Short-term augmentation of fluoxetine with clonazepam in the treatment of depression: a double-blind study. A placebo-controlled multicenter trial of Limbitrol versus its components (amitriptyline and chlordiazepoxide) in the symptomatic treatment of depressive illness. Comparative effects of limbitrol and amitriptyline on sleep efficiency and architecture. Is extended clonazepam cotherapy of fluoxetine effective for outpatients with major depression? Hypnotics as concurrent medication in depression. A placebo-controlled, double-blind comparison of flunitrazepam and lormetazepam in patients with major depression, treated with a (tri)cyclic antidepressant. A double blind study in out-patients with primary non-agitated depression treated with imipramine in combination with placebo, diazepam or dixyrazine. Alprazolam: an antidepressant? Alprazolam, desipramine, and an alprazolam-desipramine combination in the treatment of adult depressed outpatients.
Because selective serotonin reuptake inhibitors (SSRIs) require 2-4 weeks to reach efficacy, the authors determined whether clonazepam augmentation of fluoxetine is superior to fluoxetine alone at the beginning of treatment for major depression.
                Eighty adult outpatients with major depression who were rated as "moderately ill" or "markedly ill" on the Clinical Global Impression of Severity underwent 8 weeks of double-blind, randomized treatment with fluoxetine, 20 mg/day for all patients initially and 40 mg/day if needed after 6 weeks. One-half of these patients received clonazepam, 0.5 mg h.s. adjusted to two tablets by day 10 if needed, and the remainder received placebo, likewise adjusted. Clonazepam/placebo was gradually discontinued during days 21-33. Efficacy was evaluated by means of the Hamilton Depression Rating Scale, the Clinical Global Impression of Improvement, and a patient rating of global improvement.
                The patients taking clonazepam improved significantly more during the first 3 weeks of treatment according to ratings on the Hamilton scale (> or =50% improvement) and the clinician- and patient-rated global improvement measures ("much" or "very much" improved). Analysis of variance confirmed a significant effect of clonazepam for average Hamilton depression scores. No serious adverse events were found in either treatment group. Taper effects appeared modest and transitory.
                Clonazepam augmentation of fluoxetine was superior to fluoxetine alone in the first 3 weeks of treatment. This strategy may reduce suffering during early SSRI treatment, may partially suppress SSRI side effects, may increase compliance, and could possibly reduce the risk of suicide. In a multicenter, placebo-controlled, clinical trial, the efficacy of Limbitrol was compared with that of its components, amitriptyline and chlordiazepoxide. All patients had a diagnosis of primary depression. Data from 279 patients were evaluated using the Hamilton depression scale, the Beck depression inventory, and physician and patient global change measures. Statistically significant differences favoring Limbitrol occurred after 1 week of treatment, and a trend in favor of Limbitrol continued throughout the remaining 3 weeks. In most efficacy comparisons, the combination was as good as, or better than, amitriptyline alone. It was superior to chlordiazepoxide alone after 2 and 4 weeks of treatment. Each component produced an independent contribution to the total therapeutic effect: the chlordiazepoxide effect was more prominent in the first 2 weeks and the amitriptyline effect in the latter 2 weeks. A trend favoring amitriptyline over chlordiazepoxide was evident by week 4. The overall incidence of side effects was comparable in both Limbitrol- and amitriptyline-treated groups. Limbitrol-treated patients exhibited more sedation, but significantly fewer Limbitrol patients discontinued treatment prematurely because of side effects. Chlordiazepoxide-amitriptyline (Limbitrol) has been shown to be more rapidly effective than amitriptyline alone for treating depression. A double-blind, randomized study was designed to compare the effects of Limbitrol and amitriptyline on insomnia, anxiety, and depression. The rate of improvement of symptoms was faster with Limbitrol. No differences were noted between groups in the degree or rate of improvement of the sleep laboratory parameters nor in sleep Stages 1 to 4. Percentages of rapid eye movement (REM) sleep and REM latency were similarly affected by the drugs, but REM density showed a significantly greater decrease with Limbitrol. Phasic REM factors may be crucial in the role of REM sleep and depression. Clonazepam cotherapy of fluoxetine was previously demonstrated to accelerate efficacy over the first 3 weeks of treatment. A new 18-week double-blind study attempted to replicate these findings to determine whether superiority would extend to 3 months and assess risks of extension.
                Fifty outpatient volunteers aged 18-65 from Seattle and Portland with moderate-marked depression received fluoxetine (20 mg) doubled at 6 weeks if needed; half took clonazepam (0.5 mg) and half took an identical placebo, 1 or 2 tablets adjusted during the first 2 weeks, until a 3-week taper at 3 months.
                No serious adverse events and no special problems with sedation or discontinuation were noted. Cotherapy was superior to fluoxetine monotherapy at Day 7 for HAM-D (t=2.03, df=48, P<0.05) and CGI-I (32 vs. 4% responders, P<0.03, Fisher Exact Test) but not otherwise. Cotherapy was effective in reducing insomnia but not anxiety or core symptoms (low mood, suicidality, reduced interest). The only significant benefit of extending treatment was a more rapid response to increased fluoxetine at 6 weeks manifested in a mean HAM-D of 9.0 and CGI-I responder rate of 76% after 8 weeks compared to 16 weeks for monotherapy.
                Small sample size (N=50) limited power and rendered conclusions tentative.
                Extended clonazepam cotherapy of fluoxetine appeared safe and effective for depressed outpatients: it was superior to fluoxetine alone early in treatment and again following fluoxetine dose increase. Cotherapy might be considered at the start of fluoxetine treatment, especially for those with insomnia, and when a dose increase of fluoxetine is anticipated.
                Copright 2002 Elsevier Science BV. The addition of benzodiazepine hypnotics to a treatment with tricyclic antidepressants has received little systematic study. In a double-blind placebo-controlled design, the effects on mood and on sleep of two benzodiazepine hypnotics (lormetazepam and flunitrazepam) were studied in patients with major depression who were also treated with maprotiline or nortriptyline. After 4 weeks of combined treatment, lormetazepam resulted in a significantly greater decrease in the score on the Hamilton Depression Subscale than placebo, while there was a non-significant trend in favour of lormetazepam in comparison with flunitrazepam. With respect to sleep EEGs, lormetazepam resulted in a significantly greater suppression of REM sleep. The differences between lormetazepam and flunitrazepam may be partly explained by the shorter half-live of lormetazepam. Sixty-three out-patients suffering from primary non-agitated depression were included in a double-blind, between-patient randomized study. All patients were treated with imipramine (100-200 mg-day) combined with either placebo, diazepam (10 mg/day) or dixyrazine (50 mg/day) for 8 weeks. The clinical efficacy assessed with a subscale of CPRS was significantly (p1 less than or equal to 0.05) better for the imipramine-dixyrazine combination than for the imipramine-diazepam or imipramine-placebo combination. Serum concentration of imipramine was significantly higher (p1 less than or equal to 0.05) in the group treated with dixyrazine than in the other two groups. Further, serum concentration of imipramine in the diazepam group was significantly lower (p1 less than or equal to 0.05) than in the placebo group. At the end of the study, 67% in both the placebo and the diazepam group and 86% in the dixyrazine group were practically symptom-free. The antidepressant efficacy of alprazolam (ALP) was tested in a double-blind controlled comparison with desipramine (DMI) and an ALP-DMI combination in outpatients diagnosed with major depressive disorder by Research Diagnostic Criteria (90% met criteria for endogenous subtype). Following a placebo period of at least 1 week, subjects who continued to meet severity criteria defined by Hamilton Depression Rating Scale (HDRS) scores were administered oral doses of the active medication (N = 79), in a dose ratio of 1 mg ALP:50 mg DMI:1 mg ALP + 50 mg DMI. Treatment continued for 6 weeks, and all subjects who completed at least 2 weeks (N = 69) were included in endpoint analyses. Following the placebo baseline, symptoms were rated again at day 5 and at the end of weeks 1, 2, 4, and 6. Final doses averaged 4.6 +/- 1.3 mg for the ALP group, 230 +/- 61 mg for the DMI group, and 4.6 +/- 1.2 mg ALP + 229.5 +/- 1.2 mg DMI for the combination group. The final outcome was a comparable degree of improvement at the endpoint among the three treatment groups on measures of depression (HDRS and Beck Depression Inventory), anxiety (Hamilton Anxiety Rating Scale), and global improvement (Global Assessment Scale, and Physician and Patient Global Impressions). A similar outcome was found for the subgroup of patients who completed all 6 weeks (N = 56). Endpoint analyses also showed that ALP-treated subjects responded sooner and continued to show improvement throughout the course of the study on measures of depression, anxiety, and global status. These results suggest that ALP alone is as effective as a standard tricyclic for the acute treatment of patients with major depressive disorder and that significant improvement may occur within the first week of medication. Side effect profiles were compared among treatment groups and are discussed, as are other clinical studies that have investigated ALP's potential antidepressant efficacy.
The potential benefits of adding a benzodiazepine to an antidepressant must be balanced judiciously against possible harms including development of dependence and accident proneness, on the one hand, and against continued suffering following no response and drop out, on the other.