Lilly Research Laboratories, Indianapolis
Massachusetts General Hospital, Boston
University of Pennsylvania, Philadelphia
Princeton Biomedical Research, Princeton
Seattle Clinical Research Center, Seattle
Lilly Research Laboratories, Indianapolis
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Correspondence: Dr David Michelson, Lilly Research Laboratories, Lilly Corporate Center, Drop Code 2423, Indianapolis, IN 46285, USA. Tel: (317) 277-6443; Fax: (317) 277-3262; e-mail: dmichelson{at}lilly.com
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ABSTRACT |
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Aims Systematically to assess symptoms and effects on daily functioning related to interruption of SSRI therapy.
Method Patients treated with fluoxetine, setraline or paroxetine underwent identical five-day periods of treatment interruption and continued active treatment under double-blind, order-randomised conditions, with regular assessment of new symptoms.
Results Placebo substitution for paroxetine was associated with increases in the number and severity of adverse events following the second missed dose, and increases in functional impairment at five days. Placebo substitution for sertraline resulted in less pronounced changes, while interruption of fluoxetine was not associated with any significant increase in symptomatology.
Conclusions Abrupt interruption of SSRI treatment can result in a syndrome characterised by specific physical and psychological symptoms. Incidence, timing and severity of symptoms vary among SSRIs in a fashion that appears to be related to plasma elimination characteristics.
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INTRODUCTION |
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METHOD |
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Study design
Following an initial assessment, the study consisted of two five-day
periods separated by at least two weeks but not more than four weeks. Under
double-blind, order-randomised conditions, all subjects underwent placebo
substitution during one five-day period and continued treatment with their
usual selective serotonin reuptake inhibitor (SSRI) during the other five-day
period. Subjects continued treatment with the SSRI at all other times.
Assessments
Patients completed a 17-item adverse event scale (see Appendix) daily for
five days following study entry and during the two blinded periods. Items
queried were based on reports from previous studies
(Rosenbaum et al,
1998). Each item was rated from 0 to 3 (absent, mild, moderate or
severe) and scores were reported as the change from the most symptomatic of
the five days immediately following study entry. At baseline and at the end of
each five-day period, the HRSD-21, the State Anxiety Inventory (SAI;
Spielberger, 1983) and a
self-rated assessment of social and occupational functioning during the
previous four days (see Appendix) were administered. Scores for these
assessments are reported for each period as the change from baseline (visit
1). Spontaneous reports of adverse events were also collected at all visits.
Supine and standing heart rate and blood pressure were measured at each visit,
using an automated monitoring device (Welch-Allyn, Skaneateles Falls, NY).
Laboratory assessments
Screening chemistries, urinalysis and complete blood counts were obtained
at the initial visit. In order to determine steady-state and post-interruption
plasma drug concentrations, samples were obtained at 18.00 h on the fifth day
of each blinded period. Drug assays were performed by commercial laboratories
(fluoxetine: Oneida, Whitesboro, NY; setraline and paroxetine: MedTox
Laboratories, St Paul, MN).
Statistical analysis
We conducted analyses comparing the blinded periods (placebo interruption
v. continued active medication) within each medication group. These
analyses were based on a crossover analysis of variance with sequence, patient
within sequence, period (one or two) and interruption (present or absent)
factors in the model. If the crossover effect was statistically significant at
a level of 0.10, the interruption effect was based on the analysis of first
period results only. Confidence limits were constructed using the
least-squares means and associated standard errors from the analysis of
variance. Analysis of total adverse events was based on logarithmic
transformation of the data because of non-constant variance
(heteroscedasticity). Confidence limits for total adverse events were
constructed using the non-parametric method of Hodges & Lehmann
(1963). Within-group
comparisons of binary measures were performed using Prescott's
(1981) test.
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RESULTS |
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Symptom measures
Placebo substitution, but not continued active medication, was associated
with statistically significant increases in total numbers of solicited adverse
events for patients treated with paroxetine but not those treated with
sertraline or fluoxetine, by the end of the fourth day
(Table 2). Increases in
symptoms for patients treated with paroxetine became statistically significant
as early as the time of the second dose of placebo
(Fig. 1). Mean severity
worsened by the end of the fourth day of placebo substitution for 13 of the 17
items on the solicited adverse events scale among patients treated with
paroxetine, for three out of 17 among patients treated with sertraline, and
for no items among patients treated with fluoxetine. Among patients taking
paroxetine, mean severity of most items increased by between 0.5 and 1 on the
four-point scale. For both paroxetine-treated and sertraline-treated patients,
dizziness was the item with the greatest number of patients reporting an
increase in severity (percentage of paroxetine patients worsening: active
treatment 5.7%, placebo 57.1%, P<0.001; percentage of setraline
patients worsening: active treatment 6.1%, placebo 42.4%, P=0.002).
Patients taking paroxetine also experienced statistically significantly
worsened severity in nausea, unusual dreams, tiredness or fatigue,
irritability, unstable or rapidly changing mood, difficulty concentrating,
muscle aches, feeling tense, chills, trouble sleeping, agitation and diarrhoea
during placebo substitution reactive to active treatment. Patients treated
with sertraline experienced statistically significantly worsened severity in
dizziness, nausea and unusual dreams during placebo substitution relative to
active treatment. Spontaneously reported adverse events followed a pattern
similar to that of solicited events, with increases for patients treated with
paroxetine in dizziness (placebo substitution 33.3%, active treatment 0.0%;
P<0.001), headache (placebo substitution 27.8%, active treatment
5.5%; P=0.008), nausea (placebo substitution 16.7%, active treatment
0.0%; P=0.031) and anxiety (placebo substitution 16.7%, active
treatment 2.8%; P=0.025).
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Among patients treated with sertraline there was an increase in the number spontaneously reporting dizziness during placebo interruption (placebo substitution 35.3%, active treatment 5.9%; P=0.007). Among patients treated with fluoxetine there was no statistically significant increase in spontaneous reports of any symptom during placebo substitution. At the end of the placebo substitution period, patients taking paroxetine, but not those taking fluoxetine or setraline, demonstrated statistically significant increases in HRSD-21 and SAI scores compared with the continued drug period (Table 2). There was no significant relationship between either dose or time on drug and new symptoms.
Functional impairment
Patients treated with paroxetine reported statistically significant
deterioration in functioning at work, relationships, social activities and
overall functioning, while patients treated with sertraline reported
deterioration in overall functioning, and patients treated with fluoxetine
reported no change in any area of functioning following placebo substitution
(Table 2).
Vital signs
Patients treated with paroxetine experienced a statistically significant
increase in standing heart rate and orthostatic change in heart rate (beats
per minute) during placebo substitution relative to active medication (mean
standing heart rate: active medication 78.7 (s.d.=12.2), placebo substitution
82.3 (s.d.=15.9), P=0.37; mean orthostatic change in heart rate:
active medication 8.5 (s.d.=8.8), placebo substitution 12.5 (s.d.=13.1,
P=0.020). There were no statistically significant changes in either
measure among patients treated with sertraline or fluoxetine, and supine and
standing blood pressure were similar for all groups during both
conditions.
Plasma concentrations
Mean plasma drug concentrations (ng/ml) during active treatment and
following placebo substitution, respectively, were as follows.
Fluoxetine/norfluoxetine: active 264.6 (s.d.=160.3), placebo substitution
197.7 (s.d.=132.5), mean percentage reduction 29.7% (s.d.=15.8%);
sertraline/desmethylsertraline: active 87.7 (s.d.=63.0), placebo substitution
26.0 (s.d.=33.0), mean percentage reduction 73.5% (s.d.=11.7%); paroxetine:
active 46.7 (s.d.=33.4), placebo substitution 6.9 (s.d.=11.8), mean percentage
reduction 86.7% (s.d.=12.9%). Percentage reduction in plasma concentrations
across drug groups was statistically significantly correlated with new adverse
events (r=0.56, P<0.01); however, within individual drug
groups, correlations between new events and percentage reduction in
concentration were not significant (fluoxetine r=0.0,
P=0.98; sertraline r=0.19, P=0.30; paroxetine
r=0.27, P=0.13). Neither absolute drug concentration in the
steady state nor absolute change in concentration after interruption
correlated with emergence of new symptoms following treatment interruption for
any group.
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DISCUSSION |
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These data are consistent with reports from controlled clinical studies (Rosenbaum et al, 1998) and epidemiological data (Price et al, 1996) suggesting that abrupt interruption of SSRI treatment is associated with the emergence of physical and psychological symptoms in a manner that suggests a relationship to drug plasma half-life. Our study differs from previous interruption studies in assessing the time course of symptom onset, symptom severity and the association of symptoms with functional impairment as well as changes in plasma drug concentrations.
Limitations
Several factors limit the interpretation of these data. Although the groups
were well matched for baseline characteristics, patients were not randomised
to treatment groups, and selection bias or expectations about the treatment
groups could have influenced the results. This is unlikely to have been a
significant factor, however, since the comparison periods were double-blind
and order-randomised, and any effects due to patient or clinician expectations
should have been observed during both periods. Also, a study in which patients
were prospectively randomised to different treatments demonstrated results
consistent with those observed here (Fava
et al, 1998).
Another limitation relates to the comparability of doses of the individual agents and to how these doses affected outcomes. The manufacturers' recommended doses were empirically derived from efficacy studies conducted separately for each drug, and could theoretically have differing biological activity at relevant loci. However, the drugs have similar preclinical serotonin (5-HT) profiles, the mean dose for each drug was modestly above the initial recommended starting dose and within its reported effective antidepressant range, and the doses reflect usual clinical practice, suggesting that they are comparable. Furthermore, the paroxetine mean dose was somewhat closer to the initial recommended starting dose than either the fluoxetine or sertraline dose, and any bias would be expected to be in the direction of symptom reduction for patients treated with paroxetine relative to the other treatment groups. Hence, it seems unlikely that the observed results are an artefact of dosing differences among the drugs.
Finally, crossover designs can be vulnerable to carryover effects. However, tests for carryover suggest that it was not a problem for most variables analysed. The few variables that reached statistical significance (P<0.1) were re-analysed using only patients from the first period, and the results were unchanged.
Perhaps the most important limitation of this study is the restriction of treatment interruptions to five days. It is possible that longer periods could be associated with the onset of symptoms among patients treated with fluoxetine or worsened symptoms among any of the treatment groups. We note, however, that interruptions of up to eight days demonstrate patterns of effects consistent with those reported here (Rosenbaum et al, 1998), and it seems unlikely that clinically relevant interruptions (as opposed to discontinuation) would last significantly longer than this. With respect to discontinuation of medication, longer periods may be more relevant to fluoxetine. In one trial (Zajecka et al, 1998) patients with major depression successfully treated with fluoxetine for 12-14 weeks and then abruptly switched to placebo reported a modest but statistically significant increase in dizziness (which was reported by approximately 10% of discontinuing patients over the following six weeks compared with approximately 4% of those continued on fluoxetine), without evidence of other signs and symptoms. These figures probably represent low estimates of the incidence of this symptom, since assessments were obtained by spontaneous rather than solicited reports.
Clinical relevance
A previous report (Rosenbaum et
al, 1998) suggests that SSRI-related discontinuation
syndromes, although uncomfortable, are self-limited and generally resolve
within 1-2 weeks; our results are consistent with these findings. In this
context, the most important clinical risks seem more likely to be related to
appropriate recognition and management than to the morbidity of the symptoms
as such. Discontinuation symptoms can include prominent psychological
manifestations, and patients who experience discontinuation symptoms after
stopping medication could be misdiagnosed as having relapsed, and as a result
have therapy reinstituted prematurely. Similarly, a body of data suggests that
many patients have gaps in medication compliance or stop medication
spontaneously, and our results suggest that some patients, particularly those
taking paroxetine, will develop interruption-related symptoms that may be
viewed as breakthrough depressive symptoms or some other condition (e.g.
influenza). The degree to which such problems actually result in inappropriate
or unnecessary treatment, however, is not known.
Also of clinical interest is time of exposure. We did not find an increased risk related to longer exposures. This finding is consistent with the hypothesis that a minimum period is required to establish new physiological conditions related to drug administration, but that drug-related changes are stable once in place.
Finally, an important clinical question is the degree to which new symptoms following treatment interruption represent a specific, drug-related phenomenon rather than depressive relapse. The characteristic presence and predominance following interruption of specific physical symptoms including dizziness and nausea are not typical of depression, and suggest instead an acute disruption of a drug-induced homoeostasis. Our findings are also consistent with effects observed with other drugs, such as rebound hypertension following discontinuation of antihypertensives, again suggesting a specific interruption effect. None the less, because the diagnoses of both discontinuation syndromes and depression are based on descriptive findings rather than markers of underlying pathophysiological processes, we cannot definitively rule out the possibility that some or all of the observed increases in symptoms are related to relapse of underlying illness.
Potential mechanisms underlying symptom production
The mechanisms which underlie discontinuation phenomena are incompletely
understood, but symptom production appears to be most closely related to the
rate at which internal disruptions occur. Although fluoxetine, sertraline and
paroxetine have some differences in their in vitro receptor profiles
(Richelson, 1996,
1998), the most apparent
difference is in their pharmacokinetic half-lives, and the resulting rate of
clearance of parent drug and active metabolites from relevant pharmacodynamic
targets. We observed a pattern of symptom emergence and increased severity
which parallels the plasma half-lives of the drugs, strongly suggesting that
half-life is indeed the most important factor. This finding is consistent with
data from other drug classes, such as antihypertensives, implicating shorter
plasma half-life in producing these phenomena
(Rickels et al, 1988;
Schweizer et al,
1990; Noyes et al,
1991).
The nature of the symptoms observed could potentially be related to a primary effect on serotonin production, release or receptors, to secondary effects on systems modulated by serotonergic pathways, or some combination of these. Although secondary effects may be important, the pattern of individual symptom frequency observed here supports a primary aetiological role for alterations in serotonin homoeostasis. Consistent with previous studies, dizziness was the most common symptom for both paroxetine- and sertraline-treated patients (reported spontaneously in approximately a third of both groups). Dizziness is commonly observed in the context of 5-HT1A receptor stimulation, and its high incidence during placebo substitution is consistent with a primary effect on serotonergic neurotransmission (Grof et al, 1993). Another common symptom was nausea, thought to be mediated by the 5-HT3 receptor, and serotonin is believed to have important roles in modulating psychological symptoms observed in this study, such as nervousness and agitation (Kilpatrick et al, 1990; Richelson, 1998). It is likely, however, that other factors also influence symptoms. The changes in heart rate observed during treatment interruption in the paroxetine group, for example, could represent alterations in noradrenergic-sympathetic nervous system function.
Relationships to plasma drug concentrations
Neither doses nor absolute plasma drug levels correlated with symptoms
associated with treatment interruption for any group. Plasma concentrations
achieved at a given dose of an SSRI vary widely between individuals and do not
correlate with efficacy (Nielsen et
al, 1991; Amsterdam et
al, 1997), and plasma concentrations may not accurately
reflect brain exposure. In this regard, a recent report on brain paroxetine
and fluoxetine concentrations measured by magnetic resonance spectroscopy
before and after treatment interruption suggests a relationship between higher
steady-state brain concentrations of paroxetine and new symptoms experienced
when treatment is interrupted (details available from the first author upon
request). However, it is also likely that the lack of correlation between
symptoms and plasma concentrations reflects individual differences in
concentration-effect relationships at the receptor level, and that the lack of
a dose-symptom relationship parallels the lack of a therapeutic dose-response
relationship.
By contrast, there was a statistically significant relationship across all drug groups between percentage reduction in plasma concentration and the appearance of new symptoms. Within each individual drug group this relationship was not statistically significant (although correlations appeared to increase from fluoxetine to sertraline to paroxetine in the predicted direction). This is probably because in the group with the most symptoms, namely those treated with paroxetine, virtually all drug had been eliminated in most patients at the time of measurement, because differences in half-life across drugs are much greater and more important than those among individuals taking any single drug, and because inter-individual differences in plasma concentration reflect not only half-life but also absorption, protein binding and distribution. These findings, while not providing definitive proof of a role for half-life in the development of new symptoms after treatment interruption, are consistent with the hypothesis that it is the major risk factor.
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Clinical Implications and Limitations |
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LIMITATIONS
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APPENDIX |
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Self-assessment of occupational and social functioning
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REFERENCES |
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Demyttenaere, K. (1997) Compliance during treatment with antidepressants. Journal of Affective Disorders, 43, 27-39.[CrossRef][Medline]
Fava, M., Rosenbaum, J., Hoog, S. L., et al (1998) A comparison of symptoms following treatment interruption: evidence from a randomized, double-blind trial with fluoxetine, sertraline, and paroxetine. European Psychiatry, 13 (suppl. 4), 204.
Grof, P., Joffe, R., Kennedy, S., et al (1993) An open study of oral flesinoxan, a 5-HT1A receptor agonist, in treatment-resistant depression. International Clinical Psychopharmacology, 8, 167-172.[Medline]
Hamilton, M. A. (1967) Development of a rating scale for primary depressive illness. British Journal of Social and Clinical Psychology, 6, 278-296.
Hodges, J. L. & Lehmann, E. I. (1963) Estimates of location based on rank tests. The Annals of Mathematical Statistics, 34, 598-611.
Kilpatrick, G. J., Bunce, K. T. & Tyers, M. B. (1990) 5-HT3 receptors. Medicinal Research Reviews, 10, 441-475.[Medline]
Nielsen, O. A., Morsing, I., Petersen, J. S., et al (1991) Paroxetine and imipramine treatment of depressive patients in a controlled multicentre study with plasma amino acid measurements. Acta Psychiatrica Scandinavica, 84, 233-241.[Medline]
Noyes, R. Jr, Garvey, M. J., Cook, B., et al (1991) Controlled discontinuation of benzodiazepine treatment for patients with panic disorder. American Journal of Psychiatry, 148, 517-523.[Abstract]
Prescott, R. J. (1981) The comparison of success rates in cross-over trials in the presence of an order effect. Applied Statistics, 30, 9-15.
Price, J. S., Waller, P. C., Wood, S. M., et al (1996) A comparison of the post-marketing safety of four selective serotonin re-uptake inhibitors including the investigation of symptoms occurring on withdrawal. British Journal of Clinical Pharmacology, 42, 757-763.[Medline]
Richelson, E. (1996) Synaptic effects of antidepressants. Journal of Clinical Psychopharmacology, 16 (suppl. 2), 1-7.[CrossRef][Medline]
Richelson, E. (1998) Serotonin: and what about its side effects? Depression and Anxiety, 7 (suppl. 1), 18-20.[CrossRef][Medline]
Rickels, K., Fox, I. L., Greenblatt, D. J., et al (1988) Clorazepate and Iorazepam: clinical improvement and rebound anxiety. American Journal of Psychiatry, 145, 312-317.[Abstract]
Rosenbaum, J. F., Fava, M., Hoog, S. L., et al (1998) Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biological Psychiatry, 44, 77-87.[CrossRef][Medline]
Schweizer, E., Rickels, K., Case, W. G., et al (1990) Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper. Archives of General Psychiatry, 47, 908-915.[Abstract]
Spielberger, C. D. (1983) Manual for the State Trait Anxiety Inventory. Palo Alto, CA: Consulting Psychologists.
Zajecka, J., Fawcett, J., Amsterdam, J., et al (1998) Safety of abrupt discontinuation of fluoxetine: a randomized, placebo-controlled study. Journal of Clinical Psychopharmacology, 18, 193-197.[CrossRef][Medline]
Received for publication February 26, 1999. Revision received June 25, 1999. Accepted for publication August 17, 1999.