193
Journal of Affective Disorders, 20 (1990) 193-200 Elsevier
JAD 00757
Fluoxetine
in tricyclic refractory
major depressive
disorder
Charles M. Beasley, Jr., Mary E. Sayler, Gregory E. Cunningham, Alan M. Weiss and Daniel N. Masica Division ofClinical Neurosciences,
Lilly Research Laboratories, Eli Lilly and Compqv, IN 46285, U.S.A.
Lilly Corporate Center, Indianapolis,
(Received 16 October 1989) (Accepted 27 July 1990)
Summary Data regarding open-label treatment with fluoxetine following failure to respond to tricyclic antidepressants (TCAs) or intolerance of TCA side effects, suggest a response rate between 51.4% and 62.1%, depending on the definition of TCA refractoriness employed. Double-blind study of this issue would
extend these findings. Fluoxetine is well tolerated in patients unable to tolerate TCAs. Within this population, more than 80% of patients unable to tolerate TCAs found fluoxetine acceptable. Fluoxetine, as an alternative to polypharmaceutical augmentation, may represent a logical choice as the next step in therapy for a patient who has initially been treated with a TCA and has proven refractory or intolerant.
Key words:
Fluoxetine;
Refractory
depression;
Tricyclic
Introduction Fluoxetine from tricyclic
antidepressants
(Fuller et al., 1974; Richelson and Nelson, 1984; Richelson and Pfenning, 1984; Wander et al., hydrochloride antidepressants
(Prozac@)
differs
(TCAs), monoamine oxidase inhibitors (MAOIs), and the atypical second generation compounds (amoxapine, maprotiline, trazodone) in that it selectively inhibits as opposed to inhibiting serotonin uptake, norepinephrine or dopamine uptake; does not antagonize neurotransmitter receptors; and is without monoamine oxidase inhibitory activity
Address for correspondence: Charles M. Beasley, Jr., M.D., Lilly Research Laboratories, Lilly Corporate Center, 31/2, Indianapolis, IN 46285, U.S.A. 0165-0327/90/$03.50
1986). weeks)
Furthermore, following non-acute (2-4 exposure it does not lead to a downregu-
lation of fi-adrenergic receptors or decreased /3adrenergic stimulated CAMP generation, but is associated with downregulation of 5-HT, recep-
tors (Schmidt et al., 1977; Wong and Baymaster, 1981; Wong et al., 1985). Electrophysiologic studies (Blier et al., 1988) suggest that it results in a net increase in transsynaptic serotonergic transmission due to decreased presynaptic inhibitory autoreceptor function. The unique pharmacology of fluoxetine gives rise to questions regarding potential differential response to TCAs and fluoxetine. However, the
6 1990 Elsevier Science Publishers B.V. (Biomedical
Division)
194
efficacy of fluoxetine in treating unselected cases of major depressive disorder (MDD) is equivalent to that of TCAs. Three large, multicenter trials comparing fluoxetine to placebo have shown response rates (21-item Hamilton Rating Scale for Depression (HAMD,,) decrease of 2 50%) of: 63% (n = 123, dose: variable) (Stark and Hardison, 1985); 61% (n = 71, dose: 40 mg/day) (Wernicke et al., 1987); and 65% (n = 68, dose: 40 mg/day) (Wernicke et al., 1988). In a large, multicenter, direct comparison with imipramine, the response rate for fluoxetine was 63% (n = 123, dose: variable) and for the imipramine 65% (n = 131, dose: 85% of patients 2 150 mg/day) (Stark and Hardison, 1985). In spite of the similarity of the response rate for fluoxetine to that of TCAs in unselected cases of MDD, the potential for differential response to TCAs and fluoxetine in special populations remains. Reimherr et al. (1984) retrospectively analyzed response in patients treated with fluoxetine or imipramine in a double-blind trial. Of patients with poor or questionable past response to antidepressants who were treated with imipramine (n = 27) 30% were responders. For a similar population treated with fluoxetine (n = 40) 43% responded. When only definite non-responders to prior therapies were considered, the response rate for fluoxetine remained 43%, but the response rate for imipramine declined to 21%. These data suggest that a significant percentage of patients failing TCA therapy A major issue
may respond
to fluoxetine.
in studying refractory depression is the definition of ‘refractory’. Various definitions of adequacy of a therapeutic trial and lack of adequate change in severity have been developed, but there is no universal consensus (Schatzberg et al., 1983; Roose et al., 1986; Paykel and Van Woerkom, 1987; Delgado et al., 1988; Georgatos and McCue, 1988). Since there is no consensus as to what constitutes an adequate therapeutic trial of an antidepressant agent, it is important to examine various levels of refractoriness when addressing efficacy of a particular antidepressant class in patients ‘refractory’ to another class. There is potential interest in both a rigidly defined primary pharmacologically refractory illness as well as a more clinically meaningful concept of refractory illness com-
bining patients who cannot tolerate a given agent along with those whose illness will not respond even with high doses and lengthy trials. Methods
Patients treated in double-blind fashion with placebo or one of three tricyclic antidepressants (imipramine, amitriptyline, doxepin) in one of five protocols evaluating the antidepressant efficacy of fluoxetine during acute treatment were eligible for crossover to open-label treatment with fluoxetine if: (1) the patient completed at least 2 weeks of double-blind therapy and terminated early because of lack of efficacy or an adverse event; (2) the patient completed the study and, in the opinion of the investigator, ‘failed to show clinically significant response’ to the double-blind therapy; or (3) the patient terminated the study early but under circumstances different from (1) above (e.g., discontinuing double-blind therapy before completion of 2 weeks for adverse events) and thus could be considered by the sponsor on an individual basis for cross-over. In these five protocols, subjects were adult inpatients and outpatients meeting DSM-III criteria for major depression but of at least 4 weeks duration, with a HAMD,, 2 20 immediately prior to beginning double-blind therapy. Patients underwent a l-week, single-blind, placebo period prior to beginning double-blind therapy. If HAMD,, dropped below 20 or decreased 20% or more during that placebo week, patients were discontinued. Patients’ clinical status was monitored weekly with Clinical Global Impression (CGI) HAMD,,, Severity and Change Scales, Raskin Depression Scale, Covi Anxiety Scale, Self-Rating Symptom Scale (58), and Patient Global Impression Scale. In one protocol with amitriptyline the length of double-blind therapy was 5 weeks, while in two with imipramine and two with doxepin the length was 6 weeks. The TCA dosage could be titrated up to 300 mg/day in four protocols, and up to 200 mg/day in one doxepin protocol, where all patients were older than 64 years. Patients who were taking a tricyclic at the time of termination from the double-blind study were given 1 week off drug before beginning fluoxetine and those crossing over from placebo started fluoxetine treatment at
195
the time of termination. Eight of 188 double-blind, TCA-treated patients who crossed over to openlabel fluoxetine actually had up to 3 weeks of open-label TCA following completion of the double-blind protocol prior to the 1 week off drug before beginning open-label fluoxetine. For these eight patients, all analyses (efficacy and tolerability) of TCA therapy consider only the period of double-blind TCA treatment. Six of 149 doubleblind, placebo-treated patients who crossed over to open-label fluoxetine actually had 1 week off therapy before beginning fluoxetine. After beginning fluoxetine, patients continued to be evaluated on a weekly basis during the first 6 weeks of open-label therapy (patients crossed over from double-blind TCA therapy were eligible for up to 54 weeks of fluoxetine therapy) and less frequently thereafter. They were evaluated with the same instruments and examinations as during the double-blind portion of the study. Fluoxetine could be titrated up to 80 mg/day for all crossover, open-label therapy patients. In order to analyze the data in a fashion comparable to the initial acute double-blind antidepressant trials, analysis was restricted to a consideration of changes during the first 6 weeks (5 weeks for double-blind amitriptyline patients) of open-label fluoxetine therapy. We employed three definitions of refractoriness to TCA that incorporate increasingly restrictive criteria: (I) Definition I (a) Crossed over from double-blind TCA therapy; TABLE
(b) Received any length of TCA therapy up to double-blind
completion;
(cl Received any dose of TCA; (4 HAMD,, 2 16 at initiation of fluoxetine. (II) Definition 2 Crossed over from double-blind TCA therapy; Received at least 4 weeks TCA therapy; Received any dose of TCA therapy; Failed to improve by a 2 50% decrease in HAMD,, during TCA therapy; (e) HAMD,, 2 16 at initiation of fluoxetine. (III) Definition 3 (a) Crossed over from double-blind TCA therapy; (b) Received at least 4 weeks of TCA therapy; (c) Received dose of at least 150 mg/day of TCA at some point during the double-blind trial; (d) Failed to improve by a 2 30% decrease in HAMD,, during TCA therapy; (e) HAMD,, 2 16 at initiation of fluoxetine. (a) (b) (c) (d)
Results Demographics Table 1 displays demographic characteristics of several groups of patients treated with TCAs during double-blind therapy. Patients refractory to TCAs by Definition 2 who crossed over to openlabel fluoxetine (column 4) differed little at baseline from either TCA responders (column 2) or the general population of other TCA-treated patients (column 1 - responders and non-responders, either failing to meet Definition 2 or meeting Definition 2 and electing not to cross over). Additionally,
1
DEMOGRAPHIC
CHARACTERISTICS
OF PATIENTS
1 All patients (except Defin. 2 refractory who did cross to fluox.) Number (male : female) Age (years) a Baseline HAMD a Final HAMD ’ Maximum TCA dose (mUday) a Mean+SD.
a
RECEIVING
DOUBLE-BLIND
2 All patients HAMD,, 1 2 50%
82:150 47*15 2s+ 6 lo* 7
65 : 121 46_+15 27k 6 7f 4
225 + 65
225 5 65
TCA FOR AT LEAST 4 WEEKS
3 All Defin. 2 refractory patients who did not cross to fluox. 0:l 44 35 16 200
4 All Defin. 2 refractory patients who did cross to fluox. 17146 49*15 28+ 5 22k 5 240 k 68
196 TABLE
2
RESPONSE ACHIEVED PATIENTS MENT
RATES AND MAXIMUM DOSE OF DRUG DURING DOUBLE-BLIND THERAPY FOR RECEIVING AT LEAST 4 WEEKS OF TREAT-
Drug
N” (o/c response)
Amitriptyline Doxepin Imipramine Fluoxetine Placebo
20 88 187 313 130
(45) (61) (66) (61) (38)
Dose achieved (mean i SD)
(mg/day)
Responders
Non-responders
253 * 57 209 + 65 230 2 64 74+13 _
286 i 45 205 * 80 241 _t 51 17* 8 _
Response: t 50% decrease in HAMD,, total from initiation treatment to last visit. “ N: number of patients completing 4+ weeks.
of
only one patient who qualified as refractory by Definition 2 elected not to cross over to fluoxetine (column 3). Efficucy in double-blind therapy Table 2 displays the response rates (responder: 2 50% decrease in HAMD,, from initiation of active medication to last visit on double-blind therapy) for patients completing at least 4 weeks of double-blind therapy and having complete HAMD,,s at baseline and endpoint. Data from multiple protocols for an individual drug were combined in this table. Overall, 463 patients began double-blind TCA therapy and 295 (64%) completed at least 4 weeks, of which 186 (63%) were responders. For double-blind fluoxetine, 457 patients began therapy and 313 (68%) completed at least 4 weeks, of which 192 (61%) were responders. For double-blind placebo, 235 patients began therapy, 130 (55%) completed at least 4 weeks, and 49 (38%) of these were responders. Table 2 also indicates the maximum dose of drug achieved for some period of time during double-blind therapy for each drug, broken down for responders vs. non-responders. These data are for only those patients who remained in doubleblind therapy at least 4 weeks. Although there was considerable interpatient variability, the means for all TCA-treated groups were in excess of 200 mg/day.
Efficacy in TCA refructoty depresson Of the 463 patients who entered double-blind TCA therapy and 235 patients who entered double-blind placebo therapy, 188 TCA patients and 149 placebo patients crossed over to open-label fluoxetine. Of the 188 TCA patients, three did not have complete HAMD,, scores recorded at double-blind baseline, and two did not have complete HAMD,, scores recorded during double-blind therapy prior to crossing over to open-label fluoxetine; these five patients have been eliminated from the efficacy analysis. Two of the 149 placebo patients did not have complete HAMD,, scores recorded at double-blind baseline and have been eliminated from the efficacy analysis. Fifteen of the remaining 183 patients crossed over from TCA, and five of the remaining 147 patients crossed over from placebo did not have complete HAMD?, scores recorded at the initiation of fluoxetine; these patients have been eliminated from the efficacy analysis. An additional 11 TCA patients and nine placebo patients were eliminated from the efficacy analyses as their HAMD,, scores were not 2 16 at the initiation of fluoxetine. Twentyfive of the remaining 157 TCA patients and 28 of the remaining 133 placebo patients were eliminated from efficacy analyses as they did not complete at least 4 weeks of open-label treatment with fluoxetine. These patients were eliminated from the efficacy analyses in order to equate time of exposure to fluoxetine with time of exposure to TCA as required by the two more restrictive definitions of TCA refractoriness and to equate the exposure time for patients included in Table 2 which reports response rate during double-blind therapy. There were 237 patients (132 - TCA, 105 ~placebo) remaining after 4 weeks of open-label fluoxetine, from the 290 who began fluoxetine. with a total HAMD,, score 2 16 and for whom complete baseline and endpoint data were available. This constitutes 82% of the original 290 patients. Table 3 summarizes our findings regarding efficacy of fluoxetine in TCA refractory depression. This table also summarizes the efficacy of fluoxetine in double-blind placebo non-responders. Data include the HAMD,, and CGI Severity scales. Changes are from baseline (immediately prior to beginning open-label fluoxetine) to the last visit or
197 TABLE
3
FLUOXETINE
EFFICACY N
Baseline HAMD,,
IN TCA REFRACTORY
a
Baseline CGI Severity
a
AND
PLACEBO
NON-RESPONSIVE
PATIENTS
HAMD change a
CGI Severity change a
%Response HAMD,, ’
SRemission HAMD,, ’
?&Remission CGI Severity
Definition 1 TCA Placebo e
132 105
25.6 (5.5) 25.0 (5.3)
4.40 (0.77) 4.35 (0.68)
- 13.1 (8.5) * - 13.0 (8.2) *
- 1.82 (1.35) * - 1.68 (1.27) *
62.1 61.9
31.1 30.5
51.5 46.7
Definition 2 TCA Placebo e
53 53
26.2 (6.3) 22.8 (4.5)
4.51 (0.89) 4.26 (0.65)
- 11.8 (8.7) * - 11.0 (8.3) *
-1.55 (1.25) * - 1.55 (1.31) *
52.8 54.7
20.8 41.5
34.0 47.2
Definition 3 TCA Placebo e
35 44
26.5 (5.3) 23.5 (4.5)
4.60 (0.77) 4.32 (0.67)
-12.0 (7.6) * - 12.2 (8.1) *
-1.57 (1.20) * - 1.64 (1.31) *
51.4 59.1
17.1 45.5
31.4 50.0
Patients were treated with open-label fluoxetine for 4+ weeks. a Mean (SD). b HAMD,, decrease > 50% from baseline to last visit. ’ HAMD,, I 7 at last visit. d CGI Severity of 1 or 2 at last visit. ’ Placebo patients meet the length of double-blind therapy and maximum definitions but dosage criteria are not applicable. * P < 0.001 (Wilcoxon signed rank test).
6 weeks of open-label fluoxetine for patients continuing past that point. Since patients crossing over to open-label fluoxetine from double-blind amitriptyline had received a maximum of 5 weeks of arnitriptyline, efficacy assessment for those patients was restricted to the first 5 weeks of fluoxetine therapy. All patients were treated at least 4 weeks with open-label fluoxetine. Group mean changes in both HAMD,, and CGI Severity scales indicate that TCA refractory patients of all definitions, and the comparable placebo groups, all showed statistically significant (P < 0.001) improvement from baseline to endpoint. In addition to these analyses, several categorical data analyses were performed. Response (HAMD,, decrease 2 50%) and remission (final HAMD,, I 7) rates were calculated, as well as CGI Severity remission rates (final of 1 or 2). As can be seen in Table 3, these categorical rates of improvement for TCA refractory patients decreased from Definition 1 to Definition 3. This pattern is more apparent in the HAMD,, and CGI remission rates than in the HAMD,, response rates. This pattern of decreased improvement is not apparent among the patients initially treated with double-blind placebo. Differences in improvement rates on fluoxetine between TCAthe
visit
at
allowable
HAMD;L, decrease
criteria
d
of the respective
and placebo-treated patients are more apparent when considering remission rates than response rates. Mean baseline and final visit HAMD,, scores are shown in Table 4 for the TCA refractory patients organized by definition of refractoriness and category of response (as defined by HAMD,, change) within those definitions. These data provide information regarding the extent of improveTABLE
4
PRE- AND POST-TREATMENT MEAN HAMD,, FOR RESPONDERS AND NON-RESPONDERS TO OPEN-LABEL FLUOXETINE AMONG TCA REFRACTORY PATIENTS N
Baseline HAMD,, mean (SD)
Final HAMD,, mean (SD)
Definition 1 Responders a Non-responders
82 50
25.5 (5.1) 35.8 (6.1)
7.3 (3.7) 21.2 (6.4)
Definition 2 Responders a Non-responders
28 25
25.6 (6.0) 26.8 (6.7)
7.9 (3.6) 21.6 (6.4)
Definition 3 Responders a Non-responders
18 17
25.9 (5.4) 27.1 (5.3)
8.3 (3.8) 21.0 (4.5)
Patients were treated a HAMD,, decrease
with open-label fluoxetine for 4+ z 50% from baseline to last visit.
weeks.
198 TABLE
5
DISCONTINUATIONS
SECONDARY
TO ADVERSE
Open-label
therapy
Fluoxetme
TCA
Flumetine
from TCA
451 85 18.6
463 137 29.6
188 25 13.3
Double-blind
Entered Discontinued secondary to AE % Discontinued secondary to AE
EVENTS therapy
ment among those patients defined categorically as responders. Maximum dosages of fluoxetine for responders and non-responders who were refractory to TCAs by the various definitions above were: Definition 1 - responders 73 + 11, non-responders 78 f 11: Definition 2 ~ responders 74 f 9, non-responders 78 f 11; Definition 3 - responders 74 f 9. non-responders 79 i_ 9 mg/day. These doses were comparable to those achieved on fluoxetine during double-blind therapy by both responders and non-responders. Tolerability of fluoxetine Relative tolerability of potentially bothersome adverse events (AEs) associated with fluoxetine therapy relative to TCA therapy was assessed by comparing rates of discontinuation from therapy due to AEs during the various components of the study. For this analysis, all patients were considered during the entire time period of the doubleblind trials (5 or 6 weeks) and then during the first 6 weeks of open-label fluoxetine (first 5 weeks for those patients crossed over from amitriptyline who could receive a maximum of 5 weeks of TCA therapy). This procedure was adopted to equate the time period of risk during which TCAs and fluoxetine could be discontinued. Table 5 displays data for patients entered and discontinued for AEs during double-blind therapy with fluoxetine and TCAs and then during cross-over therapy with fluoxetine from double-blind TCA. Recall that these patients could cross over to fluoxetine for either lack of antidepressant response or AEs with TCAs. In the double-blind portion of the study, patients treated with fluoxetine and TCAs were approximately equal, 457 and 463 respectively.
Flumetine secondary
from TCA to AE
85 16 1X.8
Rates of discontinuation for AEs during double-blind treatment were 18.6% for fluoxetine and 29.6% for TCAs. It is notable that among those 188 patients crossed over to open-label fluoxetine from TCAs, the rate of discontinuation for AEs, 13.3%. was actually lower than in the double-blind fluoxetine group. Of the 137 patients who discontinued a TCA secondary to an AE, 85 elected to undergo open-label fluoxetine therapy. Of these 85. only 16 (18.8%) discontinued fluoxetine during 6 weeks of therapy (or 5 weeks for double-blind amitriptyline patients). In other words, of 85 patients unable to tolerate TCAs, 81.2% tolerated fluoxetine through an equivalent period of time. There were 110 patients who continued openlabel fluoxetine, after crossing over from doubleblind TCA, for longer than 6 weeks and up to 1 year. Of these. 15 discontinued for an AE, giving a rate of 13.6% for delayed discontinuation.
Discussion A major issue in evaluating these findings regarding the efficacy of fluoxetine in the treatment of patients with depression refractory to TCAs is the lack of a parallel control group. Several considerations bear on this issue. First. these patients had just failed a single-blind placebo period of 1 week as well as TCA therapy, with adequacy of TCA therapy defined by several sets of increasingly rigorous criteria. This argues against a substantial placebo response contributing to the response to fluoxetine. However, treatment with fluoxetine was open-label, and it was known to be an experimental drug. This might contribute some additional placebo effect, particularly in a patient population who voluntarily chose to participate in
199
this open-label treatment rather than being randomly assigned. On the whole then, some placebo response might have contributed to the fluoxetine response, but it would be expected to be at least somewhat less than the approximately 40% seen in double-blind placebo-controlled trials (Stark and Hardison, 1985; Wernicke et al., 1987, 1988). Another important issue in considering efficacy is the potential for spontaneous remission during the fluoxetine period of therapy. By the end of 6 weeks of fluoxetine, these patients had been in treatment for as long as 14 weeks (1 week placebo washout, 6 weeks double-blind TCA, 1 week off drug, 6 weeks fluoxetine). Given that period of observation, some patients might be cycling out of the episode for which they entered treatment. It is difficult to estimate the extent to which such spontaneous remissions may have contributed to the observed efficacy of fluoxetine. The response rate (51.4-62.1%. depending on the definition) to open-label fluoxetine in TCA refractory depression is comparable to that reported in response to monoamine oxidase inhibitors in TCA refractory depression. McGrath et al. (1978) reported a 59% response rate to phenelzine in patients with mood reactive depression refractory to imipramine, and Georgotas et al. (1983) reported a 65% response rate in geriatric patients with depression refractory to TCA therapy. The lack of numerical differences between these rates of response among patients initially treated with TCAs and those of patients initially treated with placebo deserve special comment. Larger differences in response rates, with a relatively greater response among patients initially treated with placebo, might be expected if the TCA therapy was acting to select a group of patients with refractory depression. Additionally, it might be expected that patients initially treated with and refractory to TCAs would have a lower response rate during open-label fluoxetine than those treated with fluoxetine during double-blind therapy. With the more restrictive Definitions (2 and 3) of refractoriness, the response to open-label fluoxetine among patients refractory to TCAs does show a trend toward being less than that seen among patients refractory to placebo and being less than that seen with double-blind fluoxetine therapy, Furthermore, the differences in remission
rates suggest that the TCA- and placebo-treated groups were different. The further investigation of the impact of fluoxetine in such disorders would best be accomplished through reallocation of patients failing to improve on double-blind TCA to double-blind placebo, repeat TCA, or fluoxetine. For ethical reasons, such a study is unlikely to occur. Alternatively, reallocation to double-blind therapy with a different TCA or a member of another therapeutic class (MAOI) might yield improved, but still approximate, data regarding the above issues. The tolerability data are perhaps less potentially confounded than the efficacy data. The fluoxetine discontinuation rate of 18.8% among the 85 patients who could not tolerate TCAs did not differ from that of the unselected, randomly assigned fluoxetine population whose discontinuation rate for AEs was 18.6%. These data are particularly notable given the aggressive dosing of fluoxetine. For all Definition groups, the mean daily dose of fluoxetine exceeded 70 mg, which is considerably higher than the 20-40 mg/day doses currently used most frequently. It might be argued that since this treatment was open-label, patients might be better prepared for AEs and, therefore, more tolerant. Offsetting such a possibility is the fact that fluoxetine was experimental during these trials. Such a compound might well be expected to raise additional concerns in a patient prone to experience AEs. References Blier, P.. Chaput. Y. and deMontigny, C. (1988) Long-term 5-HT reuptake blockade, but not monoamine oxidase inhibition, decreases the function of terminal 5-HT autoreceptors: an electrophysiological study in the rat brain. Arch. Pharmacol. 337. 246-254. Delgado. P. et al. (1988) Efficacy of fluvoxamine in treatmentrefractory depression. J. Affect. Disord. 15, 55-60. Fuller. R., Perry, K. and Molloy, B. (1974) Effect of an uptake inhibitor on serotonin metabolism in rat brain: studies with 3-( p-trifluoromethylphenoxy)-N-methy1-3-phenylpropylamine (Lilly 110140). Life Sci. 15. 1161-1171. Georgotas, A. and McCue. R. (1988) What is the adequate length of an antidepressant trial in the elderly? Presented at the Annual Meeting of the Society of Biological Psychiatry. Montreal, May 4, 1988. Georgotas, A. et al. (1983) Resistant geriatric depressions and therapeutic response to monoamine oxidase inhibitors. Biol. Psychiatry 18, 195-205.
McGrath. P. et al. (1978) Treatment of tricyclic refractory depression with a monoamine oxidase inhibitor. Psychopharmacol. Bull. 23. 169-172. Paykel. E. and Van Woerkom, A. (1987) Pharmacologic treatment of resistant depression. Psychiatr. Ann. 17, 327-331. Rein&err, F. et al. (1984) Characteristics of responders to fluoxetine. Psychopharmacol. Bull. 20, 70-72. Richelson, E. and Nelson, A. (1984) Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. J. Pharmacol. Exp. Ther. 230, 94-102. Richelson, E. and Pfenning, M. (1984) Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: most antidepressants selectively block norepinephrine uptake. Eur. J. Pharmacol. 104, 217-286. Roose, S. et al. (1986) Tricyclic nonresponders: phenomenology and treatment. Am. J. Psychiatry 143, 345-348. Schatzberg, A. et al. (1983) Survey of depressed patients who have failed to respond to treatment. In: J. Davis and J. Moss (Eds.), The Affective Disorders. American Psychiatric Press, Washington, DC. Schmidt, M.J. and Thornberry J.F. (1977) Norepinephrinestimulated cyclic AMP accumulation in brain slices in vitro
after serotonin depletion or chronic administration of selective amine reuptake inhibitors. Arch. Int. Pharmacodyn. 229. 42-51. Stark, P. and Hardison. C. (1985) A review of multicenter controlled studies of fluoxetine vs. imipramine and placebo in outpatients with major depressive disorder. J. Clin. Psychiatry 46, 53-58. Wander, T., Nelson, A.. Okazaki, H. and Richelson, E. (1986) Antagonism by antidepressants of serotonin S, and Sz receptors of normal human brain in vitro. Eur. J. Pharmacol. 132. 115-121. Wernicke, J. et al. (1987) Fixed-dose fluoxetine therapy for depression. Psychopharmacol. Bull. 23. 164-168. Wernicke, J. et al. (1988) Low-dose fluoxetine therapy for depression. Psychopharmacol. Bull. 24, 183-188. Wang, D.T. and Bymaster, F.P. (1981) Subsensitivity of serotonin receptors after long-term treatment of rats with fluoxetine. Res. Commun. Chem. Pathol. Pharmacol. 32. 41-51. Wong, D.T., Reid, L.R., Bymaster. F.P. and Threlkeld, P.G. (1985) Chronic effects of fluoxetine. a selective inhibitor of serotonin uptake, on neurotransmitter receptors. J. Neural Transm. 64, 251-269.
Journal of Affective Disorders, 20 (1990) 193-200 Elsevier
JAD 00757
Fluoxetine
in tricyclic refractory
major depressive
disorder
Charles M. Beasley, Jr., Mary E. Sayler, Gregory E. Cunningham, Alan M. Weiss and Daniel N. Masica Division ofClinical Neurosciences,
Lilly Research Laboratories, Eli Lilly and Compqv, IN 46285, U.S.A.
Lilly Corporate Center, Indianapolis,
(Received 16 October 1989) (Accepted 27 July 1990)
Summary Data regarding open-label treatment with fluoxetine following failure to respond to tricyclic antidepressants (TCAs) or intolerance of TCA side effects, suggest a response rate between 51.4% and 62.1%, depending on the definition of TCA refractoriness employed. Double-blind study of this issue would
extend these findings. Fluoxetine is well tolerated in patients unable to tolerate TCAs. Within this population, more than 80% of patients unable to tolerate TCAs found fluoxetine acceptable. Fluoxetine, as an alternative to polypharmaceutical augmentation, may represent a logical choice as the next step in therapy for a patient who has initially been treated with a TCA and has proven refractory or intolerant.
Key words:
Fluoxetine;
Refractory
depression;
Tricyclic
Introduction Fluoxetine from tricyclic
antidepressants
(Fuller et al., 1974; Richelson and Nelson, 1984; Richelson and Pfenning, 1984; Wander et al., hydrochloride antidepressants
(Prozac@)
differs
(TCAs), monoamine oxidase inhibitors (MAOIs), and the atypical second generation compounds (amoxapine, maprotiline, trazodone) in that it selectively inhibits as opposed to inhibiting serotonin uptake, norepinephrine or dopamine uptake; does not antagonize neurotransmitter receptors; and is without monoamine oxidase inhibitory activity
Address for correspondence: Charles M. Beasley, Jr., M.D., Lilly Research Laboratories, Lilly Corporate Center, 31/2, Indianapolis, IN 46285, U.S.A. 0165-0327/90/$03.50
1986). weeks)
Furthermore, following non-acute (2-4 exposure it does not lead to a downregu-
lation of fi-adrenergic receptors or decreased /3adrenergic stimulated CAMP generation, but is associated with downregulation of 5-HT, recep-
tors (Schmidt et al., 1977; Wong and Baymaster, 1981; Wong et al., 1985). Electrophysiologic studies (Blier et al., 1988) suggest that it results in a net increase in transsynaptic serotonergic transmission due to decreased presynaptic inhibitory autoreceptor function. The unique pharmacology of fluoxetine gives rise to questions regarding potential differential response to TCAs and fluoxetine. However, the
6 1990 Elsevier Science Publishers B.V. (Biomedical
Division)
194
efficacy of fluoxetine in treating unselected cases of major depressive disorder (MDD) is equivalent to that of TCAs. Three large, multicenter trials comparing fluoxetine to placebo have shown response rates (21-item Hamilton Rating Scale for Depression (HAMD,,) decrease of 2 50%) of: 63% (n = 123, dose: variable) (Stark and Hardison, 1985); 61% (n = 71, dose: 40 mg/day) (Wernicke et al., 1987); and 65% (n = 68, dose: 40 mg/day) (Wernicke et al., 1988). In a large, multicenter, direct comparison with imipramine, the response rate for fluoxetine was 63% (n = 123, dose: variable) and for the imipramine 65% (n = 131, dose: 85% of patients 2 150 mg/day) (Stark and Hardison, 1985). In spite of the similarity of the response rate for fluoxetine to that of TCAs in unselected cases of MDD, the potential for differential response to TCAs and fluoxetine in special populations remains. Reimherr et al. (1984) retrospectively analyzed response in patients treated with fluoxetine or imipramine in a double-blind trial. Of patients with poor or questionable past response to antidepressants who were treated with imipramine (n = 27) 30% were responders. For a similar population treated with fluoxetine (n = 40) 43% responded. When only definite non-responders to prior therapies were considered, the response rate for fluoxetine remained 43%, but the response rate for imipramine declined to 21%. These data suggest that a significant percentage of patients failing TCA therapy A major issue
may respond
to fluoxetine.
in studying refractory depression is the definition of ‘refractory’. Various definitions of adequacy of a therapeutic trial and lack of adequate change in severity have been developed, but there is no universal consensus (Schatzberg et al., 1983; Roose et al., 1986; Paykel and Van Woerkom, 1987; Delgado et al., 1988; Georgatos and McCue, 1988). Since there is no consensus as to what constitutes an adequate therapeutic trial of an antidepressant agent, it is important to examine various levels of refractoriness when addressing efficacy of a particular antidepressant class in patients ‘refractory’ to another class. There is potential interest in both a rigidly defined primary pharmacologically refractory illness as well as a more clinically meaningful concept of refractory illness com-
bining patients who cannot tolerate a given agent along with those whose illness will not respond even with high doses and lengthy trials. Methods
Patients treated in double-blind fashion with placebo or one of three tricyclic antidepressants (imipramine, amitriptyline, doxepin) in one of five protocols evaluating the antidepressant efficacy of fluoxetine during acute treatment were eligible for crossover to open-label treatment with fluoxetine if: (1) the patient completed at least 2 weeks of double-blind therapy and terminated early because of lack of efficacy or an adverse event; (2) the patient completed the study and, in the opinion of the investigator, ‘failed to show clinically significant response’ to the double-blind therapy; or (3) the patient terminated the study early but under circumstances different from (1) above (e.g., discontinuing double-blind therapy before completion of 2 weeks for adverse events) and thus could be considered by the sponsor on an individual basis for cross-over. In these five protocols, subjects were adult inpatients and outpatients meeting DSM-III criteria for major depression but of at least 4 weeks duration, with a HAMD,, 2 20 immediately prior to beginning double-blind therapy. Patients underwent a l-week, single-blind, placebo period prior to beginning double-blind therapy. If HAMD,, dropped below 20 or decreased 20% or more during that placebo week, patients were discontinued. Patients’ clinical status was monitored weekly with Clinical Global Impression (CGI) HAMD,,, Severity and Change Scales, Raskin Depression Scale, Covi Anxiety Scale, Self-Rating Symptom Scale (58), and Patient Global Impression Scale. In one protocol with amitriptyline the length of double-blind therapy was 5 weeks, while in two with imipramine and two with doxepin the length was 6 weeks. The TCA dosage could be titrated up to 300 mg/day in four protocols, and up to 200 mg/day in one doxepin protocol, where all patients were older than 64 years. Patients who were taking a tricyclic at the time of termination from the double-blind study were given 1 week off drug before beginning fluoxetine and those crossing over from placebo started fluoxetine treatment at
195
the time of termination. Eight of 188 double-blind, TCA-treated patients who crossed over to openlabel fluoxetine actually had up to 3 weeks of open-label TCA following completion of the double-blind protocol prior to the 1 week off drug before beginning open-label fluoxetine. For these eight patients, all analyses (efficacy and tolerability) of TCA therapy consider only the period of double-blind TCA treatment. Six of 149 doubleblind, placebo-treated patients who crossed over to open-label fluoxetine actually had 1 week off therapy before beginning fluoxetine. After beginning fluoxetine, patients continued to be evaluated on a weekly basis during the first 6 weeks of open-label therapy (patients crossed over from double-blind TCA therapy were eligible for up to 54 weeks of fluoxetine therapy) and less frequently thereafter. They were evaluated with the same instruments and examinations as during the double-blind portion of the study. Fluoxetine could be titrated up to 80 mg/day for all crossover, open-label therapy patients. In order to analyze the data in a fashion comparable to the initial acute double-blind antidepressant trials, analysis was restricted to a consideration of changes during the first 6 weeks (5 weeks for double-blind amitriptyline patients) of open-label fluoxetine therapy. We employed three definitions of refractoriness to TCA that incorporate increasingly restrictive criteria: (I) Definition I (a) Crossed over from double-blind TCA therapy; TABLE
(b) Received any length of TCA therapy up to double-blind
completion;
(cl Received any dose of TCA; (4 HAMD,, 2 16 at initiation of fluoxetine. (II) Definition 2 Crossed over from double-blind TCA therapy; Received at least 4 weeks TCA therapy; Received any dose of TCA therapy; Failed to improve by a 2 50% decrease in HAMD,, during TCA therapy; (e) HAMD,, 2 16 at initiation of fluoxetine. (III) Definition 3 (a) Crossed over from double-blind TCA therapy; (b) Received at least 4 weeks of TCA therapy; (c) Received dose of at least 150 mg/day of TCA at some point during the double-blind trial; (d) Failed to improve by a 2 30% decrease in HAMD,, during TCA therapy; (e) HAMD,, 2 16 at initiation of fluoxetine. (a) (b) (c) (d)
Results Demographics Table 1 displays demographic characteristics of several groups of patients treated with TCAs during double-blind therapy. Patients refractory to TCAs by Definition 2 who crossed over to openlabel fluoxetine (column 4) differed little at baseline from either TCA responders (column 2) or the general population of other TCA-treated patients (column 1 - responders and non-responders, either failing to meet Definition 2 or meeting Definition 2 and electing not to cross over). Additionally,
1
DEMOGRAPHIC
CHARACTERISTICS
OF PATIENTS
1 All patients (except Defin. 2 refractory who did cross to fluox.) Number (male : female) Age (years) a Baseline HAMD a Final HAMD ’ Maximum TCA dose (mUday) a Mean+SD.
a
RECEIVING
DOUBLE-BLIND
2 All patients HAMD,, 1 2 50%
82:150 47*15 2s+ 6 lo* 7
65 : 121 46_+15 27k 6 7f 4
225 + 65
225 5 65
TCA FOR AT LEAST 4 WEEKS
3 All Defin. 2 refractory patients who did not cross to fluox. 0:l 44 35 16 200
4 All Defin. 2 refractory patients who did cross to fluox. 17146 49*15 28+ 5 22k 5 240 k 68
196 TABLE
2
RESPONSE ACHIEVED PATIENTS MENT
RATES AND MAXIMUM DOSE OF DRUG DURING DOUBLE-BLIND THERAPY FOR RECEIVING AT LEAST 4 WEEKS OF TREAT-
Drug
N” (o/c response)
Amitriptyline Doxepin Imipramine Fluoxetine Placebo
20 88 187 313 130
(45) (61) (66) (61) (38)
Dose achieved (mean i SD)
(mg/day)
Responders
Non-responders
253 * 57 209 + 65 230 2 64 74+13 _
286 i 45 205 * 80 241 _t 51 17* 8 _
Response: t 50% decrease in HAMD,, total from initiation treatment to last visit. “ N: number of patients completing 4+ weeks.
of
only one patient who qualified as refractory by Definition 2 elected not to cross over to fluoxetine (column 3). Efficucy in double-blind therapy Table 2 displays the response rates (responder: 2 50% decrease in HAMD,, from initiation of active medication to last visit on double-blind therapy) for patients completing at least 4 weeks of double-blind therapy and having complete HAMD,,s at baseline and endpoint. Data from multiple protocols for an individual drug were combined in this table. Overall, 463 patients began double-blind TCA therapy and 295 (64%) completed at least 4 weeks, of which 186 (63%) were responders. For double-blind fluoxetine, 457 patients began therapy and 313 (68%) completed at least 4 weeks, of which 192 (61%) were responders. For double-blind placebo, 235 patients began therapy, 130 (55%) completed at least 4 weeks, and 49 (38%) of these were responders. Table 2 also indicates the maximum dose of drug achieved for some period of time during double-blind therapy for each drug, broken down for responders vs. non-responders. These data are for only those patients who remained in doubleblind therapy at least 4 weeks. Although there was considerable interpatient variability, the means for all TCA-treated groups were in excess of 200 mg/day.
Efficacy in TCA refructoty depresson Of the 463 patients who entered double-blind TCA therapy and 235 patients who entered double-blind placebo therapy, 188 TCA patients and 149 placebo patients crossed over to open-label fluoxetine. Of the 188 TCA patients, three did not have complete HAMD,, scores recorded at double-blind baseline, and two did not have complete HAMD,, scores recorded during double-blind therapy prior to crossing over to open-label fluoxetine; these five patients have been eliminated from the efficacy analysis. Two of the 149 placebo patients did not have complete HAMD,, scores recorded at double-blind baseline and have been eliminated from the efficacy analysis. Fifteen of the remaining 183 patients crossed over from TCA, and five of the remaining 147 patients crossed over from placebo did not have complete HAMD?, scores recorded at the initiation of fluoxetine; these patients have been eliminated from the efficacy analysis. An additional 11 TCA patients and nine placebo patients were eliminated from the efficacy analyses as their HAMD,, scores were not 2 16 at the initiation of fluoxetine. Twentyfive of the remaining 157 TCA patients and 28 of the remaining 133 placebo patients were eliminated from efficacy analyses as they did not complete at least 4 weeks of open-label treatment with fluoxetine. These patients were eliminated from the efficacy analyses in order to equate time of exposure to fluoxetine with time of exposure to TCA as required by the two more restrictive definitions of TCA refractoriness and to equate the exposure time for patients included in Table 2 which reports response rate during double-blind therapy. There were 237 patients (132 - TCA, 105 ~placebo) remaining after 4 weeks of open-label fluoxetine, from the 290 who began fluoxetine. with a total HAMD,, score 2 16 and for whom complete baseline and endpoint data were available. This constitutes 82% of the original 290 patients. Table 3 summarizes our findings regarding efficacy of fluoxetine in TCA refractory depression. This table also summarizes the efficacy of fluoxetine in double-blind placebo non-responders. Data include the HAMD,, and CGI Severity scales. Changes are from baseline (immediately prior to beginning open-label fluoxetine) to the last visit or
197 TABLE
3
FLUOXETINE
EFFICACY N
Baseline HAMD,,
IN TCA REFRACTORY
a
Baseline CGI Severity
a
AND
PLACEBO
NON-RESPONSIVE
PATIENTS
HAMD change a
CGI Severity change a
%Response HAMD,, ’
SRemission HAMD,, ’
?&Remission CGI Severity
Definition 1 TCA Placebo e
132 105
25.6 (5.5) 25.0 (5.3)
4.40 (0.77) 4.35 (0.68)
- 13.1 (8.5) * - 13.0 (8.2) *
- 1.82 (1.35) * - 1.68 (1.27) *
62.1 61.9
31.1 30.5
51.5 46.7
Definition 2 TCA Placebo e
53 53
26.2 (6.3) 22.8 (4.5)
4.51 (0.89) 4.26 (0.65)
- 11.8 (8.7) * - 11.0 (8.3) *
-1.55 (1.25) * - 1.55 (1.31) *
52.8 54.7
20.8 41.5
34.0 47.2
Definition 3 TCA Placebo e
35 44
26.5 (5.3) 23.5 (4.5)
4.60 (0.77) 4.32 (0.67)
-12.0 (7.6) * - 12.2 (8.1) *
-1.57 (1.20) * - 1.64 (1.31) *
51.4 59.1
17.1 45.5
31.4 50.0
Patients were treated with open-label fluoxetine for 4+ weeks. a Mean (SD). b HAMD,, decrease > 50% from baseline to last visit. ’ HAMD,, I 7 at last visit. d CGI Severity of 1 or 2 at last visit. ’ Placebo patients meet the length of double-blind therapy and maximum definitions but dosage criteria are not applicable. * P < 0.001 (Wilcoxon signed rank test).
6 weeks of open-label fluoxetine for patients continuing past that point. Since patients crossing over to open-label fluoxetine from double-blind amitriptyline had received a maximum of 5 weeks of arnitriptyline, efficacy assessment for those patients was restricted to the first 5 weeks of fluoxetine therapy. All patients were treated at least 4 weeks with open-label fluoxetine. Group mean changes in both HAMD,, and CGI Severity scales indicate that TCA refractory patients of all definitions, and the comparable placebo groups, all showed statistically significant (P < 0.001) improvement from baseline to endpoint. In addition to these analyses, several categorical data analyses were performed. Response (HAMD,, decrease 2 50%) and remission (final HAMD,, I 7) rates were calculated, as well as CGI Severity remission rates (final of 1 or 2). As can be seen in Table 3, these categorical rates of improvement for TCA refractory patients decreased from Definition 1 to Definition 3. This pattern is more apparent in the HAMD,, and CGI remission rates than in the HAMD,, response rates. This pattern of decreased improvement is not apparent among the patients initially treated with double-blind placebo. Differences in improvement rates on fluoxetine between TCAthe
visit
at
allowable
HAMD;L, decrease
criteria
d
of the respective
and placebo-treated patients are more apparent when considering remission rates than response rates. Mean baseline and final visit HAMD,, scores are shown in Table 4 for the TCA refractory patients organized by definition of refractoriness and category of response (as defined by HAMD,, change) within those definitions. These data provide information regarding the extent of improveTABLE
4
PRE- AND POST-TREATMENT MEAN HAMD,, FOR RESPONDERS AND NON-RESPONDERS TO OPEN-LABEL FLUOXETINE AMONG TCA REFRACTORY PATIENTS N
Baseline HAMD,, mean (SD)
Final HAMD,, mean (SD)
Definition 1 Responders a Non-responders
82 50
25.5 (5.1) 35.8 (6.1)
7.3 (3.7) 21.2 (6.4)
Definition 2 Responders a Non-responders
28 25
25.6 (6.0) 26.8 (6.7)
7.9 (3.6) 21.6 (6.4)
Definition 3 Responders a Non-responders
18 17
25.9 (5.4) 27.1 (5.3)
8.3 (3.8) 21.0 (4.5)
Patients were treated a HAMD,, decrease
with open-label fluoxetine for 4+ z 50% from baseline to last visit.
weeks.
198 TABLE
5
DISCONTINUATIONS
SECONDARY
TO ADVERSE
Open-label
therapy
Fluoxetme
TCA
Flumetine
from TCA
451 85 18.6
463 137 29.6
188 25 13.3
Double-blind
Entered Discontinued secondary to AE % Discontinued secondary to AE
EVENTS therapy
ment among those patients defined categorically as responders. Maximum dosages of fluoxetine for responders and non-responders who were refractory to TCAs by the various definitions above were: Definition 1 - responders 73 + 11, non-responders 78 f 11: Definition 2 ~ responders 74 f 9, non-responders 78 f 11; Definition 3 - responders 74 f 9. non-responders 79 i_ 9 mg/day. These doses were comparable to those achieved on fluoxetine during double-blind therapy by both responders and non-responders. Tolerability of fluoxetine Relative tolerability of potentially bothersome adverse events (AEs) associated with fluoxetine therapy relative to TCA therapy was assessed by comparing rates of discontinuation from therapy due to AEs during the various components of the study. For this analysis, all patients were considered during the entire time period of the doubleblind trials (5 or 6 weeks) and then during the first 6 weeks of open-label fluoxetine (first 5 weeks for those patients crossed over from amitriptyline who could receive a maximum of 5 weeks of TCA therapy). This procedure was adopted to equate the time period of risk during which TCAs and fluoxetine could be discontinued. Table 5 displays data for patients entered and discontinued for AEs during double-blind therapy with fluoxetine and TCAs and then during cross-over therapy with fluoxetine from double-blind TCA. Recall that these patients could cross over to fluoxetine for either lack of antidepressant response or AEs with TCAs. In the double-blind portion of the study, patients treated with fluoxetine and TCAs were approximately equal, 457 and 463 respectively.
Flumetine secondary
from TCA to AE
85 16 1X.8
Rates of discontinuation for AEs during double-blind treatment were 18.6% for fluoxetine and 29.6% for TCAs. It is notable that among those 188 patients crossed over to open-label fluoxetine from TCAs, the rate of discontinuation for AEs, 13.3%. was actually lower than in the double-blind fluoxetine group. Of the 137 patients who discontinued a TCA secondary to an AE, 85 elected to undergo open-label fluoxetine therapy. Of these 85. only 16 (18.8%) discontinued fluoxetine during 6 weeks of therapy (or 5 weeks for double-blind amitriptyline patients). In other words, of 85 patients unable to tolerate TCAs, 81.2% tolerated fluoxetine through an equivalent period of time. There were 110 patients who continued openlabel fluoxetine, after crossing over from doubleblind TCA, for longer than 6 weeks and up to 1 year. Of these. 15 discontinued for an AE, giving a rate of 13.6% for delayed discontinuation.
Discussion A major issue in evaluating these findings regarding the efficacy of fluoxetine in the treatment of patients with depression refractory to TCAs is the lack of a parallel control group. Several considerations bear on this issue. First. these patients had just failed a single-blind placebo period of 1 week as well as TCA therapy, with adequacy of TCA therapy defined by several sets of increasingly rigorous criteria. This argues against a substantial placebo response contributing to the response to fluoxetine. However, treatment with fluoxetine was open-label, and it was known to be an experimental drug. This might contribute some additional placebo effect, particularly in a patient population who voluntarily chose to participate in
199
this open-label treatment rather than being randomly assigned. On the whole then, some placebo response might have contributed to the fluoxetine response, but it would be expected to be at least somewhat less than the approximately 40% seen in double-blind placebo-controlled trials (Stark and Hardison, 1985; Wernicke et al., 1987, 1988). Another important issue in considering efficacy is the potential for spontaneous remission during the fluoxetine period of therapy. By the end of 6 weeks of fluoxetine, these patients had been in treatment for as long as 14 weeks (1 week placebo washout, 6 weeks double-blind TCA, 1 week off drug, 6 weeks fluoxetine). Given that period of observation, some patients might be cycling out of the episode for which they entered treatment. It is difficult to estimate the extent to which such spontaneous remissions may have contributed to the observed efficacy of fluoxetine. The response rate (51.4-62.1%. depending on the definition) to open-label fluoxetine in TCA refractory depression is comparable to that reported in response to monoamine oxidase inhibitors in TCA refractory depression. McGrath et al. (1978) reported a 59% response rate to phenelzine in patients with mood reactive depression refractory to imipramine, and Georgotas et al. (1983) reported a 65% response rate in geriatric patients with depression refractory to TCA therapy. The lack of numerical differences between these rates of response among patients initially treated with TCAs and those of patients initially treated with placebo deserve special comment. Larger differences in response rates, with a relatively greater response among patients initially treated with placebo, might be expected if the TCA therapy was acting to select a group of patients with refractory depression. Additionally, it might be expected that patients initially treated with and refractory to TCAs would have a lower response rate during open-label fluoxetine than those treated with fluoxetine during double-blind therapy. With the more restrictive Definitions (2 and 3) of refractoriness, the response to open-label fluoxetine among patients refractory to TCAs does show a trend toward being less than that seen among patients refractory to placebo and being less than that seen with double-blind fluoxetine therapy, Furthermore, the differences in remission
rates suggest that the TCA- and placebo-treated groups were different. The further investigation of the impact of fluoxetine in such disorders would best be accomplished through reallocation of patients failing to improve on double-blind TCA to double-blind placebo, repeat TCA, or fluoxetine. For ethical reasons, such a study is unlikely to occur. Alternatively, reallocation to double-blind therapy with a different TCA or a member of another therapeutic class (MAOI) might yield improved, but still approximate, data regarding the above issues. The tolerability data are perhaps less potentially confounded than the efficacy data. The fluoxetine discontinuation rate of 18.8% among the 85 patients who could not tolerate TCAs did not differ from that of the unselected, randomly assigned fluoxetine population whose discontinuation rate for AEs was 18.6%. These data are particularly notable given the aggressive dosing of fluoxetine. For all Definition groups, the mean daily dose of fluoxetine exceeded 70 mg, which is considerably higher than the 20-40 mg/day doses currently used most frequently. It might be argued that since this treatment was open-label, patients might be better prepared for AEs and, therefore, more tolerant. Offsetting such a possibility is the fact that fluoxetine was experimental during these trials. Such a compound might well be expected to raise additional concerns in a patient prone to experience AEs. References Blier, P.. Chaput. Y. and deMontigny, C. (1988) Long-term 5-HT reuptake blockade, but not monoamine oxidase inhibition, decreases the function of terminal 5-HT autoreceptors: an electrophysiological study in the rat brain. Arch. Pharmacol. 337. 246-254. Delgado. P. et al. (1988) Efficacy of fluvoxamine in treatmentrefractory depression. J. Affect. Disord. 15, 55-60. Fuller. R., Perry, K. and Molloy, B. (1974) Effect of an uptake inhibitor on serotonin metabolism in rat brain: studies with 3-( p-trifluoromethylphenoxy)-N-methy1-3-phenylpropylamine (Lilly 110140). Life Sci. 15. 1161-1171. Georgotas, A. and McCue. R. (1988) What is the adequate length of an antidepressant trial in the elderly? Presented at the Annual Meeting of the Society of Biological Psychiatry. Montreal, May 4, 1988. Georgotas, A. et al. (1983) Resistant geriatric depressions and therapeutic response to monoamine oxidase inhibitors. Biol. Psychiatry 18, 195-205.
McGrath. P. et al. (1978) Treatment of tricyclic refractory depression with a monoamine oxidase inhibitor. Psychopharmacol. Bull. 23. 169-172. Paykel. E. and Van Woerkom, A. (1987) Pharmacologic treatment of resistant depression. Psychiatr. Ann. 17, 327-331. Rein&err, F. et al. (1984) Characteristics of responders to fluoxetine. Psychopharmacol. Bull. 20, 70-72. Richelson, E. and Nelson, A. (1984) Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. J. Pharmacol. Exp. Ther. 230, 94-102. Richelson, E. and Pfenning, M. (1984) Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: most antidepressants selectively block norepinephrine uptake. Eur. J. Pharmacol. 104, 217-286. Roose, S. et al. (1986) Tricyclic nonresponders: phenomenology and treatment. Am. J. Psychiatry 143, 345-348. Schatzberg, A. et al. (1983) Survey of depressed patients who have failed to respond to treatment. In: J. Davis and J. Moss (Eds.), The Affective Disorders. American Psychiatric Press, Washington, DC. Schmidt, M.J. and Thornberry J.F. (1977) Norepinephrinestimulated cyclic AMP accumulation in brain slices in vitro
after serotonin depletion or chronic administration of selective amine reuptake inhibitors. Arch. Int. Pharmacodyn. 229. 42-51. Stark, P. and Hardison. C. (1985) A review of multicenter controlled studies of fluoxetine vs. imipramine and placebo in outpatients with major depressive disorder. J. Clin. Psychiatry 46, 53-58. Wander, T., Nelson, A.. Okazaki, H. and Richelson, E. (1986) Antagonism by antidepressants of serotonin S, and Sz receptors of normal human brain in vitro. Eur. J. Pharmacol. 132. 115-121. Wernicke, J. et al. (1987) Fixed-dose fluoxetine therapy for depression. Psychopharmacol. Bull. 23. 164-168. Wernicke, J. et al. (1988) Low-dose fluoxetine therapy for depression. Psychopharmacol. Bull. 24, 183-188. Wang, D.T. and Bymaster, F.P. (1981) Subsensitivity of serotonin receptors after long-term treatment of rats with fluoxetine. Res. Commun. Chem. Pathol. Pharmacol. 32. 41-51. Wong, D.T., Reid, L.R., Bymaster. F.P. and Threlkeld, P.G. (1985) Chronic effects of fluoxetine. a selective inhibitor of serotonin uptake, on neurotransmitter receptors. J. Neural Transm. 64, 251-269.
