Fluoxetine Treatment

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Am J Psychiatry 157:9, September 2000 1423

Article

Timing of Onset of Antidepressant ResponseWith Fluoxetine Treatment

Andrew A. Nierenberg, M.D.

Amy H. Farabaugh, M.A.

Jonathan E. Alpert, M.D., Ph.D.

Johanna Gordon, B.A.

John J. Worthington, M.D.

Jerrold F. Rosenbaum, M.D.

Maurizio Fava, M.D.

Objective: The purpose of this study

was to assess the time until onset of anti-depressant response with fluoxetinetreatment.

Method: The authors evaluated 182 out-patients with major depression who hada sustained acute response to fluoxetinetreatment. The outpatients received 8weeks of treatment with 20 mg/day of flu-oxetine and were assessed biweekly withthe 17-item Hamilton Depression RatingScale. The onset of response was definedas a 30% decrease in score on the Hamil-ton depression scale that persisted andled to a 50% decrease by week 8. The Ka-

plan-Meier product limit and Cox regres-sion analysis were used to model the rela-tionship between relevant variables andtime until onset of response.

Results: The authors found that at weeks

2, 4, and 6, the probabilities of having anonset of response (for responders) were55.5%, 24.7%, and 9.3%, respectively. Thecumulative probabilities of onset of re-sponse at each time point were 55.5%,80.2%, and 89.5%. Neither demographicsnor clinical characteristics of depressionpredicted time until initial response.

Conclusions: These data suggest thatmore than half of eventual responders tofluoxetine treatment at 8 weeks start torespond by week 2; over 75% start to re-spond by week 4. Conversely, the lack of

onset of response at 46 weeks was asso-ciated with about a 73%88% chance thatpatients would not have an onset of re-sponse by 8 weeks.

(Am J Psychiatry 2000; 157:14231428)

The onset of antidepressant effects has great clinicalrelevance. Patients and those treating them want and needto know when to expect the beginning of improvement.The issue of time until onset of antidepressant response was initially addressed by Pollack (1), who found that imi-pramine effectively treated depression; antidepressantbenefits were observed as early as the first or second day and usually within 1 week. Although antidepressants de-veloped over the ensuing decades improve some symp-toms quickly (2, 3), all classes of antidepressant medica-tions have a delayed but variable onset of improvement of the full depressive syndrome (4).

Investigators have claimed that certain antidepressantshave faster onsets of action than others. In the late 1970sand early 1980s claims were made that amoxapine could work faster than other tricyclic antidepressants (5, 6). Forexample, Fabre (7) found significant improvement withamoxapine but not with maprotiline in the first week of treatment. The marketing claim of the more rapid efficacy of amoxapine has not withstood the test of time in clinicalpractice.

The timing of onset of clinical improvement with the se-lective serotonin reuptake inhibitors (SSRIs) fluoxetine,sertraline, paroxetine, and citalopram, as well as with bu-propion, trazodone, nefazodone, and mirtazapine, hasbeen studied less extensively than the timing of improve-ment with the older generation of tricyclic antidepres-

sants and monoamine oxidase inhibitors. Head-to-headstudies of SSRIs and tricyclic antidepressants have indi-cated parallel improvements when measured by standarddepression scales (811). In addition, on the basis of thehypothesis that combined norepinephrine and serotoninuptake inhibition causes a more rapid down-regulation of beta adrenergic receptors than with norepinephrine alone(12), Nelson and colleagues (13) found that combining flu-oxetine and desipramine resulted in faster antidepressanteffects than with desipramine alone. With a similar line of reasoning, that dual action speeds up response, a fasteronset of action has been reported for venlafaxine than forSSRIs (3).

The purpose of this report was to assess the time untilresponse with open fluoxetine treatment and to deter-mine the variables associated with fast and slow response.To define clinical improvement, we decided to use a 30%reduction in score on the 17-item Hamilton DepressionRating Scale (14) at baseline, without a subsequent in-crease at follow-up visits, on the basis of findings by No-bler et al. (15) and consistent with the work of Mller andcolleagues (16). Nobler et al. (15) defined clinical improve-ment as a 30%, 40%, 60%, or 70% decrease in scores on theHamilton depression scale during the course of ECT treat-ments; they assessed time until onset of response withright unilateral or bilateral ECT with low- or high-energy delivery on the basis of seizure threshold. The criterion of


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1424 Am J Psychiatry 157:9, September 2000

TIME UNTIL FLUOXETINE RESPONSE

a 30% reduction in baseline scores on the Hamilton de-pression scale was found to best discriminate time untilthe onset of response between effective and less effectiveforms of ECT. To model time to onset, we used survivalanalysis because of its greater sensitivity detecting differ-ences in the onset of response (15) compared to linear re-gression and random regression models.

Method

The initial study group consisted of 384 outpatients (210 women, 55%) between the ages of 18 and 65 (mean age=39.9 years, SD=10.5) who met the cri teria for major depressive disor-der as measured by the Structured Clinical Interview for DSM-III-RPatient Version (17) and who had a 17-item Hamilton depres-sion scale score of 16 or higher at baseline. None of the subjectsentering the study had failed to respond to an adequate antide-pressant trial during the current episode. The purpose of this par-ent study was to generate a number of prospective nonre-sponders to fluoxetine for further study of options to induceresponse in nonresponders. Patients who entered the open trialreceived a fixed dose of 20 mg/day of fluoxetine for 8 weeks. TheHamilton depression scale was administered at baseline and thenevery 2 weeks to assess depression severity. Patients met every 2 weeks with physicians to discuss the benefits of medication, sideeffects, and adverse events. The study was conducted by the De-pression and Clinical Research Program at Massachusetts Gen-eral Hospital, and the study protocol was approved by Massachu-setts General Hospital s institutional review board. All subjectshad to be able to understand the written informed consent state-ment and sign it voluntarily. Rights of confidentiality were re-viewed. After complete description of the study to the subjects, written informed consent was obtained.

Exclusion criteria included having a history of organic mentaldisorders, history of seizure disorder, serious or unstable medi-cal illness, substance use disorder (including alcohol) within thelast 6 12 months, serious suicidal risk, pregnancy, lactation,schizophrenia, delusional disorder, psychotic disorders notelsewhere classified, mood congruent or mood-incongruentpsychosis, bipolar disorder, significant antisocial personality disorder, history of multiple adverse drug reactions or intoler-ance of or nonresponse to study drugs, concomitant use of non-study psychotropic drugs, and clinical or laboratory evidence of hypothyroidism.

Treatment response was defined as a 50% decrease in scoreon the Hamilton depression scale from baseline to endpoint; re-mission was defined as a final Hamilton depression scale scoreof 7 or lower (18, 19). Time until onset of response was defined asthe first time point at which the score on the Hamilton depres-sion scale decreased by 30% from baseline without a subsequentincrease. By including only those without any increase in Hamil-

ton depression scale scores, we excluded patients who had aplacebo pattern of nonsustained response (20). The responding group represented the best-case scenario: group members had atrue drug pattern of response and responded or experienced re-mission by the end of the 8-week trial. The rationale for segre-gating responders was that if nonresponders were included inthe same group, the time until onset of response would be de-layed because of a reduced overall response rate and would leadto a false conclusion about the time until response for respond-ers (21).

Survival analysis (22) was used to assess the time until onset of response and the time until response. The probability of never

having an onset of response was calculated according to themethods of Laska and Siegel (21) by using the formula

in which p is the proportion of the group with a response andS(t) is the cumulative probability that the time to onset of re-sponse is greater than t among patients with a response. In con-trast, the more conventional measure is H(t), the cumulativeprobability that the time until onset of response is greater than tamong all patients, including those without a response. Cox re-gression analysis for proportional hazards was used to model thecovariates of the time until onset of response and the time untilresponse. Chi-square analysis and unpaired t tests were used forcategorical and continuous variables, respectively, to assess dif-ferences between the group with a persistent response and the re-mainder of the patient group.

Results

A total of 324 (84.4%) of the 384 patients in the study completed the open trial; there were 60 dropouts (15.6%).

Of the 384 patients, 193 (50.3%) responded, and 148(38.5%) had acute remission with final Hamilton depres-sion scale scores of 7 or lower. (Of the 193 responders, 148[76.7%] experienced remission of their symptoms. Of 324 who completed the study, 193 [59.6%] responded, and 148[45.7%] experienced remission of their symptoms.) A totalof 182 (94.3%) of the 193 patients who met the criteria forresponse were included in the responder group; the crite-ria were all data points present, a 30% decrease in baselinescore on the Hamilton depression scale without subse-quent exacerbation, and a 50% reduction in baseline scoreon the Hamilton depression scale after 8 weeks of treat-ment with 20 mg/day of fluoxetine. The response group

consisted of 98 (54%) women, with an overall mean age of 40.6 years (SD=9.8) and a baseline mean Hamilton depres-sion scale score of 19.2 (SD=3.0). Responders had a meanposttreatment Hamilton depression scale score at 8 weeksof 5.0 (SD=2.4) and a mean percentage decrease in scorefrom baseline of 74% (SD=12%). The mean duration of thecurrent episode of depression for responders was 3.3 years(SD=5.6). A total of 206 (57%) of the 360 patients with eval-uable durations of the current episode of depression haddurations of less than 2 years. The mean age at onset of thefirst depressive episode was 26.7 years (SD=13.9). Differ-ences in demographic and baseline clinical variables be-tween sustained responders (N=182) and the group of nonresponders, dropouts, and nonsustained responders(N=202) were not statistically significant (Table 1 and Ta-ble 2), except that the sustained responders had slightly lower baseline Hamilton depression scale scores and weremore likely to be employed.

We found that at weeks 2, 4, and 6, when the entiregroup of patients was assessed, 26.0%, 19.7%, and 11.7% of the patients, respectively, showed an onset of response asdefined as a sustained 30% decrease in baseline score onthe Hamilton depression scale that led to a final decrease

1 p1 p( ) pS(t)+

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NIERENBERG, FARABAUGH, ALPERT, ET AL.

of 50%. Cumulative probabilities of onset of response at

each time point were 26.0%, 45.7%, and 57.4%. Alterna-tively, time until response with the criterion of a 50% de-crease in baseline score on the Hamilton depression scaleshowed probabilities of response at weeks 2, 4, and 6 of 10.6%, 21.8%, and 16.0%; cumulative probabilities of re-sponse at the time points were 10.6%, 32.4%, and 48.4%,respectively, and 61.4% at week 8.

When responders were assessed with life table analysis,55.5%, 24.7%, and 9.3% had an onset of response at weeks2, 4, and 6; cumulative response rates at each time point were 55.5%, 80.2%, and 89.5% (21). Mean time to onset of response was 3.8 weeks. Alternatively, the portions of thegroup to respond (response defined as a 50% decrease inbaseline score on the Hamilton depression scale) were18.1%, 36.8%, and 26.4% for weeks 2, 4, and 6; cumulativeprobabilities of response were 18.1%, 54.9%, and 81.3%.Mean time to response was 4.9 weeks. The difference be-tween the mean time to onset of response and the meantime to response was 1.1 weeks. With the use of completeranalysis, we found that the probability of a patient neverhaving an onset of response, given that onset had not oc-curred by weeks 2, 4, or 6, was associated with the proba-bility of never having an onset of response (55%, 73%, and

88%, respectively). Neither demographics (age and sex)

nor characteristics of depression (duration of current epi-sode, number of episodes, age at onset of first episode,and baseline score on Hamilton depression scale) pre-dicted time to initial response or time to response by Cox regression analysis for proportional hazards.

Discussion

The results of this study suggest that in a best-case sce-nario, more than half of the eventual responders to a fixeddose of fluoxetine will start to respond to treatment by week 2, with over 75% starting to respond by week 4. Nopredictors of time to response were found. These datashow that if patients have not experienced an onset of re-sponse by weeks 4 or 6, they have about a 73% 88%chance of not exhibiting an onset of response by the end of the 8-week trial. We previously reported that nonre-sponders at weeks 4 and 6 were less likely to become re-sponders at week 8, whereas early responders at weeks 2or 4 were more likely to be responders at week 8 (23). Thecurrent study extends these findings from a totally differ-ent study group to model the time until onset of responserather than just the time until response.

TABLE 1. Demographic and Clinical Characteristics of Patients With Major Depression Who Did or Did Not Respond to Flu-oxetine Over 8 Weeks

Characteristic Total Group (N=384) Responders (N=182)Nonresponders, Nonsustained

Responders, and Dropouts (N=202) AnalysisN % N % N % 2 (df=1) p

Female gender 210 55 98 54 112 55 0.10 0.75Education 3.56 0.06

Less than a college degree 167 43 70 38 97 48

College degree or more 217 57 112 62 105 52Employment 9.05 0.003Employed 240 63 128 70 112 55Unemployed 144 38 54 30 90 45

Marital status 0.43 0.51Never married 184 48 84 46 100 50Married at least once 200 52 98 54 102 50

Mean SD Mean SD Mean SD t (df=314) p

Number of depressive episodesper patient a 3.7 5.8 4.0 6.8 3.1 5.2 1.00 0.32

a Number of episodes could not be determined for 67 patients (26 responders and 41 nonresponders/nonsustained responders, and dropouts).

TABLE 2. Age, Characteristics of Depression, and Scores on the Hamilton Depression Scale for Patients With Major Depres-sion Who Did or Did Not Respond to Fluoxetine Over 8 Weeks

Variable

Total Group(N=384)

Responders(N=182)

Nonresponders,NonsustainedResponders,

and Dropouts(N=202) Analysis

Mean SD Mean SD Mean SD t df pAge (years) 39.9 10.5 40.6 9.8 39.2 11.1 1.24 382 0.22Age at first major episode of depression (years) 25.9 13.4 26.8 13.9 25.1 12.9 1.25 382 0.21Duration of current episode (years) 3.6 7.7 3.3 5.6 3.6 6.3 0.43 382 0.67Score on Hamilton depression scale

Baseline 19.7 3.4 19.2 3.0 20.2 3.8 2.90 382 0.004Endpoint 9.6 6.6 5.0 2.4 15.5 5.5 23.06 382


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Previous studies of the time until onset of response re-vealed variable results because of differences in antide-pressants studied and methods applied. Katz and col-leagues (2) compared the onset of response betweenimipramine and amitriptyline and noted that patients anxiety, cognitive impairment, and depressed mood im-proved in the first week, at least for those patients who re-covered by the end of the antidepressant trial. AlthoughKatz and colleagues (2) postulated that imipramine causedneurochemical changes within the first week of treatment,the clinical relevance of these changes, outside of the seda-tion caused by antihistaminergic effects, were question-able. Most theories of antidepressant action now postulatethat immediate uptake inhibition of catecholamines and/or indoleamines initiates adaptive responses in pre- andpostsynaptic receptors, followed by subsequent changes inproto-oncogenes and brain-derived neurotrophic factors.These final changes occur only after long-term (i.e., weeks)of exposure to antidepressants (4, 24).

Determining the onset of response to antidepressants is

further complicated by the placebo effect. Quitkin andcolleagues (25) assessed the onset and persistence of clin-ical improvement. Their patients were randomly assignedto receive placebo, imipramine, desipramine, phenelzinesulfate, or mianserin hydrochloride in multiple random-ized clinical trials and were assessed with the Clinical Glo-bal Impressions (CGI) scale. Results showed a differencebetween placebo and true drug patterns of response whenpersistent response was considered. True drug effect wasnoted to occur by the 21st day of treatment, whereas theplacebo effect occurred within the first 2 weeks. In a fol-low-up study, Quitkin and colleagues (26) compared pla-cebo and true drug response and found that true drug re-

sponse was characterized by a 2-week delay in onset of response and persistent improvement.

Another study by Quitkin and colleagues (27) associ-ated anticipation of help and sudden improvement withresponse to placebo. Those with gradual improvement with placebo may have had spont ane ous remission.Those with sudden onset of response with placebo had atendency to lose their response within the first few weeksor had a response that was inconsistent from week to week. Quitkin and colleagues (20) suggested that the neu-rophysiologic process that accounts for early abrupt im-provement is the same for those with a placebo-patternresponse to a drug and those who respond to placebo.Both an early placebo effect and a specific drug responseoccur in drug treatment, and gradual improvement indrug treatment includes spontaneous remission as wellas a true drug response.

In contrast to the findings of Quitkin and colleagues (20,27), Stassen and colleagues (28, 29) as well as M ller andcolleagues (16, 30) and M ller and M ller (31) found thatan early response to antidepressants was a robust predic-tor of sustained improvement. M ller and M ller (31)pointed out the difficulties in comparing studies at the on-

set of response because of the heterogeneity of methodsand definitions of response. No studies could be found,however, that assessed variables associated with time untilresponse.

In addition, there are methodological and conceptualchallenges in modeling time until onset of response. Lim-ited consensus exists for the definition of the onset of an-tidepressant response because of the heterogeneity of rating scales and the statistical analyses employed (3, 21,32, 33). For example, self- and therapist-rated scales havediffered in specificity and sensitivity, leading to limitedconventional means to define onset of response. It hasbeen noted that patients perceive improvement laterthan do therapists, and of course, the onset of response isdirectly related to the definition of response. Stassen andcolleagues (28) defined the onset of response as a 20% re-duction in score on the 17-item Hamilton depressionscale without a subsequent increase in score. Their find-ings suggested that this definition was predictive of main-tenance of improvement. Angst and colleagues (19) re-

quired a 50% reduction in baseline depression measuresto define onset of response, plus a cutoff Hamilton de-pression scale score of less than 10. The criterion of a 50%reduction of baseline severity has been frequently used.Montgomery (33) suggested, however, that a 50% reduc-tion was too insensitive and that a 25% reduction in base-line severity be used, with the rationale that 25% is half of 50%. In an earlier study, Montgomery (33) used a decreaseof 4 points in score on the Montgomery- sberg Depres-sion Rating Scale to define onset of response. Others haveused the CGI and other rating scales. We used a 30% de-crease in baseline score on the Hamilton depression scaleto define onset of response, informed by the work of No-

bler and colleagues (15).The time until onset of response is dependent on the se-

lected response criteria. Stricter response criteria are asso-ciated with a later onset of response (31, 34). M ller andcolleagues (16) reanalyzed data from clinical trials of bro-faromine compared to imipramine. By asking, When did you first feel better?, they directly rated patients reportsof onset of response; they also used the von Zerssen Adjec-tive Mood Scale. The Hamilton depression scale was usedas a therapist-rated measure. By using a decrease of 33%,50%, or 60% from baseline scores on the Hamilton depres-sion scale and the von Zerssen Adjective Mood Scale as re-sponse criteria, the investigators highlighted slightchanges in response criteria that led to differences in timeuntil onset. As one would expect, the greater the decreasein Hamilton depression scale score to define response, theslower the time until onset. The patients global ratings of time until onset had a correlation coefficient of r=0.61 when baseline scores on the Hamilton depression scaledecreased 33% (16), which is a finding similar to that of Katz et al. (2) and Stassen and colleagues (28, 29). Stassenand et al. indicated that early onset is a reliable predictorof maintenance of improvement.


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How clinicians should apply these data to clinical prac-tice is anything but straightforward. If one asserts that anantidepressant trial of fluoxetine at a fixed dose of 20 mg should be 8 weeks long, then if no response is detected by the sixth week, our data suggest that it is highly unlikely that a response will occur within the next 2 weeks. Thedose should be increased, the drug should be augmented with another drug, or the patient should be switched toanother drug. On the other hand, if one asserts that an ad-equate trial is 12 weeks long, then these data are not appli-cable. We do not know if these data are generalizable toother SSRIs or to non-SSRI antidepressants.

The results should be tempered by the following study limitations: treatment was open, without blinding of thesubjects or the evaluators; no placebo control group wasincluded; measurements of improvement were made biweekly, and the time until onset could have been soonerthan that interval; the Hamilton depression scale may have been insufficiently sensitive to measure the changesin depression associated with the time until onset of re-

sponse; a fixed dose of 20 mg/day of fluoxetine was givenfor 8 weeks; and the study used fluoxetine only, and its re-sults and may or may not be generalizable to that of otherantidepressants. Nevertheless, these results may have eco-logical validity in open clinical practice. The study wasoriginally designed to generate a group of nonrespondersto fluoxetine for further random assignment, not to evalu-ate the time until onset of response in the open phase of treatment. The study design could be viewed either as alimitation (e.g., onset of response was not assessed fre-quently enough) or a strength (e.g., raters were not biasedfor response at any particular time point). Finally, almosthalf of this group of patients were chronically depressed (2 years or more), with a mean duration of 3.3 years (SD=5.6)for the current depressive episode. Although regressionanalysis showed that the length of the current episode didnot predict time until onset of response, time to response,or time to remission, it is possible that this group of pa-tients was skewed to be more chronically ill than what would be typically encountered in clinical practice.

Conclusions

The onset of response for most responders to fluoxetineshould be observed within 2 4 weeks of beginning treat-ment, with about 10% of the eventual responders starting to feel better after 6 weeks in an 8-week trial. Conversely,the lack of onset of response by 4 6 weeks is associated with about a 75% 88% chance that patients will not havean onset of response by 8 weeks. The mean time betweenthe onset of response and the time to response wasslightly more than 1 week. We were unable to identify baseline characteristics that could predict time until on-set of response or time to response. Similar analysesshould be applied to longer antidepressant trials and toother antidepressants.

Received July 19, 1999; revisions received Jan. 6 and March 7,2000; accepted April 14, 2000. From the De pression and Clinical Re-search Program, Massachusetts General Hospital. Address reprint re-quests to Dr. Nierenberg, Depression and Clinical Research Program,Massachusetts General Hospital, WACC 812, 15 Parkman St., Boston,MA 02114; [email protected] (e-mail).

Supported in part by NIMH grant MH-48483. Dr. Nierenberg has re-ceived honoraria from the Eli Lilly & Company speakers bureau, andhis work is supported by grants from Eli Lilly & Company.

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