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A Double-Blind, Randomized, Placebo-Controlled Trial of Pindolol Augmentation in Depressive Patients Resistant to Serotonin Reuptake Inhibitors

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A Double-Blind, Randomized, Placebo-Controlled Trial of Pindolol Augmentation in Depressive Patients Resistant to Serotonin Reuptake Inhibitors ORIGINAL ARTICLE A Double-blind, Randomized, Placebo-Controlled Trial of Pindolol Augmentation in Depressive Patients Resistant to Serotonin Reuptake Inhibitors Victor Pe´rez, MD; Joaquı´m Soler, PsyD; Dolors Puigdemont, MD; Enrique Alvarez, PhD; Grup de Recerca en Trastorns Afectius; Francesc Artigas, PhD Background: Pindolol has been reported to hasten the Asberg Scale for Depression scores were used as primary antidepressant action of selective serotonin reuptake in- measures of efficacy. hibitors in open-label and placebo-controlled trials. Pi- lot studies also suggested that pindolol could augment Results: At end point, the Hamilton and Montgomery- the antidepressant response in unresponsive patients. We Asberg scores and change from baseline in Hamilton score investigated whether the addition of pindolol can in- were not significantly different in patients taking pla- duce a rapid response in treatment-resistant patients. cebo or pindolol. The response rate was equal in both groups (12.5%). No differences in the clinical outcome Methods: After a single-blind lead-in placebo phase of were found when the various pretreatment subgroups 5 days to exclude placebo responders, 80 outpatients with were considered. At end point, the plasma concentra- major depression who did not respond to a minimum of tion of pindolol was 9.9 ± 5.1 ng/mL (mean ± SD; n = 40). 6 weeks of treatment with clomipramine hydrochlo- ride, 150 mg/d; fluoxetine hydrochloride, 40 mg/d; flu- Conclusions: Although pindolol can accelerate the an- voxamine maleate, 200 mg/d; or paroxetine hydrochlo- tidepressant action of selective serotonin reuptake in- ride, 40 mg/d, were randomly assigned to additionally hibitors in previously untreated patients, it does not elicit receive placebo (3 times daily) or pindolol (2.5 mg 3 times a rapid clinical response in treatment-resistant patients daily) for 10 days. The median number of ineffective treat- within a 10-day period. ments in the current episode was 2 (range, 1-4). Hamil- ton Rating Scale for Depression and Montgomery- Arch Gen Psychiatry. 1999;56:375-379 ESPITE THE availability of cent placebo-controlled studies suggest a wide range of antide- that pindolol (2.5 mg 3 times daily) ac- pressant drugs, clinical celerates the antidepressant action of the trials indicate that 30% to SSRIs fluoxetine hydrochloride and par- 40% of depressed pa- oxetine.14-17 In another study, no differ- Dtients fail to respond to first-line antide- ences were found in the time to response pressant treatment despite adequate dos- or response rate between fluoxetine plus age, duration, and compliance.1,2 Indeed, placebo and fluoxetine plus pindolol (2.5 up to 21% of patients with major depres- mg 3 times daily or 5 mg twice daily).18 sion who seek treatment have not recov- In open-label studies, pindolol was also ered 2 years later.3 In an attempt to solve found to elicit a clinical response in patients this problem, several augmentation strat- treated with but not responding to several egies have been devised.4 Newer antide- antidepressantdrugs,includingSSRIs(fluox- pressant drugs, such as the selective se- etine, fluvoxamine maleate, paroxetine), tri- From the Department of rotonin (5-HT) reuptake inhibitors cyclicdrugs(imipraminehydrochloride),and 9,10,19,20 Psychiatry, Hospital de Sant (SSRIs), have a less severe profile of side monoamine oxidase inhibitors. In 1 Pau (Drs Pe´rez, Soler, effects, but their response rate is compa- such study,21 no beneficial effect of the ad- Puigdemont, and Alvarez), and rable with or lower than that of tricyclic dition of pindolol was found in treatment- Department of Neurochemistry, drugs.5-7 Also, although they can be ad- resistant melancholic patients. Moreover, a Instituto de Investigaciones ministered at full effective doses from the recent double-blind crossover trial in a small Biome´dicas de Barcelona initiation of treatment, onset of response numberofpatientsshowednosignificantdif- (Dr Artigas), Barcelona, Spain. requires several weeks of treatment.8 ference between addition of placebo and pin- A complete list of the 22 collaborators of the Grup de Pindolol, a b-adrenoceptor/5-HT1A re- dolol. However, the latter authors included Recerca en Trastorns Afectius ceptor antagonist, has been used to accel- patients treated with nonserotonergic anti- (Group for Research in erate the clinical effects of antidepressant depressants, whose action is not expected to Affective Disorders) appears drugs with a primary action on seroton- be synergistically enhanced by addition of 9-13 at the end of this article. ergic neurons, including SSRIs. Re- 5-HT1A receptor antagonists. ARCH GEN PSYCHIATRY/ VOL 56, APR 1999 375 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 PATIENTS AND METHODS patients were required to be free of other serious medical conditions. Other exclusion criteria were the presence of organic mental disorders, delusions, or hallucinations; a his- PATIENTS tory of drug abuse including alcohol abuse; treatment with psychotropic medications other than benzodiazepines, b- Main inclusion criteria were the existence of a major depres- blockers, and catecholamine-depleting agents (eg, amphet- sive disorder, single or recurrent (DSM-IV23) with a current aminelike compounds); and any concomitant psychiatric episode resistant (score on the 17-item Hamilton Rating Scale illness of Axis I of DSM-IV or Axis II disorder clusters A for Depression [HAM-D].16) to pharmacological treatment and B. The use of benzodiazepines was allowed only when (minimum of 6 weeks) with the SSRIs fluoxetine hydrochlo- patients were taking them before entering the study, but ride (40 mg/d), fluvoxamine maleate (200 mg/d), and par- their dose and frequency was not changed. Patients were oxetine hydrochloride (40 mg/d), or with the nonselective not allowed to receive structured psychotherapy during the 5-HT reuptake inhibitor clomipramine hydrochloride (150 trial. To exclude the presence of individuals with chronic mg/d). These doses were fixed for at least 2 weeks before ad- depression, the duration of the current episode had to be less mission and for the rest of the trial. All patients except 2 were than 9 months, with a preceding asymptomatic period of outpatients, consecutively referred to the study by a collabo- at least 3 months.24 Patients must not have participated in rative group of psychiatrists (Group for Research in Affec- any other trial in the 3 months preceding inclusion in the tive Disorders) working in primary psychiatric care centers present study. Before the patient entered the study, plasma in Barcelona, Spain. Age range was 18 to 65 years. levels of antidepressants were monitored to check for com- After referral, these patients were examined by a team pliance with current antidepressant drug regimens. of 4 psychiatrists in an affective disorders unit at the Hospi- The degree of treatment resistance was determined ac- tal de Sant Pau, Barcelona. None of the patients had previous cording to the classification of Thase and Rush.2 A median knowledge about the possibility of participating in a clinical of 2 (range, 1-4) was obtained (Table 1). This indicated trial. The study was approved by the Ethics Committee of the that, on average, patients had been treated before the cur- Hospital de Sant Pau and the Spanish Ministry of Health. Writ- rent 5-HT reuptake inhibitor with an adequate dose (and ten informed consent was obtained from all subjects, with the for a sufficient time) of another antidepressant drug of a useofaconsentformapprovedbytheinstitutionalreviewboard, different family without obtaining an adequate response. after all procedures were fully explained. Sample size was calculated considering a response to Patients with bipolar disorder type I or II and pa- placebo of 20% in treatment-resistant patients,25 a hypo- tients at suicide risk, with a score of 3 or more on item 3 of thetical response to pindolol of 50%, and a 10% loss of pa- the HAM-D, were excluded. Pregnant or breast-feeding tients after randomization. Eighty patients were required women and women of childbearing potential not using ad- for b = .20 and a = .05. Finally, 88 white patients with a pri- equate contraceptive measures were also excluded. All mary diagnosis of major depression according to DSM-IV We conducted the present double-blind, placebo- (F2,156 = 17.2, P,.001 for HAM-D; F2,156 = 19.1, P,.001 for controlled study to examine whether pindolol can aug- MADRS; and F2,156 = 5.6, P,.004 for CGI scores) and a ment the short-term antidepressant response in patients nonsignificant effect of the treatment and the resistant to treatment with 5-HT reuptake inhibitors. These time 3 treatment interaction in all of them (Figure). The included the SSRIs fluoxetine, fluvoxamine, and parox- percentage of responder patients was the same in the 2 etine and the nonselective tricyclic drug clomipramine hy- treatment arms (12% [10/80]). Remission rate was 12% drochloride, a potent blocker of 5-HT reuptake. (10/80) in the placebo group and 10% (8/80) in the pin- dolol group (nonsignificant difference). The change in RESULTS severity, as assessed by the fall in the HAM-D score from day 0 to day 10, was not significantly different in pa- The percentage of patients completing the study was 98% tients treated with placebo or with pindolol (Table 3). (39/40) in both treatment arms. Of the 80 patients who be- No differences emerged when the different treatment sub- gan the double-blind phase of the study, 1 patient abandoned groups were considered (SSRIs together or individually the study by her own decision (placebo group) and another and clomipramine) (Table 3). At end point, the HAM-D patient because of violation of the protocol (pindolol group). and MADRS scores in the groups treated with placebo There were no significant differences in the number of pa- and pindolol were 15.7 ± 6.0 and 17.3 ± 5.7 (HAM-D) and tients who spontaneously complained of adverse events dur- 21.6 ± 8.6 and 24.2 ± 8.9 (MADRS), respectively.
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