Comparative efficacy between venlafaxine and SSRIs: a pooled analysis of patients with depression.

BACKGROUND: Serotonergic and adrenergic enhancement may be synergistic and more effective than serotonergic enhancement alone in treating depression. The dual serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine is a dual reuptake inhibitor that may therefore offer greater efficacy than selective serotonin reuptake inhibitors (SSRIs). METHODS: Data from eight randomized, double-blind, controlled studies were pooled to compare efficacy in depressed patients receiving venlafaxine/venlafaxine extended release (XR), SSRIs, or placebo for

Venlafaxine versus placebo in the preventive treatment of recurrent major depression.

BACKGROUND: Major depression is often chronic and recurrent, yet most long-term therapeutic trials are not adequately designed to assess antidepressant efficacy in recurrence prevention. Long-term efficacy and safety of prophylactic venlafaxine treatment were evaluated in outpatients with recurrent major depression. METHOD: Patients with a history of recurrent DSM-III-R major depression received open-label treatment with venlafaxine, 100 to 200 mg/day, for 6 months. Those who responded to treatment (Hamilton Rating Scale for Depression [HAM-D(21)] score < or = 12, day 56) and remained relapse-free (no more than 2 HAM-D(21) scores > 10 and no Clinical Global Impressions-Severity of Illness [CGI-S] score > or = 4, months 2-6) either continued taking venlafaxine, 100 to 200 mg/day, or were switched in a double-blind fashion to placebo for 12 months. The primary efficacy outcome was the number of patients experiencing a recurrence of major depression (CGI-S score > or = 4). The cumulative probability of recurrence was calculated using the Kaplan-Meier method of survival analysis. Data were collected from November 1992 through December 1995. RESULTS: Of the 235 patients who enrolled in the recurrence-prevention period, 225 (N = 109, venlafaxine; N = 116, placebo) provided efficacy data. Survival analysis determined a 22% cumulative probability of recurrence in venlafaxine-treated patients after 12 months compared with 55% for the placebo group (p <.001). More than twice as many placebo-treated patients (48%) as venlafaxine-treated patients (21%) discontinued treatment because of lack of efficacy (p <.001). CONCLUSION: Twelve-month maintenance venlafaxine treatment was significantly more efficacious than placebo in preventing major depression recurrence in patients who had been successfully treated with venlafaxine for 6 months.

Vagus nerve stimulation therapy randomized to different amounts of electrical charge for treatment-resistant depression: acute and chronic effects.

BACKGROUND: Major depressive disorder is a prevalent, disabling, and often chronic or recurrent psychiatric condition. About 35% of patients fail to respond to conventional treatment approaches and are considered to have treatment-resistant depression (TRD). OBJECTIVE: We compared the safety and effectiveness of different stimulation levels of adjunctive vagus nerve stimulation (VNS) therapy for the treatment of TRD. METHODS: In a multicenter, double blind study, 331 patients with TRD were randomized to one of three dose groups: LOW (0.25 mA current, 130 µs pulse width), MEDIUM (0.5-1.0 mA, 250 µs), or HIGH (1.25-1.5 mA, 250 µs). A highly treatment-resistant population (>97% had failed to respond to ≥6 previous treatments) was enrolled. Response and adverse effects were assessed for 22 weeks (end of acute phase), after which output current could be increased, if clinically warranted. Assessments then continued until Week 50 (end of long-term phase). RESULTS: VNS therapy was well tolerated. During the acute phase, all groups showed statistically significant improvement on the primary efficacy endpoint (change in Inventory of Depressive Symptomatology-Clinician Administered Version [IDS-C]), but not for any between-treatment group comparisons. In the long-term phase, mean change in IDS-C scores showed continued improvement. Post-hoc analyses demonstrated a statistically significant correlation between total charge delivered per day and decreasing depressive symptoms; and analysis of acute phase responders demonstrated significantly greater durability of response at MEDIUM and HIGH doses than at the LOW dose. CONCLUSIONS: TRD patients who received adjunctive VNS showed significant improvement at study endpoint compared with baseline, and the effect was durable over 1 year. Higher electrical dose parameters were associated with response durability.

Differential pattern of response in mood symptoms and suicide risk measures in severely ill depressed patients assigned to citalopram with placebo or citalopram combined with lithium: role of lithium levels.

The assumption that antidepressants may reduce suicide risk by reducing depressive symptoms is not based on data. Further, it is unclear if the retrospectively based anti-suicidal effects of lithium can be prospectively evaluated using lithium as an augmenting agent to antidepressants. To verify our hypothesis, we designed and conducted an exploratory proof of concept trial of four weeks duration using a randomized, double-blind, parallel group method. Forty patients were assigned to citalopram + lithium and 40 were assigned to citalopram + placebo. The primary dependent measures were the Sheehan-Suicidality Tracking Scale (S-STS) and the Montgomery-Asberg Depression Rating Scale (MADRS). The reduction of S-STS scores was large (43%) and twice that seen in MADRS scores (25%) among the eighty patients included in the trial. Both response (χ(2) = 8.8, p < 0.01) and remission (χ(2) = 4.6, p = 0.03) rates showed similar patterns. There were no significant differences in mean total S-STS change scores among patients assigned to citalopram with placebo (4.8 ± 5.1) and patients assigned to citalopram with lithium (5.1 ± 5.2). When explored further, a subgroup of the patients assigned to citalopram and lithium achieved therapeutic serum levels and had significantly higher S-STS remission rates (45% compared to 19%, p < 0.05). There were no deaths by suicide or other causes indicating that trials enrolling acutely suicidal patients are feasible. These results suggest that citalopram may have a direct therapeutic effect on suicidal thoughts and behaviors. Further, lithium when used in therapeutic doses may augment such effects. These data warrant further exploration of lithium and an antidepressant combination for anti-suicidal effects.

Can improvement in well-being and functioning be distinguished from depression improvement in antidepressant clinical trials?

The Inventory of General Life Functioning (GLF), a self-evaluation scale for patients, was developed for use in the National Institute of Mental Health Treatment of Depression Collaborative Research Program. The scale was designed to evaluate patient general well-being and functioning, areas not adequately covered by standard depression scales. We used the patient self-report version of the GLF in two imipramine-controlled clinical trials during the development of the antidepressant venlafaxine. In these double-blind studies, outpatients with depression received placebo (n = 158), venlafaxine (n = 152), or imipramine (n = 149) for up to 6 weeks. We examined the internal consistency and factor structure of the GLF, its correlation with standard depression rating scales, and its sensitivity to differential treatment effects. We found the scale to be internally consistent and moderately correlated with physician-rated measures of depression. A reported two-factor structure (general well-being and functioning) was evaluated by factor analysis. When analyses were restricted to patients who completed at least 4 weeks on therapy, the GLF displayed sensitivity to differential treatment effects. The GLF total and factor subscales demonstrated the superiority of an active therapy (venlafaxine) to placebo; the GLF factor and a 7-item subscale using only items derived from Dupuy's psychological general well-being index (PGWB) demonstrated an advantage for one active therapy (venlafaxine) over another (imipramine). The GLF is a useful complement to the standard depression rating scales because it may assess additional dimensions of the depressive syndrome.