the peroneal nerve. Mean arterial pressure, heart rate and skin blood flow were also monitored. Pain thresholds were measured by electrical tooth pain stimulation. After a 30 min rest, acupuncture needles were inserted bilaterally into the Li 11 and the Li 4 acupuncture points, and manipulated until 'chi' cramp-like sensation was reported. Electrical stimulation (2 Hz, 0.6-0.8 ms duration, maximal tolerated stimulation without discomfort) was delivered for 30 min and the physiological recordings were continued for 90 min after the end of acupuncture. In a placebo control experiment, the same procedure was followed, except that acupuncture needles were inserted subcutaneously and no manipulation or stimulation was given. The stimulator delivered pulses to an unconnected channel, hence, the same audiovisual stimuli were experienced as with acupuncture, and care was taken to ask the same questions about sensations in the placebo and the acupuncture groups. Electroacupuncture produced an increase in pain threshold which was paralleled by a transient increase in muscle sympathetic nerve activity. During acupuncture, there was a small increase in heart rate and mean arterial pressure, but there was no post-acupuncture hypotension. The placebo control procedure did not change pain threshold or sympathetic nerve traffic. The findings suggest that electroacupuncture produces moderate hypoalgesia in humans paralleled by a significant increase in muscle sympathetic nerve activity.