Three- vs four-drug antiretroviral regimens for the initial treatment of HIV-1 infection: a randomized controlled trial

Context  Three-drug antiretroviral regimens are standard of care for initial treatment of human immunodeficiency virus 1 (HIV-1) infection, but a 4-drug regimen could improve antiretroviral activity and be more effective than a 3-drug regimen. Objective  To compare the safety/efficacy of 3-drug vs 4-drug regimens for initial treatment of HIV-1 infection. Design  The AIDS Clinical Trials Group (ACTG) A5095 study, a randomized, double-blind, placebo-controlled study with enrollment and follow-up conducted from March 22, 2001, to March 1, 2005, and enrolling treatment-naive, HIV-1–infected patients with HIV-1 RNA levels of 400 copies/mL or greater from US clinical trials units of the ACTG. Interventions  Zidovudine/lamivudine plus efavirenz (3-drug regimen) vs zidovudine/lamivudine/abacavir plus efavirenz (4-drug regimen). Main Outcome Measures  Time to virologic failure (defined as time to first of 2 successive HIV-1 RNA levels 200 copies/mL at or after week 16), CD4 cell count changes, and grade 3 or 4 adverse events. HIV-1 RNA data were intent-to-treat, regardless of treatment changes. Results  Seven hundred sixty-five patients with a baseline mean HIV-1 RNA level of 4.86 log₁₀ (72 444) copies/mL and CD4 cell count of 240 cells/mm³ were randomized. After a median 3-year follow-up, 99 (26%) of 382 and 94 (25%) of 383 patients receiving the 3-drug and 4-drug regimens, respectively, reached protocol-defined virologic failure; time to virologic failure was not significantly different (hazard ratio, 0.95; 97.5% confidence interval, 0.69-1.33; P = .73). In planned subgroup analyses, increased risk for virologic failure was seen in non-Hispanic black patients (adjusted hazard ratio, 1.66; 95% confidence interval, 1.18-2.34; P = .003). At 3 years, the HIV-1 RNA level was less than 200 copies/mL in 152 (90%) of 169 and 143 (92%) of 156 patients receiving the 3-drug and 4-drug regimens, respectively (P = .59), and less than 50 copies/mL in 144 (85%) of 169 and 137 (88%) of 156 patients (P = .39). CD4 cell count increases and grade 3 or 4 adverse events were not significantly different. Conclusions  In treatment-naive patients, there were no significant differences between the 3-drug and 4-drug antiretroviral regimens; overall, at least approximately 80% of patients had HIV-1 RNA levels less than 50 copies/mL through 3 years. These results support current guidelines recommending 2 nucleosides plus efavirenz for initial treatment of HIV-1 infection; adding abacavir as a fourth drug provided no additional benefit. Clinical Trials Registration  clinicaltrials.gov Identifier: NCT00013520      

Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial

Context  Decompensated congestive heart failure (CHF) is the leading hospital discharge diagnosis in patients older than 65 years. Objective  To compare the efficacy and safety of intravenous nesiritide, intravenous nitroglycerin, and placebo. Design, Setting, and Patients  Randomized, double-blind trial of 489 inpatients with dyspnea at rest from decompensated CHF, including 246 who received pulmonary artery catheterization, that was conducted at 55 community and academic hospitals between October 1999 and July 2000. Interventions  Intravenous nesiritide (n = 204), intravenous nitroglycerin (n = 143), or placebo (n = 142) added to standard medications for 3 hours, followed by nesiritide (n = 278) or nitroglycerin (n = 216) added to standard medication for 24 hours. Main Outcome Measures  Change in pulmonary capillary wedge pressure (PCWP) among catheterized patients and patient self-evaluation of dyspnea at 3 hours after initiation of study drug among all patients. Secondary outcomes included comparisons of hemodynamic and clinical effects between nesiritide and nitroglycerin at 24 hours. Results  At 3 hours, the mean (SD) decrease in PCWP from baseline was –5.8 (6.5) mm Hg for nesiritide (vs placebo, P<.001; vs nitroglycerin, P = .03), –3.8 (5.3) mm Hg for nitroglycerin (vs placebo, P = .09), and –2 (4.2) mm Hg for placebo. At 3 hours, nesiritide resulted in improvement in dyspnea compared with placebo (P = .03), but there was no significant difference in dyspnea or global clinical status with nesiritide compared with nitroglycerin. At 24 hours, the reduction in PCWP was greater in the nesiritide group (-8.2 mm Hg) than the nitroglycerin group (-6.3 mm Hg), but patients reported no significant differences in dyspnea and only modest improvement in global clinical status. Conclusion  When added to standard care in patients hospitalized with acutely decompensated CHF, nesiritide improves hemodynamic function and some self-reported symptoms more effectively than intravenous nitroglycerin or placebo.      

Superior virological efficacy of ritonavir-boosted protease inhibitor regimens compared to single protease inhibitor therapy

Low dose-ritonavir boosted protease inhibitors are increasingly being used for the first-line antiretroviral treatment, though their virological efficacy has just poorly been compared to alternative antiretroviral therapies. Here, we retrospectively investigated the virological responses of 316 protease inhibitor-naive HIV patients receiving highly active antiretroviral treatment based on a single (n = 256) or a ritonavir-boosted protease inhibitor (n = 60), both in the background of two nucleoside analogues. - By intent-to-treat analysis, a complete initial virological response was achieved in 71.8% of all patients in the single protease inhibitor group (indinavir: 76%, ritonavir: 67.5%, nelfinavir: 70.6%) and in 88.3% (p = 0.008) of patients treated with a boosted protease inhibitor (saquinavir/r: 71.4%, indinavir/r: 92.1%, lopinavir/r: 86.6%). The multivariate risk analysis identified boosted PI treatment as an independent predictor of a complete virological response (OR = 2.8, p=0.02). Viral rebound after an initial complete virological response was observed in 28% and 17% (p = 0.06) of patients receiving a single or a dual protease inhibitor, respectively. The rate of durable viral suppression over 12 months was 44.5% and 56.7% (p = 0.09) in the respective study cohorts. Ritonavir-boosted protease inhibitors therefore seem to induce a superior virological response rate and a higher degree of sustained virological suppression.     

Efficacy and safety of adefovir dipivoxil with antiretroviral therapy: a randomized controlled trial

CONTEXT: Adefovir dipivoxil is a nucleotide analog that has demonstrated effective antiretroviral activity against human immunodeficiency virus (HIV) with once-daily administration. OBJECTIVE: To determine if adefovir confers antiretroviral or immunologic benefit when added to stable antiretroviral therapy. DESIGN: Multicenter, 24-week, randomized, double-blind, placebo-controlled study. Enrollment was conducted from June 3, 1996, through May 6, 1997. SETTING: Thirty-three US HIV treatment centers. PARTICIPANTS: Of 1171 patients screened, 442 patients infected with HIV receiving stable antiretroviral therapy for at least 8 weeks with plasma HIV RNA greater than 2500 copies/mL and CD4+ cell count above 0.20 x 10(9)/L were randomized. INTERVENTION: Patients were randomized to receive either a single 120-mg/d dose of adefovir dipivoxil (n = 219) or an indistinguishable placebo (n = 223). All patients received L-carnitine, 500 mg/d. Open-label adefovir was offered after 24 weeks and was continued until the end of the study. MAIN OUTCOME MEASURES: Changes in HIV RNA from baseline, based on area under the curve and CD4+ cell levels, adverse events, and effect of baseline genotypic resistance on response to adefovir. RESULTS: Patients assigned to adefovir demonstrated a 0.4-log10 decline from baseline in HIV RNA compared with no change in the placebo group (P<.001), which continued through 48 weeks. CD4+ cell counts did not change. During the initial 24 weeks, elevated hepatic enzyme levels (P<.001), gastrointestinal tract complaints (P<.001), and weight loss (P<.001) were associated with use of adefovir. Between 24 weeks and 48 weeks elevations in serum creatinine occurred in 60% of patients, usually returning to baseline after discontinuation of adefovir. Patients with lamivudine or lamivudine and zidovudine resistance mutations demonstrated anti-HIV effects with adefovir (P< or =.01 vs placebo group). CONCLUSIONS: This study suggests that once-daily adefovir therapy reduces HIV RNA and is active against isolates resistant to lamivudine or lamivudine and zidovudine. Nephrotoxicity occurred when treatment extended beyond 24 weeks but was reversible.     

Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial

Context  Insomnia is a common condition in older adults and is associated with a number of adverse medical, social, and psychological consequences. Previous research has suggested beneficial outcomes of both psychological and pharmacological treatments, but blinded placebo-controlled trials comparing the effects of these treatments are lacking. Objective  To examine short- and long-term clinical efficacy of cognitive behavioral therapy (CBT) and pharmacological treatment in older adults experiencing chronic primary insomnia. Design, Setting, and Participants  A randomized, double-blinded, placebo-controlled trial of 46 adults (mean age, 60.8 y; 22 women) with chronic primary insomnia conducted between January 2004 and December 2005 in a single Norwegian university-based outpatient clinic for adults and elderly patients. Intervention  CBT (sleep hygiene, sleep restriction, stimulus control, cognitive therapy, and relaxation; n = 18), sleep medication (7.5-mg zopiclone each night; n = 16), or placebo medication (n = 12). All treatment duration was 6 weeks, and the 2 active treatments were followed up at 6 months. Main Outcome Measures  Ambulant clinical polysomnographic data and sleep diaries were used to determine total wake time, total sleep time, sleep efficiency, and slow-wave sleep (only assessed using polysomnography) on all 3 assessment points. Results  CBT resulted in improved short- and long-term outcomes compared with zopiclone on 3 out of 4 outcome measures. For most outcomes, zopiclone did not differ from placebo. Participants receiving CBT improved their sleep efficiency from 81.4% at pretreatment to 90.1% at 6-month follow-up compared with a decrease from 82.3% to 81.9% in the zopiclone group. Participants in the CBT group spent much more time in slow-wave sleep (stages 3 and 4) compared with those in other groups, and spent less time awake during the night. Total sleep time was similar in all 3 groups; at 6 months, patients receiving CBT had better sleep efficiency using polysomnography than those taking zopiclone. Conclusion  These results suggest that interventions based on CBT are superior to zopiclone treatment both in short- and long-term management of insomnia in older adults. Trial Registration  clinicaltrials.gov Identifier: NCT00295386      

Moderate- vs high-dose methadone in the treatment of opioid dependence: a randomized trial

Context  Methadone hydrochloride treatment is the most common pharmacological intervention for opioid dependence, and recent interest has focused on expanding methadone treatment availability beyond traditional specially licensed clinics. However, despite recommendations regarding effective dosing of methadone, controlled clinical trials of higher-dose methadone have not been conducted. Objective  To compare the relative clinical efficacy of moderate- vs high-dose methadone in the treatment of opioid dependence. Design  A 40-week randomized, double-blind clinical trial starting in June 1992 and ending in October 1995. Setting  Outpatient substance abuse treatment research clinic at the Johns Hopkins University Bayview Campus, Baltimore, Md. Participants  One hundred ninety-two eligible clinic patients. Intervention  Daily oral methadone hydrochloride in the dose range of 40 to 50 mg (n=97) or 80 to 100 mg (n=95), with concurrent substance abuse counseling. Main Outcome Measures  Opioid-positive urinalysis results and retention in treatment. Results  By intent-to-treat analysis, through week 30 patients in the high-dose group had significantly lower rates of opioid-positive urine samples compared with patients in the moderate-dose group (53.0% [95% confidence interval {CI}, 46.9%-59.2%] vs 61.9% [95% CI, 55.9%-68.0%]; P = .047). These differences persisted during withdrawal from methadone. Through day 210 no significant difference was evident between dose groups in treatment retention (high-dose group mean retention, 159 days; moderate-dose group mean retention, 157 days). Nineteen (33%) of 57 patients in the high-dose group and 11 (20%) of 54 patients in the moderate-dose group completed detoxification. Conclusions  Both moderate- and high-dose methadone treatment resulted in decreased illicit opioid use during methadone maintenance and detoxification. The high-dose group had significantly greater decreases in illicit opiod use.      

Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial

Context  In patients with brain metastases, it is unclear whether adding up-front whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) has beneficial effects on mortality or neurologic function compared with SRS alone. Objective  To determine if WBRT combined with SRS results in improvements in survival, brain tumor control, functional preservation rate, and frequency of neurologic death. Design, Setting, and Patients  Randomized controlled trial of 132 patients with 1 to 4 brain metastases, each less than 3 cm in diameter, enrolled at 11 hospitals in Japan between October 1999 and December 2003. Interventions  Patients were randomly assigned to receive WBRT plus SRS (65 patients) or SRS alone (67 patients). Main Outcome Measures  The primary end point was overall survival; secondary end points were brain tumor recurrence, salvage brain treatment, functional preservation, toxic effects of radiation, and cause of death. Results  The median survival time and the 1-year actuarial survival rate were 7.5 months and 38.5% (95% confidence interval, 26.7%-50.3%) in the WBRT + SRS group and 8.0 months and 28.4% (95% confidence interval, 17.6%-39.2%) for SRS alone (P = .42). The 12-month brain tumor recurrence rate was 46.8% in the WBRT + SRS group and 76.4% for SRS alone group (P<.001). Salvage brain treatment was less frequently required in the WBRT + SRS group (n = 10) than with SRS alone (n = 29) (P<.001). Death was attributed to neurologic causes in 22.8% of patients in the WBRT + SRS group and in 19.3% of those treated with SRS alone (P = .64). There were no significant differences in systemic and neurologic functional preservation and toxic effects of radiation. Conclusions  Compared with SRS alone, the use of WBRT plus SRS did not improve survival for patients with 1 to 4 brain metastases, but intracranial relapse occurred considerably more frequently in those who did not receive WBRT. Consequently, salvage treatment is frequently required when up-front WBRT is not used. Trial Registration  umin.ac.jp/ctr Identifier: C000000412      

Splinting vs surgery in the treatment of carpal tunnel syndrome: a randomized controlled trial

Context  Carpal tunnel syndrome (CTS) can be treated with nonsurgical or surgical options. However, there is no consensus on the most effective method of treatment. Objective  To compare the short-term and long-term efficacy of splinting and surgery for relieving the symptoms of CTS. Design, Setting, and Patients  A randomized controlled trial conducted from October 1998 to April 2000 at 13 neurological outpatient clinics in the Netherlands. A total of 176 patients with clinically and electrophysiologically confirmed idiopathic CTS were assigned to wrist splinting during the night for at least 6 weeks (89 patients) or open carpal tunnel release (87 patients); 147 patients (84%) completed the final follow-up assessment 18 months after randomization. Main Outcome Measures  General improvement, number of nights waking up due to symptoms, and severity of symptoms. Results  In the intention-to-treat analyses, surgery was more effective than splinting on all outcome measures. The success rates (based on general improvement) after 3 months were 80% for the surgery group (62/78 patients) vs 54% for the splinting group (46/86 patients), which is a difference of 26% (95% confidence interval [CI], 12%-40%; P<.001). After 18 months, the success rates increased to 90% for the surgery group (61/68 patients) vs 75% for the splinting group (59/79 patients), which is a difference of 15% (95% CI, 3%-27%; P = .02). However, by that time 41% of patients (32/79) in the splint group had also received the surgery treatment. Conclusion  Treatment with open carpal tunnel release surgery resulted in better outcomes than treatment with wrist splinting for patients with CTS.      

Amoxicillin-clavulanate vs ciprofloxacin for the treatment of uncomplicated cystitis in women: a randomized trial

Context  The high prevalence of resistance to trimethoprim-sulfamethoxazole and other antimicrobials among Escherichia coli causing acute cystitis in women has led to increased use of alternative antibiotics. One such antibiotic, amoxicillin-clavulanate, has not been well studied. Objective  To compare the efficacy of a 3-day regimen of amoxicillin-clavulanate to that of a 3-day regimen of ciprofloxacin in the treatment of acute cystitis in women. The primary study hypothesis was that the amoxicillin-clavulanate and ciprofloxacin treatment groups would differ in clinical cure. Design, Setting, and Patients  Randomized, single-blind treatment trial of 370 women, aged 18 to 45 years, with symptoms of acute uncomplicated cystitis and a urine culture with at least 10² colony-forming units of uropathogens per milliliter from a university student health center or a health maintenance organization. Interventions  Women were randomly assigned to receive amoxicillin-clavulanate (500 mg/125 mg twice daily) or ciprofloxacin (250 mg twice daily) for 3 days and were followed up for 4 months. Main Outcome Measures  The main outcome measure was clinical cure. Secondary study outcomes of interest were microbiological cure and vaginal E coli colonization at the 2-week follow-up visit. Results  Clinical cure was observed in 93 (58%) of 160 women treated with amoxicillin-clavulanate compared with 124 (77%) of 162 women treated with ciprofloxacin (P<.001). Amoxicillin-clavulanate was not as effective as ciprofloxacin even among women infected with strains susceptible to amoxicillin-clavulanate (65 [60%] of 109 women in the amoxicillin-clavulanate group vs 114 [77%] of 149 women in the ciprofloxacin group; P = .004). The difference in clinical cure rates occurred almost entirely within the first 2 weeks after therapy. Microbiological cure at 2 weeks was observed in 118 (76%) of 156 women treated with amoxicillin-clavulanate compared with 153 (95%) of 161 women treated with ciprofloxacin (P<.001). At this visit, 45% of women in the amoxicillin-clavulanate group compared with 10% in the ciprofloxacin group had vaginal colonization with E coli (P<.001). Conclusions  A 3-day regimen of amoxicillin-clavulanate is not as effective as ciprofloxacin for the treatment of acute uncomplicated cystitis, even in women infected with susceptible strains. This difference may be due to the inferior ability of amoxicillin-clavulanate to eradicate vaginal E coli, facilitating early reinfection.      

Controlled delivery of high vs low humidity vs mist therapy for croup in emergency departments: a randomized controlled trial

Context  Children with croup are often treated with humidity even though this is not scientifically based, consumes time, and can be harmful. Although humidity using the traditional blow-by technique is similar to room air and no water droplets reach the nasopharynx, particles sized for laryngeal deposition (5-10 µm) could be beneficial. Objective  To determine whether a significant difference in the clinical Westley croup score exists in children with moderate to severe croup who were admitted to the emergency department and who received either 100% humidity or 40% humidity via nebulizer or blow-by humidity. Design and Setting  A randomized, single-blind, controlled trial conducted between 2001 and 2004 in a tertiary care pediatric emergency department. Participants  A convenience sample of 140 previously healthy children 3 months to 10 years of age with Westley croup score of more than 1 or 2 or higher (scoring system range, 0-17); 21 families refused participation. Intervention  Thirty-minute administration of humidity using traditional blow-by technique (commonly used placebo, n = 48), controlled delivery of 40% humidity (optimally delivered placebo, n = 46), or 100% humidity (n = 46) with water particles of mass median diameter 6.21 µm. Main Outcome Measure  A priori defined change in the Westley croup score from baseline to 30 and 60 minutes in the 3 groups. Results  Groups were comparable before treatment. At 30 minutes the difference in the improvement in the croup score between the blow-by and low-humidity groups was 0.03 (95% confidence interval [CI], –0.72 to 0.66), between low- and high-humidity groups, 0.16 (95% CI, –0.86 to 0.53), and between blow-by and high-humidity groups, 0.19 (95% CI, –0.87 to 0.49). Results were similar at 60 minutes. Differences between groups in pulse and respiratory rates and oxygen saturation changes were insignificant, as were proportions of excellent responders; proportions with croup score of 0 at study conclusion; and proportions receiving dexamethasone, epinephrine, or requiring additional medical care or hospitalization. Conclusions  One hundred percent humidity with particles specifically sized to deposit in the larynx failed to result in greater improvement than 40% humidity or humidity by blow-by technique. This study does not support the use of humidity for moderate croup for patients treated in the emergency department. Trial Registration  ClinicalTrials.gov Identifier: NCT00230841      

Two-dose intrapartum/newborn nevirapine and standard antiretroviral therapy to reduce perinatal HIV transmission: a randomized trial

Context  A 2-dose intrapartum/newborn nevirapine regimen reduced perinatal humanimmunodeficiency virus (HIV) transmission in Ugandan women not receiving antenatalantiretroviral therapy (ART). However, it is unknown whether the additionof the 2-dose nevirapine regimen to standard ART would further reduce perinatalHIV transmission. Objective  To determine whether a 2-dose nevirapine regimen can decrease perinataltransmission of HIV in nonbreastfeeding women receiving standard ART. Design and Setting  International, blinded, placebo-controlled, phase 3 trial enrollingwomen between May 1997 and June 2000 at clinical sites providing care forHIV infection throughout the United States, Europe, Brazil, and the Bahamas. Participants  A total of 1270 women received nevirapine (n = 642) or placebo (n =628). Infants were followed up for 6 months to determine HIV-infection status,which was available for 1248 deliveries. Intervention  A 200-mg dose of oral nevirapine to women after onset of labor and a2-mg/kg dose of oral nevirapine to newborns between 48 and 72 hours afterbirth. Main Outcome Measures  Detection of HIV infection in infants and grade 3 and 4 toxic effectsin women and newborns. Results  After review by the data and safety monitoring board, the trial wasstopped early because the overall transmission rates were significantly lowerthan assumed for the study design. Antenatal ART included zidovudine alonein 23%; combinations without protease inhibitors in 36%; and combinationswith protease inhibitors in 41%. Thirty-four percent of women had electivecesarean delivery. No significant safety concerns were identified for womenor infants. Detection of HIV infection occurred in 9 (1.4%; 95% confidenceinterval [CI], 0.6%-2.7%) of 631 nevirapine group deliveries and 10 (1.6%;95% CI, 0.8%-2.9%) of 617 placebo group deliveries. The 95% CI for the differencein transmission rate (-0.2) between the 2 study arms ranged from -1.5%in favor of nevirapine to 1.2% in favor of placebo (P= .82, Fisher exact test). The transmission rate was higher in women withlower baseline CD4 cell counts and higher delivery HIV RNA levels, but therewas no significant difference between treatment arms in any subgroup. Conclusion  Risk of perinatal HIV transmission was low and no benefit from additionalintrapartum/newborn nevirapine was demonstrated when women received prenatalcare and antenatal ART, and elective cesarean section was made available.      

Surgery vs orthosis vs watchful waiting for hallux valgus: a randomized controlled trial

CONTEXT: Hallux valgus is a common foot deformation in adults, but evidence for effectiveness of surgical and conservative treatments for this condition is limited. OBJECTIVE: To compare the effectiveness of surgical and orthotic treatment with no treatment in patients with hallux valgus. DESIGN AND SETTING: Randomized controlled trial conducted in 4 general community hospitals in Finland in 1997-1998, with a follow-up period of 12 months. PARTICIPANTS: Two hundred nine consecutive patients (mean age, 48 years; 93% women) with a painful bunion and a hallux valgus angle 35 degrees or less. INTERVENTIONS: Patients were randomly assigned to surgery (distal chevron osteotomy; n = 71), orthosis (n = 69), or a 1-year waiting list (control group, n = 69). MAIN OUTCOME MEASURES: Pain intensity during walking on a visual analog scale (0-100), patient assessment of global improvement, number of painful days, cosmetic disturbance, footwear problems, functional status, and treatment satisfaction, compared among treatment groups. RESULTS: Follow-up rates at 6 and 12 months were 99% and 98%, respectively. At 6 months, pain intensity decreased more in the surgical group than in the control group (adjusted mean differences, -20 [95% confidence interval (CI), -28 to -12]) and more in orthosis than in the control groups (adjusted mean difference, -14 [95% CI, -22 to -6. At 1 year, pain intensity decreased more in the surgical than in the control groups (adjusted mean difference, -19 [95% CI, -28 to -10]) and more than in the surgical and orthosis groups (adjusted mean difference, -14 [95% CI, -22 to -5]). At 1 year, 83%, 46%, and 24% in the surgery, orthosis, and control groups, respectively, thought they had improved compared with baseline (number needed to treat), 1.7 between surgical and control groups). Number of painful days, cosmetic disturbance, and footwear problems were least and functional status and satisfaction with treatment were best in the surgical group. CONCLUSIONS: Surgical osteotomy is an effective treatment for painful hallux valgus. Orthoses provide short-term symptomatic relief.     

Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial

Context  Electroconvulsive therapy (ECT) is highly effective for treatment of major depression, but naturalistic studies show a high rate of relapse after discontinuation of ECT. Objective  To determine the efficacy of continuation pharmacotherapy with nortriptyline hydrochloride or combination nortriptyline and lithium carbonate in preventing post-ECT relapse. Design  Randomized, double-blind, placebo-controlled trial conducted from 1993 to 1998, stratified by medication resistance or presence of psychotic depression in the index episode. Setting  Two university-based hospitals and 1 private psychiatric hospital. Patients  Of 290 patients with unipolar major depression recruited through clinical referral who completed an open ECT treatment phase, 159 patients met remitter criteria; 84 remitting patients were eligible and agreed to participate in the continuation study. Interventions  Patients were randomly assigned to receive continuation treatment for 24 weeks with placebo (n = 29), nortriptyline (target steady-state level, 75-125 ng/mL) (n = 27), or combination nortriptyline and lithium (target steady-state level, 0.5-0.9 mEq/L) (n = 28). Main Outcome Measure  Relapse of major depressive episode, compared among the 3 continuation groups. Results  Nortriptyline-lithium combination therapy had a marked advantage in time to relapse, superior to both placebo and nortriptyline alone. Over the 24-week trial, the relapse rate for placebo was 84% (95% confidence interval [CI], 70%-99%); for nortriptyline, 60% (95% CI, 41%-79%); and for nortriptyline-lithium, 39% (95% CI, 19%-59%). All but 1 instance of relapse with nortriptyline-lithium occurred within 5 weeks of ECT termination, while relapse continued throughout treatment with placebo or nortriptyline alone. Medication-resistant patients, female patients, and those with more severe depressive symptoms following ECT had more rapid relapse. Conclusions  Our study indicates that without active treatment, virtually all remitted patients relapse within 6 months of stopping ECT. Monotherapy with nortriptyline has limited efficacy. The combination of nortriptyline and lithium is more effective, but the relapse rate is still high, particularly during the first month of continuation therapy.      

Cognitive behavioral therapy for treatment of chronic primary insomnia: a randomized controlled trial

CONTEXT: Use of nonpharmacological behavioral therapy has been suggested for treatment of chronic primary insomnia, but well-blinded, placebo-controlled trials demonstrating effective behavioral therapy for sleep-maintenance insomnia are lacking. OBJECTIVE: To test the efficacy of a hybrid cognitive behavioral therapy (CBT) compared with both a first-generation behavioral treatment and a placebo therapy for treating primary sleep-maintenance insomnia. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled clinical trial conducted at a single academic medical center, with recruitment from January 1995 to July 1997. PATIENTS: Seventy-five adults (n = 35 women; mean age, 55.3 years) with chronic primary sleep-maintenance insomnia (mean duration of symptoms, 13.6 years). INTERVENTIONS: Patients were randomly assigned to receive CBT (sleep education, stimulus control, and time-in-bed restrictions; n = 25), progressive muscle relaxation training (RT; n = 25), or a quasi-desensitization (placebo) treatment (n = 25). Outpatient treatment lasted 6 weeks, with follow-up conducted at 6 months. MAIN OUTCOME MEASURES: Objective (polysomnography) and subjective (sleep log) measures of total sleep time, middle and terminal wake time after sleep onset (WASO), and sleep efficiency; questionnaire measures of global insomnia symptoms, sleep-related self-efficacy, and mood. RESULTS: Cognitive behavioral therapy produced larger improvements across the majority of outcome measures than did RT or placebo treatment. For example, sleep logs showed that CBT-treated patients achieved an average 54% reduction in their WASO whereas RT-treated and placebo-treated patients, respectively, achieved only 16% and 12% reductions in this measure. Recipients of CBT also showed a greater normalization of sleep and subjective symptoms than did the other groups with an average sleep time of more than 6 hours, middle WASO of 26.6 minutes, and sleep efficiency of 85.1%. In contrast, RT-treated patients continued to report a middle WASO of 43.3 minutes and sleep efficiency of 78.8%. CONCLUSIONS: Our results suggest that CBT represents a viable intervention for primary sleep-maintenance insomnia. This treatment leads to clinically significant sleep improvements within 6 weeks and these improvements appear to endure through 6 months of follow-up.