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Separating discontinuation symptoms from relapse
S188
S.22 Problems in long term treatment of depression
S.22 Problems in long term treatment of depression [?%%l
Separating relapse
dlscontinuatlon
symptoms
from
J.F. Rosenbaum. Massachusetts General Hospital and Harvard Medical School, Department of Psychiatry, 15 Parkman Street, WAC 812, Boston, MA 02114, USA Continuation and maintenance antidepressant therapy with antidepressants is a well-established treatment to protect recovered patients from depressive relapse and recurrence. Though the efficacy of maintenance treatment out three to five years is empirically substantiated for imipramine (Kupfer et al., 1992; Frank et al., 1990), there are fewer data to support what has become by consensus the clinical practice with the newer antidepressants such as SSRIs. Inasmuch as patients are likely at times over the long-term to abruptly interrupt for various lengths of time their maintenance treatment, one issue of interest in understanding the long-term effectiveness of antidepressants, is the impact on patient well-being and depressive symptomatology of antidepressant treatment interruption. The occurrence of distressing psychological and/or somatic symptoms upon abrupt interruption or discontinuation of most classes of medications is common. Consequences of abrupt cessation of treatment ranging from marked worsening of the original condition to a distinct syndrome specific to the post-discontinuation period have been observed with beta-blockers, antihypertensives, anticonvulsants, corticosteroids, and antiarrhytbmics as well as with most psychotropics such as sedativehypnotics, benzodiazepines, lithium, neuroleptics, TCAs, and MAOIs. Indeed, for most classes of medication to which the organism adapts, there is some perturbation when therapy, particularly higher doses and longer duration, is suddenly withdrawn. Thus it is no surprise that clinicians have registered many dozens of reports of physical and psychic distress when SSRIs, now the first-line agents for the treatment of depression due to their relatively greater tolerability and safety, are abruptly discontinued in some patients. The symptoms reported have included dizziness, nausea, sleep disturbances, flu-like symptoms, sensory disturbances, anxiety/ agitation/irritability as well as crying spells and depressed mood, among others. The “discontinuation syndrome” usually emerges within 2-4 days of interrupted treatment, though onset may be earlier in some cases. The syndrome is often of a time-limited duration and improves with treatment resumption followed by treatment taper. The rates of spontaneous report appear to be higher in agents with a shorter half-life. Nonlinear kinetics may similarly predispose to this syndrome. To address the limitations of case reports, researchers at the Massachusetts General Hospital designed controlled, parallel, double-blind interruption trials of fluoxetine, sertraline, and paroxetine in patients with major depressive disorder to study both the emergence of discontinuation symptoms and of possible emergence depressive symptoms. In the first study, patients on SSRIs and in remission for about a year on average from major depressive disorder (N = 242) were randomized to treatment interruption for 5-8 days. Using the Discontinuation-Emergent Sign and Symptoms (DESS) checklist as well as psychiatric assessments before, during, and after interruption, investigators found, as hypothesized, that shorter half-life was a key risk factor for the emergence of somatic and psychological symptoms after interruption of maintenance SSRI treatment. Significant increases in depression ratings were also observed for the shorter half-life agents which could not be explained on the sole basis of the somatic distress inasmuch as significant differences were also observed on the Symptom Questionnaire Depression sub-scale, which predominantly assesses depressive cognitions. To address whether findings would have been different if patients had been randomized to initial treatment, if the duration of treatment were briefer and if the interruption period were shorter, a second study (Fava et al., 1998) randomized patients to fluoxetine, sertraline, or paroxetine; responders to treatment who had received 10 to 16 weeks of acute drag therapy experienced two separate periods of treatment interruption with 4
to 6 days of placebo substitution. As with the first study, (Rosenbaum et al., 1998), longer half-life appeared to protect against the emergence of a discontinuation syndrome. The number of discontinuation symptoms, however, were fewer in this study than the first and diminished tinther when comparing the second of the two interruption periods, suggesting that shorter duration of treatment and repeated interruption of treatment may be associated with a decreased risk of a discontinuation syndrome. Zajecka and colleagues (1998) investigated the adverse effects out to six weeks after abrupt treatment interruption of fluoxetine to examine whether long-half life, rather than protecting against a discontinuation syndrome, simply delays it. Six weeks after randomization, comparing those who remained on fluoxetine with those abruptly switched to placebo, rare reports of dizziness were the only discontinuation-related events to emerge. The data indicated that there was no evidence of a clinically meaningful discontinuation syndrome. Fluoxetine’s long halflife appeared to accomplish what a gradual taper of a shorter half-life agent would accomplish in prevention of the syndrome’s development. Dizziness may be the best signal to allow the clinician to distinguish the discontinuation syndrome from relapse. That said, there are clinically relevant and theoretically important: questions that remain to be examined with respect to the discontinuation syndromes with antidepressants in general and SSRIs in particular. First, not all patients interrupted under similar circumstances develop the syndrome, and of those who do, the intensity varies. What patient characteristics account for these differences? Is there evidence that the emergence of the syndrome identifies patients at higher risk of relapse with treatment discontinuation, rendering the syndrome a potentially useful guide to knowing which patients might in fact safely discontinue therapy? For example there may be analogies between the dynamics of tryptophan depletion and the symptoms it produces and SSRI abrupt interruption; the emergence of symptoms with tryptophan depletion in patients on SSRIs has been reported to be predictive of later depressive relapse. Does the perturbation of the discontinuation syndrome actually cause or predispose to relapse beyond the influence of removing an effective prophylaxis? Is there a confound in the design of continuation treatment studies of SSRIs in major depression, in that subjects are often abruptly switched to placebo, possibly inflating the benefits of continuing treatment? To answer some of these questions would require a different clinical trial design than the ones accomplished to date; for example, depressive subjects in recovery on a shorter half-life SSRI would be randomized to maintain treatment, to very gradually taper treatment, or to abruptly stop treatment, with extended follow-up to examine rates of recurrence of depression. It would appear unlikely that this design will be accomplished. We are currently re-examining data from earlier studies, however, to attempt to clarify further the relationship between SSRI discontinuation events and depressive relapse. References
[l]
[2]
[3]
[4]
[5]
Fava M, Rosenbamn JF, Hoog S, Krebs W, Dillon J, Fluoxetine Collaborative Study Group. A comparison of symptoms following tteatment interruption: evidence from a randomized, double-blind trial with fluoxetine, sertraline, and paroxetine. Proceedings of the Society of Biological Psychiatry Annual Meeting, Toronto, Ontario, Canada, 1998. Frank E, Kupfer DJ, Perel JM, Comes C, Jarrett DB, Mallinger AG, et al. Three-year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry 1990; 47:1093-1099. Kupfer DJ, Frank E, Perel JM, Comes C, Mallinger AG, Thase ME, et al. Fiveyear outcome for maintenance treatment of depression. Arch Gen Psychiatry 1992; 491769-773. Rosenbamn JF, Fava M, Hoog SL, Ascroft RC, Krebs W. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry 1998; 44~77-87. Zajecka J, Fawcett J, Amsterdam J, Quitkin F, Reimherr F, Rosenbaton J, et al. J Clin Psychopbarmacol 1998; l&193-197.
S.22 Problems in long term treatment of depression
S.22 Problems in long term treatment of depression [?%%l
Separating relapse
dlscontinuatlon
symptoms
from
J.F. Rosenbaum. Massachusetts General Hospital and Harvard Medical School, Department of Psychiatry, 15 Parkman Street, WAC 812, Boston, MA 02114, USA Continuation and maintenance antidepressant therapy with antidepressants is a well-established treatment to protect recovered patients from depressive relapse and recurrence. Though the efficacy of maintenance treatment out three to five years is empirically substantiated for imipramine (Kupfer et al., 1992; Frank et al., 1990), there are fewer data to support what has become by consensus the clinical practice with the newer antidepressants such as SSRIs. Inasmuch as patients are likely at times over the long-term to abruptly interrupt for various lengths of time their maintenance treatment, one issue of interest in understanding the long-term effectiveness of antidepressants, is the impact on patient well-being and depressive symptomatology of antidepressant treatment interruption. The occurrence of distressing psychological and/or somatic symptoms upon abrupt interruption or discontinuation of most classes of medications is common. Consequences of abrupt cessation of treatment ranging from marked worsening of the original condition to a distinct syndrome specific to the post-discontinuation period have been observed with beta-blockers, antihypertensives, anticonvulsants, corticosteroids, and antiarrhytbmics as well as with most psychotropics such as sedativehypnotics, benzodiazepines, lithium, neuroleptics, TCAs, and MAOIs. Indeed, for most classes of medication to which the organism adapts, there is some perturbation when therapy, particularly higher doses and longer duration, is suddenly withdrawn. Thus it is no surprise that clinicians have registered many dozens of reports of physical and psychic distress when SSRIs, now the first-line agents for the treatment of depression due to their relatively greater tolerability and safety, are abruptly discontinued in some patients. The symptoms reported have included dizziness, nausea, sleep disturbances, flu-like symptoms, sensory disturbances, anxiety/ agitation/irritability as well as crying spells and depressed mood, among others. The “discontinuation syndrome” usually emerges within 2-4 days of interrupted treatment, though onset may be earlier in some cases. The syndrome is often of a time-limited duration and improves with treatment resumption followed by treatment taper. The rates of spontaneous report appear to be higher in agents with a shorter half-life. Nonlinear kinetics may similarly predispose to this syndrome. To address the limitations of case reports, researchers at the Massachusetts General Hospital designed controlled, parallel, double-blind interruption trials of fluoxetine, sertraline, and paroxetine in patients with major depressive disorder to study both the emergence of discontinuation symptoms and of possible emergence depressive symptoms. In the first study, patients on SSRIs and in remission for about a year on average from major depressive disorder (N = 242) were randomized to treatment interruption for 5-8 days. Using the Discontinuation-Emergent Sign and Symptoms (DESS) checklist as well as psychiatric assessments before, during, and after interruption, investigators found, as hypothesized, that shorter half-life was a key risk factor for the emergence of somatic and psychological symptoms after interruption of maintenance SSRI treatment. Significant increases in depression ratings were also observed for the shorter half-life agents which could not be explained on the sole basis of the somatic distress inasmuch as significant differences were also observed on the Symptom Questionnaire Depression sub-scale, which predominantly assesses depressive cognitions. To address whether findings would have been different if patients had been randomized to initial treatment, if the duration of treatment were briefer and if the interruption period were shorter, a second study (Fava et al., 1998) randomized patients to fluoxetine, sertraline, or paroxetine; responders to treatment who had received 10 to 16 weeks of acute drag therapy experienced two separate periods of treatment interruption with 4
to 6 days of placebo substitution. As with the first study, (Rosenbaum et al., 1998), longer half-life appeared to protect against the emergence of a discontinuation syndrome. The number of discontinuation symptoms, however, were fewer in this study than the first and diminished tinther when comparing the second of the two interruption periods, suggesting that shorter duration of treatment and repeated interruption of treatment may be associated with a decreased risk of a discontinuation syndrome. Zajecka and colleagues (1998) investigated the adverse effects out to six weeks after abrupt treatment interruption of fluoxetine to examine whether long-half life, rather than protecting against a discontinuation syndrome, simply delays it. Six weeks after randomization, comparing those who remained on fluoxetine with those abruptly switched to placebo, rare reports of dizziness were the only discontinuation-related events to emerge. The data indicated that there was no evidence of a clinically meaningful discontinuation syndrome. Fluoxetine’s long halflife appeared to accomplish what a gradual taper of a shorter half-life agent would accomplish in prevention of the syndrome’s development. Dizziness may be the best signal to allow the clinician to distinguish the discontinuation syndrome from relapse. That said, there are clinically relevant and theoretically important: questions that remain to be examined with respect to the discontinuation syndromes with antidepressants in general and SSRIs in particular. First, not all patients interrupted under similar circumstances develop the syndrome, and of those who do, the intensity varies. What patient characteristics account for these differences? Is there evidence that the emergence of the syndrome identifies patients at higher risk of relapse with treatment discontinuation, rendering the syndrome a potentially useful guide to knowing which patients might in fact safely discontinue therapy? For example there may be analogies between the dynamics of tryptophan depletion and the symptoms it produces and SSRI abrupt interruption; the emergence of symptoms with tryptophan depletion in patients on SSRIs has been reported to be predictive of later depressive relapse. Does the perturbation of the discontinuation syndrome actually cause or predispose to relapse beyond the influence of removing an effective prophylaxis? Is there a confound in the design of continuation treatment studies of SSRIs in major depression, in that subjects are often abruptly switched to placebo, possibly inflating the benefits of continuing treatment? To answer some of these questions would require a different clinical trial design than the ones accomplished to date; for example, depressive subjects in recovery on a shorter half-life SSRI would be randomized to maintain treatment, to very gradually taper treatment, or to abruptly stop treatment, with extended follow-up to examine rates of recurrence of depression. It would appear unlikely that this design will be accomplished. We are currently re-examining data from earlier studies, however, to attempt to clarify further the relationship between SSRI discontinuation events and depressive relapse. References
[l]
[2]
[3]
[4]
[5]
Fava M, Rosenbamn JF, Hoog S, Krebs W, Dillon J, Fluoxetine Collaborative Study Group. A comparison of symptoms following tteatment interruption: evidence from a randomized, double-blind trial with fluoxetine, sertraline, and paroxetine. Proceedings of the Society of Biological Psychiatry Annual Meeting, Toronto, Ontario, Canada, 1998. Frank E, Kupfer DJ, Perel JM, Comes C, Jarrett DB, Mallinger AG, et al. Three-year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry 1990; 47:1093-1099. Kupfer DJ, Frank E, Perel JM, Comes C, Mallinger AG, Thase ME, et al. Fiveyear outcome for maintenance treatment of depression. Arch Gen Psychiatry 1992; 491769-773. Rosenbamn JF, Fava M, Hoog SL, Ascroft RC, Krebs W. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry 1998; 44~77-87. Zajecka J, Fawcett J, Amsterdam J, Quitkin F, Reimherr F, Rosenbaton J, et al. J Clin Psychopbarmacol 1998; l&193-197.