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Efficacy of venlafaxine in major depression resistant to selective serotonin reuptake inhibitors
Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 1129 – 1134
Efficacy of venlafaxine in major depression resistant to selective serotonin reuptake inhibitors Jero´nimo Sa´iz-Ruiz*, Angela Iba´n˜ez, Marina Dı´az-Marsa´, Francisco Arias, Jesu´s Padı´n, Manuel Martı´n-Carrasco, Jose´ Manuel Montes, Laura Ferrando, Jose´ Luis Carrasco, Eloy Martı´n-Ballesteros, Lluis Jorda´, Lorenzo Chamorro Grupo de Investigacio´n ‘‘Ramo´n y Cajal,’’ Hospital Ramo´n y Cajal, Servicio de Psiquiatrı´a, Universidad de Alcala´, Ctra. de Colmenar Km 9.1, 28034 Madrid, Spain Accepted 1 May 2002
Abstract Introduction: Some studies suggest that venlafaxine, due to its pharmacodynamic characteristics, could be an effective drug in depression, resistant to other antidepressive agents. This investigation explores the efficacy and tolerability of venlafaxine in major depression, resistant to a selective serotonin reuptake inhibitor (SSRI). Methods: A multicenter naturalistic study was performed during 6 months and included those patients diagnosed of major depression according to the criteria of DSM-IV who had a minimum score of 18 on the Hamilton Depression Rating Scale (HAM-D) and who had not responded to previous treatment with a SSRI at therapeutic doses for a minimum of 4 weeks. The assessment of efficacy was performed with the HAM-D scale, the Montgomery – Asberg Depression Rating Scale (MADRS), the Hamilton Anxiety Rating Scale (HAM-A) and the Global Clinical Impression (GCI). Tolerability was evaluated by recording the adverse reactions and with the GCI score on overall drug tolerability. Results: A total of 69 patients, of which 59 were evaluable for efficacy (they had fulfilled at least 4 weeks of treatment), were included. About 81% of all of them obtained a reduction of at least 50% in the HAM-D, 74% were considered as ‘‘quite improved’’ or ‘‘very improved’’ in the GCI and 69% met both criteria. The mean dose of venlafaxine used was 170.4 (S.D.=43.8) mg. Of the 21 patients who did not complete the 6 months of treatment, 3 were due to lack of efficacy, 6 due to adverse effects and 12 for other reasons. About 89.2% of side effects were considered as mild or moderate. Conclusion: The results of our study support the efficacy and tolerability of venlafaxine in patients suffering from depression who have not responded to SSRI treatment. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Depression; Selective serotonin reuptake inhibitors; Venlafaxine
1. Introduction The therapeutic approach to depression still is a challenge for clinicians because antidepressive agents only achieve clinical improvement in 65 –70% of the patients and complete recovery in 40 – 50% of them (Feighner, 1994; Depression Guideline Panel, 1993; American Psychiatric Association, 1993). Although there have been important advances in recent years with the introduction of different Abbreviations: ANOVA, analysis of variance; BP, blood pressure; GCI, Global Clinical Impression; HAM-A, Hamilton Anxiety Rating Scale; HAM-D, Hamilton Depression Rating Scale; HR, heart rate; MADRS, Montgomery – Asberg Depression Rating Scale; SSRI, selective serotonin reuptake inhibitors; TAD, tricyclic antidepressants. * Corresponding author. Tel./fax: +34-91-3368829. E-mail address: [email protected] (J. Sa´iz-Ruiz).
pharmacological groups that compete with the classical antidepressive drugs due to their improved tolerability and lower toxicity, a series of limitations such as the latency time in which their effect takes place, the appearance of adverse reactions and especially their lack of efficacy in some patients continue to be posed (Frazer, 1997). In fact, even though the treatment prescription and compliance are correct, it is estimated that 25 – 30% of the patients do not respond and that intolerability occurs in 10 –20% of them (Feighner, 1994; Depression Guideline Panel, 1993; Thase and Rush, 1997). In addition, there is a subgroup of depressive patients (20 –30%) that only achieves a partial response to treatment (Fawcett and Kravitz, 1985; Fawcett, 1994), with persistence of subdepressive symptoms that is associated to high relapse rates (Simons et al., 1986; Thase et al., 1992; Mindham et al., 1973; Montgomery et al.,
0278-5846/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved. PII: S 0 2 7 8 - 5 8 4 6 ( 0 2 ) 0 0 2 4 7 - 6
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1991). The importance of these data is found in the fatal consequences that arise from an inefficient treatment of the affective disorders: depression is one of the principal risk factor for suicide (Harris and Barraclough, 1997; Nemeroff, 1994) and the persistence of depressive symptoms is associated to poor social, familial and work functioning (Rush and Thase, 1997; Wells et al., 1989). The introduction of new antidepressive agents in recent years has made possible to design reasonable alternative treatments for those patients who do not respond to a first antidepressive agent. Thus, after failure of selective serotonin reuptake inhibitors (SSRI), which are the drugs used most at present to treat outpatient depression (Thase and Rush, 1997; Frazer, 1997), several strategies have been mentioned. Some authors advocate increasing the doses of these drugs (Thase and Rush, 1997) or changing to another SSRI, which could be efficacious in 40 –70% of the cases (Zarate et al., 1996; Joffe et al., 1996; Thase et al., 1997). Others recommend substituting them with antidepressive agents having a different action mechanism (Thase and Rush, 1995). In this sense, the most updated etiopathogenic theories on depression recognize the role of both serotonin and norepinephrine in the genesis of the disease. The pharmacodynamic characteristics of new antidepressive agents such as venlafaxine, nefazodone, mirtazapine, bupropion or reboxetine are different from those of SSRI and they are also usually better tolerated and safer than the tricyclic antidepressants (TAD) (Thase and Rush, 1997). Thus, they are presented as an alternative treatment in depression and especially in patients who have not responded to SSRI. Among the drugs mentioned, venlafaxine presents the greatest pharmacodynamic similarities to the TADs, such as imipramine and amitriptyline, although it lacks muscarinic –cholinergic, histaminergic and a1-adrenergic effects. Thus, its profile of adverse reactions is similar to that of the SSRIs (Dierick et al., 1996; Clerc et al., 1994), although it differs from them because of its low protein binding in plasma and its reuptake inhibition of both serotonin and norepinephrine (Feighner, 1994). The antidepressive efficacy of this drug has been proven in studies on different population groups, including outpatients with major depression, inpatients with severe depression and melancholia or elderly patients (Guelfi et al., 1995; Lecrubier et al., 1997; Leonard, 1996; Dierick et al., 1996; Clerc et al., 1994; Mahapatra and Hackett, 1997). Recent studies of venlafaxine treatment for resistant depression conclude that venlafaxine at higher doses is a reasonably well-tolerated and effective alternative and typically should be used before TADs or monoamine oxidase inhibitors. Furthermore, future research is needed to confirm the prediction that switching a SSRI nonresponder to venlafaxine is an effective strategy (Montigny et al., 1999; Poirer and Boyer, 1999; Mitchell et al., 2000; Thase et al., 2000; Schweitzer et al., 2001). This naturalistic study, on the contrary to the traditional clinical trials, makes it possible to evaluate the efficacy and profile of the adverse effects of a drug under clinical
practice conditions (Baier, 1998). This multicenter naturalistic study was planned in order to verify the potential usefulness of venlafaxine in depressed patients who do not respond to SSRI.
2. Methods 2.1. Patient population This 6-month naturalistic study was carried out in the outpatient clinics of several Spanish hospitals coordinated by the Research Group Ramon y Cajal. Patients of both sexes, whose ages were equal to or greater than 18 years, with the DSM-IV (American Psychiatric Association, 1994) diagnosis of major depression (single, recurrent or bipolar episode), with a minimum score of 18 on the 17-item Hamilton Depression Rating Scale (HAM-D) and in which treatment with SSRI had produced an inefficacious result were included. In accordance with Joffe et al. (1996), lack of response to a certain SSRI was defined as a minimum of 4 weeks of treatment at therapeutic doses (20 mg/day of fluoxetine, 50 mg/day of sertraline, 100 mg/day of fluvoxamine, 20 mg/day of paroxetine and 20 mg/day of citalopram), with a final score in the Global Clinical Impression (GCI) of minimum improvement, without changes or worsening. Exclusion criteria for the study were considered as comorbidity with disorders due to drug abuse, psychotic disorders, obsessive-compulsive disorder and eating disorders (anorexia nervosa or bulimia nervosa). 2.2. Drug administration The patients, who fulfilled the requirements established and whenever the treatment with venlafaxine was indicated according to the criteria of the physician, were informed on the characteristics of the investigation, and once they had given their consent to participate in it, they were included in the study with an initial dose of 75 mg/day of this drug (37.5 mg twice a day). Later, the dose could be increased according to the clinical response to a maximum dose of 375 mg/day. As this a naturalistic study, there were no restrictions in the use of anxiolytic and/or hypnotic agents. 2.3. Assessment instruments All assessments were done by a trained psychiatrist with an extensive experience. Patients were assessed at the initial visit and at the end of the 2nd, 4th, 8th and 24th weeks. Treatment response was assessed with 17-item HAM-D (Hamilton, 1960), Hamilton Anxiety Rating Scale (HAMA) (Hamilton, 1959), Montgomery – Asberg Depression Rating Scale (MADRS) (Asberg et al., 1978) and sevenitem GCI (Guy, 1976) of the physician. Treatment response was evaluated in those who have completed at least 4 weeks of treatment by using a criterion of at least 50% of decrease
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on the HAM-D scale and/or a score of 1 (very much improved) or 2 (much improved) on the GCI global improvement scale. Side effects were assessed in all patients who had received at least one dose of venlafaxine. The side effects were evaluated by using the GCI scale of overall tolerability at the end of the study, measuring blood pressure (BP) and heart rate (HR) in all the visits and assessing weights at the first visit and at the end of the study. Adverse reactions were classified as mild, moderate or severe. Severe adverse reactions were defined as those influencing negatively the life quality of the patient. 2.4. Data analysis A descriptive statistical study of demographic parameters was performed and the analysis of variance (ANOVA) with posterior comparison among the groups with the Student’s t and Fisher’s Paired Tests was used to analyze the quantitative variables. The c2 test and the Fisher’s Exact Test were used to compare the qualitative variables. The statistical package chosen for this statistical evaluation was the Windows version of SPSS 7.5.
3. Results A total of 69 patients (20 males and 49 females) with a mean age of 48.9 (S.D.=13.9) years were included. Table 1 shows the main demographic and clinical data and the mean doses used of SSRI. The mean daily dose of venlafaxine at the end of the treatment was 170.4 (S.D.=43.8) mg. Table 1 Demographic and clinical characteristics of the sample Sex Male Female Mean age (years) DSM-IV diagnosis Major depressive disorder, single episode Major depressive disorder, relapsing Type I bipolar disorder, depressive episode Mean duration of actual episode (weeks) Number of previous episodes Family background Background of depression Other psychiatric background Previously prescribed SSRI Fluoxetine Sertraline Paroxetine Fluvoxamine Citalopram
20 (29%) 49 (71%) 48.9 (S.D.=13.9) 29 (42.0%) 39 (56.5%) 1 (1.4%) 18.6 (S.D.=17.8) 2.1 (S.D.=2.6) 18 (26.1%) 13 (18.8%) n
Mean doses (mg)
34 15 10 6 4
25.6 106.7 21.0 158.3 30.0
(S.D.=8.9) (S.D.=45.8) (S.D.=7.4) (S.D.=80.1) (S.D.=11.5)
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Table 2 Changes between baseline evaluation and 6-month evaluation in assessments scales Scales
Baseline
Final evaluation (6 months)
Friedman nonparametric test
HAM-D MADRS HAM-A
23.96 (S.D.=4.31) 31.13 (S.D.=5.82) 20.62 (S.D.=6.05)
8.20 (S.D.=5.54) 10.17 (S.D.=7.87) 7.35 (S.D.=5.79)
c2=143.9, P<.0001 c2=142.2, P<.0001 c2=122.5, P<.0001
Twenty-one of the 69 (30%) did not complete the 6 months of treatment. The reasons for discontinuation from the study were lack of efficacy in 3 (4%) cases, loss of follow-up in 8 (11%) patients, patient’s decision in 4 (6%) cases and side effects in 6 (9%) cases. The side effects related to the withdrawal from the study were nausea (three cases), nervousness (one case), onset of hypertension (one case), and urinary and sexual dysfunction (one case). Ten patients were excluded from the efficacy analysis, as they had not completed the 4 weeks of treatment. All scales used to assess efficacy in the final evaluation comparing to baseline showed a significant difference (Table 2): HAM-D from 23.96 (S.D.=4.31) to 8.20 (S.D.=5.54) (Friedman Nonparametric Test c2=143.9, P<.0001), MADRS from 31.13 (S.D.=5.82) to 10.17 (S.D.=7.87) (Friedman Nonparametric Test c2 =142.2, P<.0001) and HAM-A from 20.62 (S.D.=6.05) to 7.35 (S.D.=5.79) (Friedman Nonparametric Test c2=122.5, P<.0001). A 69% decrease was obtained in the HAM-D, 70% in the MADRS and 67% in the HAM-A. Regarding the primary definition of treatment response, 48 of 59 (81%) patients showed a reduction in the HAM-D score greater than 50% regarding the baseline and 44 (74%) were considered quite or very improved in the GCI of the physician. Both criteria were fulfilled in 69% of the cases (41 patients). In the tolerability analysis, all of the 69 patients who participated in the study were included. Of them, 32 (46%) did not report any adverse reaction during the study while 37 (54%) showed some adverse effect, with an intensity evaluated as mild in 12 (17%) patients, moderate in 21 (30%) and severe in 4 (6%) cases: insomnia, dry mouth, sexual dysfunction and nausea. Table 3 shows side effects. The most frequent were dry mouth (23%), gastrointestinal problems (16%), anxiety (14%) and constipation (10%). In the BP study, no overall significant change appeared in the evolution of the mean score of the systolic BP [baseline SBP of 126.03 (S.D.=15.8) mmHg and final systolic BP of 125.74 (S.D.=11.82) mmHg, ANOVA F=1.12, P=.365] or the diastolic BP [baseline DBP of 76.18 (S.D.=11.81) mmHg and final DBP 77.79 (S.D.=10.24) mmHg, ANOVA F=1.49, P=.230]. However, as has been previously mentioned, one patient was withdrawn from the study due to the onset of hypertension during the study. There were no significant changes in the HR during the study [baseline HR 76.6 (S.D.=13.5) beats/min and final HR 76.33 (S.D.=10.79) beats/min, ANOVA F=0.36, P=.834]. Regarding weight, a significant increase was observed in the final
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Table 3 Most frequent adverse effects observed during treatment with venlafaxine Adverse reactions
n (%)
Dry mouth Gastrointestinal symptomsa Anxiety Constipation Mictional disorders Sexual dysfunction Sedation Dizziness Sweating Headache Skin disorders Others
16 (23) 11 (16) 10 (14) 7 (10) 5 (7) 3 (4) 2 (3) 2 (3) 2 (3) 2 (3) 2 (3) 5 (9)
a Nausea/vomiting reported in 8 (11%) patients and the gastrointestinal discomfort reported by 3 (4%) patients are included in this section.
visit (69.5 kg, S.D.=12.0) compared to the mean on the baseline visit (68.1 kg, S.D.=12.3) (Student’s t test for paired data=2.53, P=.013). The GCI on the overall tolerability was evaluated in 47 patients who completed the 6 months of the study. In 2 (4%) patients, side effects interfered with patients’ functioning. In 24 (51%) patients, there was no significant interference with patient’s functioning . In 21 (45%) patients, there were no side effects during the study. However, we must remember the fact that the six patients that withdrew from the study did so due to adverse reactions.
4. Discussion The objective of our study was to evaluate the efficacy of venlafaxine in the treatment of depressed patients who had not responded to previous treatment with a SSRI. According to the results obtained and following a strict criterion, venlafaxine was efficient at a mean dose of 175 mg/day in two out of every three patients who received this drug for a minimum of 4 weeks, because 70% of the patients who complied with this final condition fulfilled the two primary criteria of efficacy established, that is, a reduction in the score of the HAM-D that was greater than 50% together with a ‘‘very improved’’ or ‘‘quite improved’’ GCI in the final visit. Using a less restricted evaluation, the efficacy percentage would be increased to 75% if only the GCI is considered and up to 81% if only the reduction in the HAMD is considered. In these patients, significant decreases ( P<.005) were also obtained in the final visit regarding the baseline one in all of the efficacy evaluation scales, including both the depression (HAM-D and MADRS) and the anxiety (HAM-A) ones. No previous studies that evaluated the efficacy of venlafaxine after therapeutic failure with SSRI were found in the literature. However, several double-blind trials manifested a greater efficacy of venlafaxine compared to fluoxetine in patients who were hospitalized with major
depression with melancholia and in outpatients with major depression (Dierick et al., 1996; Clerc et al., 1994). In addition, venlafaxine was efficient in a double-blind randomized study in which 75, 225 and 375 mg of this drug were compared with a placebo in outpatients with major depression (Schweitzer et al., 1991). In this work, five patients who had not improved with several antidepressive agents responded to venlafaxine. Based on these results, Nieremberg et al. (1994) performed an open study on 84 patients with resistant depression with increasing doses of venlafaxine during a 6-month period until a maximum of 450 mg/day was reached: 40% of the patients responded to treatment. Our work reveals higher recovery rates, possibly due to the different population studied because the Nieremberg group used a classical definition of ‘‘resistant depression’’ as an inclusion criterion, that is, patients who did not respond to three different antidepressive agents, one of them tricyclic or who had not responded to two antidepressives, one of them tricyclic and electroconvulsive treatment (in both cases, the fact of having tried, at least on one occasion, to strengthen the antidepressive therapy with lithium, thyroid hormones or carbamazepine was contemplated). Recent studies of venlafaxine treatment for resistant depression found response rates more similar to our study (Montigny et al., 1999; Poirer and Boyer, 1999; Mitchell et al., 2000; Schweitzer et al., 2001). Regarding the doses, the different population included in these studies can also explain why the doses used in our work were not so high. In our study, the mean dose was 170.4 (S.D.=43.8) mg/day versus 245, 260 or 300 mg/day used in the studies of Nieremberg et al. (1994), Montigny et al. (1999) and Mitchell et al. (2000). Appearance of undesirable adverse reactions is one of the most common reasons for lack of treatment compliance and consequently for the persistence of depressive symptoms (Thase and Rush, 1997). In our study, tolerability was evaluated as ‘‘fair’’ in only two patients of those who completed the study, so that 95% of them showed good tolerability to the drug. In addition, in 89% of the cases, the adverse effects were mild or moderate. However, to correctly evaluate tolerability, it is necessary to include those patients who had prematurely withdrawn from the study due to adverse effects. These added up to six, so that the percentage of poor tolerability reaches 13% of all the patients included in the study. This value is closer to that calculated by different authors on patients who do not tolerate a certain antidepressive treatment and who calculate them to be 10 –20% (Feighner, 1994; Depression Guideline Panel, 1993; Thase and Rush, 1997). In this sense, it can be stated that the nature of this present investigation, due to its observational character, makes it possible to evaluate and quantify the adverse reactions of a drug in the real conditions of its use (Baier, 1998). The percentage of patient withdrawal due to adverse reactions was 9%, a value that is similar to that reported in other studies with venlafaxine, 8% in an open study with 300 depressed (Lecable et al., 1995) and 9% in the Nierem-
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berg study on 84 patients with resistant depression (Nieremberg et al., 1994). The profile of adverse effects observed in our study is similar to that of previous studies, which have reported the appearance of nausea, headache, dry mouth, insomnia, constipation, dizziness and drowsiness as the most common (Feighner, 1994; Guelfi et al., 1995; Leonard, 1996). Although venlafaxine is similar to the SSRIs in type of undesirable effects, it seems to lack the stimulating effect of fluoxetine (Clerc et al., 1994; Scheweizer et al., 1994; Cunningham et al., 1994; Guelfi et al., 1995) although one patient in our study withdrew from the study in the first visit due to the appearance of nervousness. Venlafaxine-induced nausea appears to decrease in most patients after 4 weeks (Rudolph and Derivan, 1996; Frazer, 1997). In our study, 2 (3%) patients withdrew from the treatment early due to nausea, but the overall incidence reached was 11%. Several authors have reported the possible incidence of an increase in BP, depending on the dose, during treatment with venlafaxine. According to a review of the studies carried out, doses of up to 100 mg/day were not associated to an increase in BP that was greater than with the placebo, while in patients who received a dose between 101 and 300 mg the percentage of increase was three to four times superior to the placebo, although this increase was not maintained in half of the cases even if treatment was continued (Frazer,1997; Rudolph and Derivan, 1996). In this study, 1 (1%) patient was withdrawn due to high BP, which is similar to 0.95% of dropouts due to hypertension in more than 2000 patients entered in a venlafaxine double-blind study (Feighner, 1994). Sexual dysfunction induced by antidepressive agents is an undesirable effect that is receiving growing attention due to its high incidence (up to 40% of the patients treated could experience some form of sexual dysfunction) and to the limitations that its appearance generally provoke in treatment compliance, especially during the maintenance period (Balon et al., 1993). It has been reported that venlafaxine could also cause sexual dysfunction, more frequently in men than in women (Preskom, 1995). In our study, sexual dysfunction was reported by 4% of the patients. Finally, in spite of the advantages that observational studies offer regarding improved knowledge on how a certain drug acts under clinical conditions, the fact of this was an open study imposes limitations when interpreting the results. Thus, although the results of this investigation support the efficacy and tolerability of venlafaxine in patients with depression who have not responded to a previous treatment with a SSRI, it seems that double-blind studies need to be carried out to generalize these conclusions.
5. Conclusion The results of our study support the efficacy and tolerability of venlafaxine in patients suffering from depression who have not responded to usual doses of SSRI.
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This naturalistic study suggest that new studies using double-blind design need to be carried out to verify that venlafaxine may be effective in depressive patients who have not responded to SSRI treatment.
Acknowledgements This study was supported by Wyeth-Ayerst Laboratories.
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Rush, A.J., Thase, M.E., 1997. Strategies and tactics in the treatment of chronic depression. J. Clin. Psychiatry 58 (Suppl. 13), S14 – S22. Schweitzer, E., Weise, C., Clary, C., Fox, Y., Rickels, K., 1991. Placebocontrolled trial of venlafaxine for the treatment of major depression. J. Clin. Psychopharmacol. 11, 233 – 236. Scheweizer, E., Feighner, J., Mandos, L.A., Rickels, K., 1994. Comparison of venlafaxine and imipramine in the acute treatment of major depression in outpatients. J. Clin. Psychiatry 55 (3), 104 – 108. Schweitzer, I., Burrows, G., Tuckwell, W., Polonowita, A., Flyn, P., George, T., Theodhoros, M., Mitchell, P., 2001. Sustained response to open-label venlafaxine in drug-resistant major depression. J. Clin. Psychopharmacol. 21 (2), 185 – 189. Simons, A.D., Murphy, G.E., Levine, J.L., Wetzel, R.D., 1986. Cognitive therapy and pharmacotherapy for depression: sustained improvement over one year. Arch. Gen. Psychiatry 43, 43 – 48. Thase, M.E., Rush, A.J., 1995. Treatment resistant depression. In: Bloom, F.E., Kupfer, D.J. (Eds.), Psychopharmacology: The Fourth Generation of Progress. Raven Press, New York, NY, pp. 1081 – 1097. Thase, M.E., Rush, J., 1997. When at first you don’t need succeed: sequential strategies for antidepressant nonresponders. J. Clin. Psychiatry 58 (Suppl. 13), S23 – S29. Thase, M.E., Simons, A.D., Mcgeary, J., Cahalane, J.F., Hughes, C., Harden, T., Friedman, E., 1992. Relapse after cognitive behavior therapy of depression: potential implications for longer courses of treatment. Am. J. Psychiatry 149, 1046 – 1052. Thase, M.E., Blomgren, S.L., Birkett, M.A., Apter, J.T., Tepner, R.G., 1997. Fluoxetine treatment of patients with major depressive disorder who failed initial treatment with sertraline. J. Clin. Psychiatry 58, 16 – 21. Thase, M.E., Friedman, E.S., Howland, R.H., 2000. Venlafaxine and treatment-resistant depression. Depress. Anxiety 12 (Suppl. 1), S55 – S62. Wells, K.B., Stewart, A., Hays, R.D., Burnam, M.A., Rogers, W., Daniels, M., Berry, S., Greenfield, S., Ware, J., 1989. The functioning and wellbeing of depressed patients: results from medical outcomes study. JAMA 262, 914 – 919. Zarate, C.A., Kando, J.C., Tohen, M., Weiss, M.K., Cole, J.O., 1996. Does intolerance or lack of response with fluoxetine predict the same will happen with sertraline? J. Clin. Psychiatry 57, 67 – 71.
Efficacy of venlafaxine in major depression resistant to selective serotonin reuptake inhibitors Jero´nimo Sa´iz-Ruiz*, Angela Iba´n˜ez, Marina Dı´az-Marsa´, Francisco Arias, Jesu´s Padı´n, Manuel Martı´n-Carrasco, Jose´ Manuel Montes, Laura Ferrando, Jose´ Luis Carrasco, Eloy Martı´n-Ballesteros, Lluis Jorda´, Lorenzo Chamorro Grupo de Investigacio´n ‘‘Ramo´n y Cajal,’’ Hospital Ramo´n y Cajal, Servicio de Psiquiatrı´a, Universidad de Alcala´, Ctra. de Colmenar Km 9.1, 28034 Madrid, Spain Accepted 1 May 2002
Abstract Introduction: Some studies suggest that venlafaxine, due to its pharmacodynamic characteristics, could be an effective drug in depression, resistant to other antidepressive agents. This investigation explores the efficacy and tolerability of venlafaxine in major depression, resistant to a selective serotonin reuptake inhibitor (SSRI). Methods: A multicenter naturalistic study was performed during 6 months and included those patients diagnosed of major depression according to the criteria of DSM-IV who had a minimum score of 18 on the Hamilton Depression Rating Scale (HAM-D) and who had not responded to previous treatment with a SSRI at therapeutic doses for a minimum of 4 weeks. The assessment of efficacy was performed with the HAM-D scale, the Montgomery – Asberg Depression Rating Scale (MADRS), the Hamilton Anxiety Rating Scale (HAM-A) and the Global Clinical Impression (GCI). Tolerability was evaluated by recording the adverse reactions and with the GCI score on overall drug tolerability. Results: A total of 69 patients, of which 59 were evaluable for efficacy (they had fulfilled at least 4 weeks of treatment), were included. About 81% of all of them obtained a reduction of at least 50% in the HAM-D, 74% were considered as ‘‘quite improved’’ or ‘‘very improved’’ in the GCI and 69% met both criteria. The mean dose of venlafaxine used was 170.4 (S.D.=43.8) mg. Of the 21 patients who did not complete the 6 months of treatment, 3 were due to lack of efficacy, 6 due to adverse effects and 12 for other reasons. About 89.2% of side effects were considered as mild or moderate. Conclusion: The results of our study support the efficacy and tolerability of venlafaxine in patients suffering from depression who have not responded to SSRI treatment. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Depression; Selective serotonin reuptake inhibitors; Venlafaxine
1. Introduction The therapeutic approach to depression still is a challenge for clinicians because antidepressive agents only achieve clinical improvement in 65 –70% of the patients and complete recovery in 40 – 50% of them (Feighner, 1994; Depression Guideline Panel, 1993; American Psychiatric Association, 1993). Although there have been important advances in recent years with the introduction of different Abbreviations: ANOVA, analysis of variance; BP, blood pressure; GCI, Global Clinical Impression; HAM-A, Hamilton Anxiety Rating Scale; HAM-D, Hamilton Depression Rating Scale; HR, heart rate; MADRS, Montgomery – Asberg Depression Rating Scale; SSRI, selective serotonin reuptake inhibitors; TAD, tricyclic antidepressants. * Corresponding author. Tel./fax: +34-91-3368829. E-mail address: [email protected] (J. Sa´iz-Ruiz).
pharmacological groups that compete with the classical antidepressive drugs due to their improved tolerability and lower toxicity, a series of limitations such as the latency time in which their effect takes place, the appearance of adverse reactions and especially their lack of efficacy in some patients continue to be posed (Frazer, 1997). In fact, even though the treatment prescription and compliance are correct, it is estimated that 25 – 30% of the patients do not respond and that intolerability occurs in 10 –20% of them (Feighner, 1994; Depression Guideline Panel, 1993; Thase and Rush, 1997). In addition, there is a subgroup of depressive patients (20 –30%) that only achieves a partial response to treatment (Fawcett and Kravitz, 1985; Fawcett, 1994), with persistence of subdepressive symptoms that is associated to high relapse rates (Simons et al., 1986; Thase et al., 1992; Mindham et al., 1973; Montgomery et al.,
0278-5846/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved. PII: S 0 2 7 8 - 5 8 4 6 ( 0 2 ) 0 0 2 4 7 - 6
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1991). The importance of these data is found in the fatal consequences that arise from an inefficient treatment of the affective disorders: depression is one of the principal risk factor for suicide (Harris and Barraclough, 1997; Nemeroff, 1994) and the persistence of depressive symptoms is associated to poor social, familial and work functioning (Rush and Thase, 1997; Wells et al., 1989). The introduction of new antidepressive agents in recent years has made possible to design reasonable alternative treatments for those patients who do not respond to a first antidepressive agent. Thus, after failure of selective serotonin reuptake inhibitors (SSRI), which are the drugs used most at present to treat outpatient depression (Thase and Rush, 1997; Frazer, 1997), several strategies have been mentioned. Some authors advocate increasing the doses of these drugs (Thase and Rush, 1997) or changing to another SSRI, which could be efficacious in 40 –70% of the cases (Zarate et al., 1996; Joffe et al., 1996; Thase et al., 1997). Others recommend substituting them with antidepressive agents having a different action mechanism (Thase and Rush, 1995). In this sense, the most updated etiopathogenic theories on depression recognize the role of both serotonin and norepinephrine in the genesis of the disease. The pharmacodynamic characteristics of new antidepressive agents such as venlafaxine, nefazodone, mirtazapine, bupropion or reboxetine are different from those of SSRI and they are also usually better tolerated and safer than the tricyclic antidepressants (TAD) (Thase and Rush, 1997). Thus, they are presented as an alternative treatment in depression and especially in patients who have not responded to SSRI. Among the drugs mentioned, venlafaxine presents the greatest pharmacodynamic similarities to the TADs, such as imipramine and amitriptyline, although it lacks muscarinic –cholinergic, histaminergic and a1-adrenergic effects. Thus, its profile of adverse reactions is similar to that of the SSRIs (Dierick et al., 1996; Clerc et al., 1994), although it differs from them because of its low protein binding in plasma and its reuptake inhibition of both serotonin and norepinephrine (Feighner, 1994). The antidepressive efficacy of this drug has been proven in studies on different population groups, including outpatients with major depression, inpatients with severe depression and melancholia or elderly patients (Guelfi et al., 1995; Lecrubier et al., 1997; Leonard, 1996; Dierick et al., 1996; Clerc et al., 1994; Mahapatra and Hackett, 1997). Recent studies of venlafaxine treatment for resistant depression conclude that venlafaxine at higher doses is a reasonably well-tolerated and effective alternative and typically should be used before TADs or monoamine oxidase inhibitors. Furthermore, future research is needed to confirm the prediction that switching a SSRI nonresponder to venlafaxine is an effective strategy (Montigny et al., 1999; Poirer and Boyer, 1999; Mitchell et al., 2000; Thase et al., 2000; Schweitzer et al., 2001). This naturalistic study, on the contrary to the traditional clinical trials, makes it possible to evaluate the efficacy and profile of the adverse effects of a drug under clinical
practice conditions (Baier, 1998). This multicenter naturalistic study was planned in order to verify the potential usefulness of venlafaxine in depressed patients who do not respond to SSRI.
2. Methods 2.1. Patient population This 6-month naturalistic study was carried out in the outpatient clinics of several Spanish hospitals coordinated by the Research Group Ramon y Cajal. Patients of both sexes, whose ages were equal to or greater than 18 years, with the DSM-IV (American Psychiatric Association, 1994) diagnosis of major depression (single, recurrent or bipolar episode), with a minimum score of 18 on the 17-item Hamilton Depression Rating Scale (HAM-D) and in which treatment with SSRI had produced an inefficacious result were included. In accordance with Joffe et al. (1996), lack of response to a certain SSRI was defined as a minimum of 4 weeks of treatment at therapeutic doses (20 mg/day of fluoxetine, 50 mg/day of sertraline, 100 mg/day of fluvoxamine, 20 mg/day of paroxetine and 20 mg/day of citalopram), with a final score in the Global Clinical Impression (GCI) of minimum improvement, without changes or worsening. Exclusion criteria for the study were considered as comorbidity with disorders due to drug abuse, psychotic disorders, obsessive-compulsive disorder and eating disorders (anorexia nervosa or bulimia nervosa). 2.2. Drug administration The patients, who fulfilled the requirements established and whenever the treatment with venlafaxine was indicated according to the criteria of the physician, were informed on the characteristics of the investigation, and once they had given their consent to participate in it, they were included in the study with an initial dose of 75 mg/day of this drug (37.5 mg twice a day). Later, the dose could be increased according to the clinical response to a maximum dose of 375 mg/day. As this a naturalistic study, there were no restrictions in the use of anxiolytic and/or hypnotic agents. 2.3. Assessment instruments All assessments were done by a trained psychiatrist with an extensive experience. Patients were assessed at the initial visit and at the end of the 2nd, 4th, 8th and 24th weeks. Treatment response was assessed with 17-item HAM-D (Hamilton, 1960), Hamilton Anxiety Rating Scale (HAMA) (Hamilton, 1959), Montgomery – Asberg Depression Rating Scale (MADRS) (Asberg et al., 1978) and sevenitem GCI (Guy, 1976) of the physician. Treatment response was evaluated in those who have completed at least 4 weeks of treatment by using a criterion of at least 50% of decrease
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on the HAM-D scale and/or a score of 1 (very much improved) or 2 (much improved) on the GCI global improvement scale. Side effects were assessed in all patients who had received at least one dose of venlafaxine. The side effects were evaluated by using the GCI scale of overall tolerability at the end of the study, measuring blood pressure (BP) and heart rate (HR) in all the visits and assessing weights at the first visit and at the end of the study. Adverse reactions were classified as mild, moderate or severe. Severe adverse reactions were defined as those influencing negatively the life quality of the patient. 2.4. Data analysis A descriptive statistical study of demographic parameters was performed and the analysis of variance (ANOVA) with posterior comparison among the groups with the Student’s t and Fisher’s Paired Tests was used to analyze the quantitative variables. The c2 test and the Fisher’s Exact Test were used to compare the qualitative variables. The statistical package chosen for this statistical evaluation was the Windows version of SPSS 7.5.
3. Results A total of 69 patients (20 males and 49 females) with a mean age of 48.9 (S.D.=13.9) years were included. Table 1 shows the main demographic and clinical data and the mean doses used of SSRI. The mean daily dose of venlafaxine at the end of the treatment was 170.4 (S.D.=43.8) mg. Table 1 Demographic and clinical characteristics of the sample Sex Male Female Mean age (years) DSM-IV diagnosis Major depressive disorder, single episode Major depressive disorder, relapsing Type I bipolar disorder, depressive episode Mean duration of actual episode (weeks) Number of previous episodes Family background Background of depression Other psychiatric background Previously prescribed SSRI Fluoxetine Sertraline Paroxetine Fluvoxamine Citalopram
20 (29%) 49 (71%) 48.9 (S.D.=13.9) 29 (42.0%) 39 (56.5%) 1 (1.4%) 18.6 (S.D.=17.8) 2.1 (S.D.=2.6) 18 (26.1%) 13 (18.8%) n
Mean doses (mg)
34 15 10 6 4
25.6 106.7 21.0 158.3 30.0
(S.D.=8.9) (S.D.=45.8) (S.D.=7.4) (S.D.=80.1) (S.D.=11.5)
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Table 2 Changes between baseline evaluation and 6-month evaluation in assessments scales Scales
Baseline
Final evaluation (6 months)
Friedman nonparametric test
HAM-D MADRS HAM-A
23.96 (S.D.=4.31) 31.13 (S.D.=5.82) 20.62 (S.D.=6.05)
8.20 (S.D.=5.54) 10.17 (S.D.=7.87) 7.35 (S.D.=5.79)
c2=143.9, P<.0001 c2=142.2, P<.0001 c2=122.5, P<.0001
Twenty-one of the 69 (30%) did not complete the 6 months of treatment. The reasons for discontinuation from the study were lack of efficacy in 3 (4%) cases, loss of follow-up in 8 (11%) patients, patient’s decision in 4 (6%) cases and side effects in 6 (9%) cases. The side effects related to the withdrawal from the study were nausea (three cases), nervousness (one case), onset of hypertension (one case), and urinary and sexual dysfunction (one case). Ten patients were excluded from the efficacy analysis, as they had not completed the 4 weeks of treatment. All scales used to assess efficacy in the final evaluation comparing to baseline showed a significant difference (Table 2): HAM-D from 23.96 (S.D.=4.31) to 8.20 (S.D.=5.54) (Friedman Nonparametric Test c2=143.9, P<.0001), MADRS from 31.13 (S.D.=5.82) to 10.17 (S.D.=7.87) (Friedman Nonparametric Test c2 =142.2, P<.0001) and HAM-A from 20.62 (S.D.=6.05) to 7.35 (S.D.=5.79) (Friedman Nonparametric Test c2=122.5, P<.0001). A 69% decrease was obtained in the HAM-D, 70% in the MADRS and 67% in the HAM-A. Regarding the primary definition of treatment response, 48 of 59 (81%) patients showed a reduction in the HAM-D score greater than 50% regarding the baseline and 44 (74%) were considered quite or very improved in the GCI of the physician. Both criteria were fulfilled in 69% of the cases (41 patients). In the tolerability analysis, all of the 69 patients who participated in the study were included. Of them, 32 (46%) did not report any adverse reaction during the study while 37 (54%) showed some adverse effect, with an intensity evaluated as mild in 12 (17%) patients, moderate in 21 (30%) and severe in 4 (6%) cases: insomnia, dry mouth, sexual dysfunction and nausea. Table 3 shows side effects. The most frequent were dry mouth (23%), gastrointestinal problems (16%), anxiety (14%) and constipation (10%). In the BP study, no overall significant change appeared in the evolution of the mean score of the systolic BP [baseline SBP of 126.03 (S.D.=15.8) mmHg and final systolic BP of 125.74 (S.D.=11.82) mmHg, ANOVA F=1.12, P=.365] or the diastolic BP [baseline DBP of 76.18 (S.D.=11.81) mmHg and final DBP 77.79 (S.D.=10.24) mmHg, ANOVA F=1.49, P=.230]. However, as has been previously mentioned, one patient was withdrawn from the study due to the onset of hypertension during the study. There were no significant changes in the HR during the study [baseline HR 76.6 (S.D.=13.5) beats/min and final HR 76.33 (S.D.=10.79) beats/min, ANOVA F=0.36, P=.834]. Regarding weight, a significant increase was observed in the final
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Table 3 Most frequent adverse effects observed during treatment with venlafaxine Adverse reactions
n (%)
Dry mouth Gastrointestinal symptomsa Anxiety Constipation Mictional disorders Sexual dysfunction Sedation Dizziness Sweating Headache Skin disorders Others
16 (23) 11 (16) 10 (14) 7 (10) 5 (7) 3 (4) 2 (3) 2 (3) 2 (3) 2 (3) 2 (3) 5 (9)
a Nausea/vomiting reported in 8 (11%) patients and the gastrointestinal discomfort reported by 3 (4%) patients are included in this section.
visit (69.5 kg, S.D.=12.0) compared to the mean on the baseline visit (68.1 kg, S.D.=12.3) (Student’s t test for paired data=2.53, P=.013). The GCI on the overall tolerability was evaluated in 47 patients who completed the 6 months of the study. In 2 (4%) patients, side effects interfered with patients’ functioning. In 24 (51%) patients, there was no significant interference with patient’s functioning . In 21 (45%) patients, there were no side effects during the study. However, we must remember the fact that the six patients that withdrew from the study did so due to adverse reactions.
4. Discussion The objective of our study was to evaluate the efficacy of venlafaxine in the treatment of depressed patients who had not responded to previous treatment with a SSRI. According to the results obtained and following a strict criterion, venlafaxine was efficient at a mean dose of 175 mg/day in two out of every three patients who received this drug for a minimum of 4 weeks, because 70% of the patients who complied with this final condition fulfilled the two primary criteria of efficacy established, that is, a reduction in the score of the HAM-D that was greater than 50% together with a ‘‘very improved’’ or ‘‘quite improved’’ GCI in the final visit. Using a less restricted evaluation, the efficacy percentage would be increased to 75% if only the GCI is considered and up to 81% if only the reduction in the HAMD is considered. In these patients, significant decreases ( P<.005) were also obtained in the final visit regarding the baseline one in all of the efficacy evaluation scales, including both the depression (HAM-D and MADRS) and the anxiety (HAM-A) ones. No previous studies that evaluated the efficacy of venlafaxine after therapeutic failure with SSRI were found in the literature. However, several double-blind trials manifested a greater efficacy of venlafaxine compared to fluoxetine in patients who were hospitalized with major
depression with melancholia and in outpatients with major depression (Dierick et al., 1996; Clerc et al., 1994). In addition, venlafaxine was efficient in a double-blind randomized study in which 75, 225 and 375 mg of this drug were compared with a placebo in outpatients with major depression (Schweitzer et al., 1991). In this work, five patients who had not improved with several antidepressive agents responded to venlafaxine. Based on these results, Nieremberg et al. (1994) performed an open study on 84 patients with resistant depression with increasing doses of venlafaxine during a 6-month period until a maximum of 450 mg/day was reached: 40% of the patients responded to treatment. Our work reveals higher recovery rates, possibly due to the different population studied because the Nieremberg group used a classical definition of ‘‘resistant depression’’ as an inclusion criterion, that is, patients who did not respond to three different antidepressive agents, one of them tricyclic or who had not responded to two antidepressives, one of them tricyclic and electroconvulsive treatment (in both cases, the fact of having tried, at least on one occasion, to strengthen the antidepressive therapy with lithium, thyroid hormones or carbamazepine was contemplated). Recent studies of venlafaxine treatment for resistant depression found response rates more similar to our study (Montigny et al., 1999; Poirer and Boyer, 1999; Mitchell et al., 2000; Schweitzer et al., 2001). Regarding the doses, the different population included in these studies can also explain why the doses used in our work were not so high. In our study, the mean dose was 170.4 (S.D.=43.8) mg/day versus 245, 260 or 300 mg/day used in the studies of Nieremberg et al. (1994), Montigny et al. (1999) and Mitchell et al. (2000). Appearance of undesirable adverse reactions is one of the most common reasons for lack of treatment compliance and consequently for the persistence of depressive symptoms (Thase and Rush, 1997). In our study, tolerability was evaluated as ‘‘fair’’ in only two patients of those who completed the study, so that 95% of them showed good tolerability to the drug. In addition, in 89% of the cases, the adverse effects were mild or moderate. However, to correctly evaluate tolerability, it is necessary to include those patients who had prematurely withdrawn from the study due to adverse effects. These added up to six, so that the percentage of poor tolerability reaches 13% of all the patients included in the study. This value is closer to that calculated by different authors on patients who do not tolerate a certain antidepressive treatment and who calculate them to be 10 –20% (Feighner, 1994; Depression Guideline Panel, 1993; Thase and Rush, 1997). In this sense, it can be stated that the nature of this present investigation, due to its observational character, makes it possible to evaluate and quantify the adverse reactions of a drug in the real conditions of its use (Baier, 1998). The percentage of patient withdrawal due to adverse reactions was 9%, a value that is similar to that reported in other studies with venlafaxine, 8% in an open study with 300 depressed (Lecable et al., 1995) and 9% in the Nierem-
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berg study on 84 patients with resistant depression (Nieremberg et al., 1994). The profile of adverse effects observed in our study is similar to that of previous studies, which have reported the appearance of nausea, headache, dry mouth, insomnia, constipation, dizziness and drowsiness as the most common (Feighner, 1994; Guelfi et al., 1995; Leonard, 1996). Although venlafaxine is similar to the SSRIs in type of undesirable effects, it seems to lack the stimulating effect of fluoxetine (Clerc et al., 1994; Scheweizer et al., 1994; Cunningham et al., 1994; Guelfi et al., 1995) although one patient in our study withdrew from the study in the first visit due to the appearance of nervousness. Venlafaxine-induced nausea appears to decrease in most patients after 4 weeks (Rudolph and Derivan, 1996; Frazer, 1997). In our study, 2 (3%) patients withdrew from the treatment early due to nausea, but the overall incidence reached was 11%. Several authors have reported the possible incidence of an increase in BP, depending on the dose, during treatment with venlafaxine. According to a review of the studies carried out, doses of up to 100 mg/day were not associated to an increase in BP that was greater than with the placebo, while in patients who received a dose between 101 and 300 mg the percentage of increase was three to four times superior to the placebo, although this increase was not maintained in half of the cases even if treatment was continued (Frazer,1997; Rudolph and Derivan, 1996). In this study, 1 (1%) patient was withdrawn due to high BP, which is similar to 0.95% of dropouts due to hypertension in more than 2000 patients entered in a venlafaxine double-blind study (Feighner, 1994). Sexual dysfunction induced by antidepressive agents is an undesirable effect that is receiving growing attention due to its high incidence (up to 40% of the patients treated could experience some form of sexual dysfunction) and to the limitations that its appearance generally provoke in treatment compliance, especially during the maintenance period (Balon et al., 1993). It has been reported that venlafaxine could also cause sexual dysfunction, more frequently in men than in women (Preskom, 1995). In our study, sexual dysfunction was reported by 4% of the patients. Finally, in spite of the advantages that observational studies offer regarding improved knowledge on how a certain drug acts under clinical conditions, the fact of this was an open study imposes limitations when interpreting the results. Thus, although the results of this investigation support the efficacy and tolerability of venlafaxine in patients with depression who have not responded to a previous treatment with a SSRI, it seems that double-blind studies need to be carried out to generalize these conclusions.
5. Conclusion The results of our study support the efficacy and tolerability of venlafaxine in patients suffering from depression who have not responded to usual doses of SSRI.
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This naturalistic study suggest that new studies using double-blind design need to be carried out to verify that venlafaxine may be effective in depressive patients who have not responded to SSRI treatment.
Acknowledgements This study was supported by Wyeth-Ayerst Laboratories.
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