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Methodological approaches to the long-term study of antidepressants
EurPsychiatry 1996;11:109-115
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© Elsevier, Paris
Methodological approaches to the long-term study of antidepressants F Rouillon 1, L Steru 2, S
Wood 2
I Department of Psychiatry, H3pital Louis-Mourier, University Paris VII, 178 rue des Renouillers, 92701 Colombes cedex; 21TEM (Institute for the Technical Evaluation of Medicines), 93 avenue de Fontainebleau, 94276 Le Kremlin-Bic~tre cedex, France
Summary - It has long been known that most patients with bipolar disorder have a course marked by multiple recurrence of major depressive and manic episodes. More recently, many epidemiological studies have shown that at least 50% of unipolar depressive patients have one or more subsequent episodes of depression in their lifetimes. Likewise, relapse following successful short-term treatment of depression is so common that it is now recommended to prolong treatment in the form of maintenance pharmacotberapy.Interest in preventing the recurrence of depression has been stimulated by the results from long-term trials involving antidepressant drugs and lithium. However, these pharmacologicalstudies suffer somewhat from methodologicaldeficits, making difficult any clear and complete interpretationof their results. While some methodological recommendationshave now been established to compensate for previous deficits (eg, definition of relapse and recurrence, duration of acute and maintenance treatments, statistical analysis of efficacy), unfortunately, many key points still remain to be resolved (eg, selection of patients, dosage in maintenance and prophylacticphases, maximum length of a course of treatment, etc). long-term [ clinical trial / antidepressant / methodology
INTRODUCTION Depression is a c o m m o n l y occurring disorder having a chronic and relapsing course (NIH/NIMH Consensus, 1985). Since the affective disorder can often be severe enough to reduce the patient's w o r k c a p a c i t y and to disrupt social relations, the social and e c o n o m i c consequences can be very important ( J o n s s o n a n d B e b b i n g t o n , 1993). F u r t h e r m o r e , d e p r e s s i v e disorders are associated with increased m o r b i d i t y f r o m a l m o s t all p h y s i c a l i l l n e s s e s a n d with an increased risk o f mortality f r o m these illnesses and from suicide. The l o n g e r the d e p r e s s i v e e p i s o d e persists or the m o r e f r e q u e n t l y r e l a p s e s o c c u r , the g r e a t e r the l o n g - t e r m c o n s e q u e n c e s for the patient are l i k e l y to be. F o r this reason, m a i n t e n a n c e and continuation t r e a t m e n t s are n o w b e c o m i n g the d o m i n a n t s t r a t e g y in the m a n a g e m e n t o f d e p r e s s i o n , thus necessitating the evaluation o f the l o n g - t e r m effic a c y o f antidepressant c o m p o u n d s . This p r o b a b l y explains why European regulatory agencies r e q u i r e p r o o f o f the l o n g - t e r m e f f i c a c y o f n e w antidepressants before a p p r o v i n g t h e m for marketing and use in practice. Unfortunately, our k n o w l e d g e o f the treatment o f recurrent depression consists o f little m o r e than clinical i m p r e s s i o n s from
the treating physicians; to date v e r y few c o n t r o l l e d studies h a v e b e e n p e r f o r m e d (less than 30) on the m a i n t e n a n c e and p r o p h y l a c t i c e f f i c a c y o f antidepressants ( L o o n e n and Z w a n i k k e n , 1990; B e l s h e r and Costello, 1988). In addition, there are multiple m e t h o d o l o g i c a l p r o b l e m s i n h e r e n t in l o n g - t e r m c l i n i c a l t r i a l s in a f f e c t i v e d i s o r d e r s t h a t r e n d e r interpretation o f the results difficult: - M a n y o f the d o u b l e - b l i n d studies carried out to date have no p r e - i n c l u s i o n p e r i o d b e f o r e p r o p h y lactic treatment (table I). - T h e d u r a t i o n o f the p r o p h y l a c t i c p h a s e s t u d i e d varied w i d e l y (ranging f r o m 6 to 36 months), thus confusing analysis o f the prevention o f r e l a p s e (up to six m o n t h s after resolution) and p r e v e n t i o n o f recurrence (more than six months after resolution). - The n u m b e r o f patients was l o w (less than 30 p e r treatment g r o u p ) in m o r e than half the l o n g - t e r m c o n t r o l l e d studies p e r f o r m e d to date (tables I-III). - O n l y two tricyclic antidepressants ( T C A s ) (amitriptyline and i m i p r a m i n e ) , one q u a d r i c y c l i c antid e p r e s s a n t a n d one m o n o a m i n e o x i d a s e i n h i b i t o r (MAOI) have been evaluated under double-blind conditions. In contrast, a l m o s t all the n e w selective serotonin r e u p t a k e inhibitors (SSRIs) (zimelidine, fluoxetine, sertraline, citalopram, paroxetine) have been studied in this w a y (table III).
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Table I. Long-term controlled studies of antidepressant treatments versus placebo (without preinclusion period).
Author
Preinclusion period (months)
Treatment
Number of patients
Duration of prophylactic treatment (months)
Efficacy
Seager & Bird, 1962
0
28
6
I>P
Kay et al, 1970
0
102
7
A > P/D
Mindham et al, 1973
0
92
6
A>P
Klerman et al, 1974
0
92
8
A>P
Van Praag & De Haan, 1980 Stein et al, 1980
0
20
24
5-HTP > P
0
55
6
A>P
Glen et al, 1984
0
Imipramine placebo Amitriptyline placebo/diazepam Amitriptyline imipramine placebo Amitriptyline placebo 5-HTP placebo Amitriptyline placebo Amitriptyline placebo lithium
26
36
A = Li = P A + Li > P
I: imipramine; P: placebo; A: amitriptyline; D: diazepam; Li: lithium.
- The criteria used to describe relapse patterns, the study designs, the population recruited (in- or outpatients) all differed from one study to another, making it very difficult to perform a retrospective meta-analysis of the available results. In order to improve the quality and consistency of the assessment of the long-term use of antidepressants, some consensus approach concerning these methodological problems/discrepancies must be agreed upon. This review suggests some recommendations that should be taken into c o n s i d e r a t i o n in the design of future protocols on the long-term study of antidepressant m o l e c u l e s and discusses the drawbacks and problems inherent in the conception and performance of these trials. SUGGESTED DEFINITIONS Methodological discrepancies between protocols of different long-term studies on antidepressants (eg, duration of treatment/follow-up) have tended to derive from different ideas of what defines the efficacy of a long-term treatment (recovery, prevention of relapse, prevention of remission). While efficacy c r i t e r i a f o r s h o r t - t e r m trials s e e m r e l a t i v e l y straightforward (improvement of depressive symptoms), those of long-term trials seem more obscure. For example, it has not been clear if the disappearance of depressive symptoms during a longterm trial constituted a temporary remission of the
episode or a full recovery, and should new depressive symptoms emerge, whether this should be considered as a reappearance of the previous episode or as a new episode. This confusion of terminology has prevented the conception of protocols having consistent timeframes of patient evaluation. Below we offer several definitions of criteria essential to the study of the long-term efficacy of antidepressant treatment that should be considered when designing protocols for long-term trials.
Evolution of the depressive episode Remission Remission defined as short-term marked improvement of the patient, having a symptom score on current established rating scales within the range for non-depressed individuals (eg, H A M D < 7). Some authors suggest that full and partial remission should be distinguished according to the degree of improvement attained (Kupfer and Frank, 1992). Full recovery Full recovery is considered to have been obtained if the level of improvement persists for at least six months.
Relapse Exacerbation of an ongoing depressive episode after an initial brief suppression of symptoms (not
Methodological approaches to the long-term study of antidepressants
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Table II. Long-term controlled studies of antidepressant treatments versus placebo (with preinclusion period).
Author
Preinclusion period (months)
Treatment
Coppen et al, 1978
1.5
Amitriptyline placebo
Kane et al, 1982
6
Bialos et al, 1982
44.4
Imipramine lithium placebo Amitriptyline placebo Nomifensine placebo Imipramine lithium placebo Phenelzine placebo Imipramine and/or placebo Maprotiline (75 mg) maprotiline (37.5 mg) placebo
Lendresse et al, 1984
2
Prien et al, 1984
2
Harrison al, 1986
1.5
Frank et al, 1990
5
Rouillon et al, 1991
2
Number of patients
Duration of prophylactic treatment (months)
Efficacy
29
12
A>P
18
24
I=P Li > I or P
17
6
A>P
303
6
N >P
110
24
I>P Li = P
12
6
Phen > P
128
36
I>P
1,t 41
12
M (75) > M (37.5) > P
A: amitriptyline; P: placebo; I: imipramine; Li: lithium; N: nomifensine; Phen: phenelzine; M: maprotiline.
T a b l e III. Long-term controlled studies of SSRIs.
Author
Preinclusion period (months)
Treatment
Number of patients
Duration of prophylactic treatment (months)
Efficacy
Montgomery et al, 1988
6
220
12
F>P
Dunbar & Mewett, 1991
2
135
12
Pa > P
Montgomery & Rasmussen, 1991
1.5
Fluoxetine placebo Paroxetine placebo Citalopram placebo
147
6
C>P
Doogan & Caillard, 1992
2
Sertraline placebo
480
11
S>P
F: fluoxetine; P: placebo; Pa: paroxetine; C: citalopram; S: sertraline.
lasting for a sufficient amount of time to be considered as a r e c o v e r y ) defines relapse. Several e x p e r t s h a v e s u g g e s t e d that any d e t e r i o r a t i o n occurring within six months of response to treatment should be considered as relapse. Thus relapse represents a re-emergence of the initial depressive episode, not the occurrence of an independent secondary episode (see recurrence below). Recurrence A new episode of depression after a full recovery from the prior episode had been established, ie, an
episode of depression emerging at least six months after the improvement of the patient. These definitions are partially arbitrary, deriving from the medical model where relapse and recurrence of a disease are distinguished by the causes of the two episodes (eg, whether two episodes of fever result from the same or different bacterium). When Klerman et al (1974) initially suggested the distinction between relapse and recurrence of depression should be based on a time criterion (six months), they based this proposition on the fact that the likelihood of reappearance of depressive symptoms is
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greatest in the four to six months following initial symptomatic recovery. Furthermore, according to Kraepelin (1913), the average length of a depressive episode is approximately six months when no pharmacological treatment is administered. Nevertheless, despite the arbitrary nature o f these definitions, their use as conventions should help to organise the study o f relapse and recurrence of depression into clinically meaningful, and consistent, timeframes (Thase, 1990). Treatment
phase
Acute phase This includes the initiation of the antidepressant drug, either administered alone or associated with psychotherapeutic treatment, and alternate therapies for treatment non-responders. An acceptable improvement usually appears in three to six weeks. Continuation therapy This aims to prevent relapse and to maintain optimum clinical effects over four to six months using a stable dose of medication. Maintenance therapy This is prescribed over a period of one or more years to avoid recurrence of depression. STUDY DESIGNS Studies on the long-term use of antidepressants take their major strategic points from short-term studies and can be conceived in either open or double-blind settings. Open studies, while easier to perform, can not be used to provide statistical evaluation of the prophylactic efficacy of an antidepressant treatment. Such long-term studies can be carried out using various protocols: - as an open trial c o m p a r i n g two r a n d o m i s e d groups of patients, one treated by the experimental antidepressant, the other by a reference compound (randomised, open comparative study); - in single-blind versus placebo; and - by comparing for each patient the number of depressive episodes emerging in a patient during a period of treatment by a new antidepressant to the number of previous episodes occurring during the same length of time when untreated (one group, non-blind, mirror design). Mirror design studies have the advantage o f being pragmatic, avoiding the need for placebo, but do not take into account numerous non-specific factors. Even if these studies give a good indication of efficacy, their results must be interpreted with
caution. Only controlled trials carried out in double-blind conditions can be used to draw any definitive conclusions, but suffer from the fact that they can be very demanding on resources and pose ethical problems w h e n placebo is a d m i n i s t e r e d to depressed patients over a long period of time. Two types of long-term controlled trials can be conceived: - Start trials are similar in their c o n c e p t i o n to short-term studies, if not in duration, and can be carried out versus placebo or against a reference compound. The problems here are that no recognised antidepressant can be assumed to be a 'reference' in the normal sense of the word in the prev e n t i o n o f r e l a p s e or r e c u r r e n c e , and, w h i l e requiring large numbers of patients, such trials can only provide a relative estimation of efficacy. - Discontinuous studies include in the comparative blind phase only those patients responding to the experimental antidepressant during an open preinclusion phase. Their design has the advantage of reducing the period during which patients receive placebo compared to that in the start-trials and increases the likelihood of distinguishing a difference between study product and placebo. Furthermore, such trials correspond better to actual clinically accepted regimens for antidepressant therapy, which separate the acute treatment phase from phases of relapse and recurrence. However, these trials risk having an over-representation of patients who r e s p o n d to the study p r o d u c t and c o n s e quently exposing these to a risk o f withdrawal problems at the brutal change of prescribed treatment at the end of the pre-inclusion period when run-in (active) treatment is changed to placebo for those studies using placebo control in double-blind conditions (Grof, 1994). INCLUSION CRITERIA When designing a comparative long-term trial, it is suggested that the following criteria be met in a study population. Recognition
The illness should be syndromically defined using recognised diagnosis criteria (DSM-III-R, DSMIV, ICD-10, etc) and/or a score above a pathological threshold on a recognised depression scale. Recurrence
The usual practice has been to study patients with an established history of at least one previous epi-
Methodologicalapproachesto the long-termstudy of antidepressants sode of depression during the five years immediately prior to the trial (Montgomery et al 1989). This establishes a control rate of recurrence for each patient that enables the potential agent to be tested over the study period in this respect. Resolution The use of a symptom-free period helps to establish that an episode o f depression has properly resolved. Thus, this third criterion reduces a source o f confusion between relapses o f inadequately treated depression and the occurrence of a new depressive episode. The s y m p t o m - f r e e period before randomisation at the end of the open preinclusion phase can be defined by a good improvement (> 50% reduction in depressive symptoms) and/or an absolute score on a standardised rating scale that falls outside the range of clinical depression (eg, < 10 on the Hamilton Depression Scale). The diagnosis of the patient population should be c h o s e n a c c o r d i n g to the m e d i c a t i o n u n d e r study; for studies of bipolar patients - lithium, carbamazepine, valproate, clonazepam, etc; and for studies on unipolar patients - antidepressants (TCAs, SSRIs). Some co-morbid conditions (non-affective psychiatric disorders, chronic medical illnesses, personality disorders, alcoholism, chronic history, drug resistance, etc) are often exclusion criteria in short-term studies. However, these are also risk factors for relapse of depression, making such populations interesting for long-term study. Thus there is some discrepancy between the criteria required so as to include patients with high risk of relapse and recurrence of depression important in a study of the prophylactic efficacy of a drug and those criteria required to ensure good study reliability. ASSESSMENT The depression scales used in l o n g - t e r m antidepressant studies are the same as those used in short-term studies (eg, M A D R S , HAMD, etc); nevertheless, other semi-logistic measurements can be useful, such as social adjustment or quality of life, particularly for a long-term study design. In addition, a pharmaco-economic approach can be interesting, evaluating the direct costs (eg, number of consultations in addition to those necessary for clinical surveillance, length of hospitalisation, cost of side-effects, suicide attempts, physical illness in case of drop-out) and the indirect costs (eg, the reduction of work capacity) to give an estimation of the cost-benefit relation of the product.
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S o m e indicators seem to be more s p e c i a l l y suited for use in long-term studies than short-term trials. For example, the likelihood of suicide is obviously greater in a follow-up period of one year, than in one of just six weeks. Thus, in longterm trials, parameters such as suicide, attempted suicide, mania or hypomania, and impulsive obsessional behaviour requiring additional treatment should be monitored. Since patients with intolerance to an antidepressant are excluded from long-term trials during the pre-inclusion phases, the assessment of tolerability is inevitabily different in these trials from that in short-term studies. Side effects are less frequent, but they could be more severe. M o r e o v e r , the longer the duration of the study, the worse the patient compliance. Nevertheless, the annual mean drop-out rate due to side effects in long-term studies is only 10-15% (Rouillon et al, 1992). Finally, some authors have suggested that biological markers, thought to be related to relapse or recurrence of depression, should be e v a l u a t e d (Thase, 1990). For example, it seems that abnormal results in the dexamethasone suppression test are predictive of relapse despite clinical remission. Similarly, a decrease in the latency of rapid eye movement (REM) in electroencephalographic sleep or a decrease in the proportion of slow-wave sleep are proposed to be correlated with a higher risk of relapse (Thase, Simons and Monroe, 1990, u n p u b l i s h e d results). It c o u l d be advisable to maintain prophylactic therapy for as long as a patient continues to present such abnormal biological markers. TREATMENT There are many treatments that could be used as potential reference compounds in long-term prophylactic studies. Lithium salts are usually prescribed for bipolar disorders, but can be given alone or in association with antidepressants for unipolar disorders as well. Carbamazepine is useful in bipolar disorders but seems to be better than lithium in the treatment of rapid cyclers disease and in schizo-affective disorders (Okuma et al, 1981). In short-term trials in depression, TCAs have generally been the products of choice when selecting a reference compound. However, the long-term efficacy of these treatments has been very poorly studied, thus rendering their suitability as "reference" compounds in long-term trials somewhat doubtful. Controlled studies against placebo of the long-term treatment with TCAs are required in
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order to produce satisfactory accepted standards against which the effectiveness of new experimental drugs can be compared. The duration of treatment in a long-term prophylactic study should be planned so as to separate the acute phase o f treatment ( 6 - 8 weeks) f r o m the continuation phase (4-6 months) and the preventative t r e a t m e n t o f r e c u r r e n c e ( o v e r a period o f years). What the optimal length of treatment in such a study should be is not clear, there being only one double-blind study with antidepressant (imipramine versus placebo) that has assessed efficacy up to five years (Kupfer et al, 1992). However, it is clear that treatment must be tapered off gradually over a period of several months (25-33% monthly decrements as proposed by Loonen and Z w a n i k k e n , 1990) in order to prevent withdrawal problems and to minimise recurrence after long-term administration of antidepressant. Similarly, there is no scientific proof of the best dose o f antidepressant to be used in l o n g - t e r m treatment, although two opposing strategies concerning this point have been proposed: i) the dose of drug administered during the continuation phase should be reduced to no less than approximately 50-66% of that necessary for acute treatment. This proposition for a minimal effective dose is substantiated by clinical practice. The only double-blind c o m p a r i s o n between two doses of antidepressant performed to date (Rouillon et al, 1991) demonstrated that a m e d i u m reduction of the active dose of maprotiline (150 mg/day) to 75 mg/day was better at preventing recurrence of depression than a large reduction in dose to just 37.5 mg/day; ii) the results from a recent Pittsburgh study (Kupfer et al, 1992) now suggest that it is advisable to maintain the full dose of treatment in the continuation phase. In this study, a full dose of imipramine appeared better than a medium dose of this drug in the long-term treatment of depression. The mean daily dose administered was around 250 mg and a low rate of relapse was observed (7.6% in six m o n t h s with i m i p r a m i n e and interpersonal psychotherapy) c o m p a r e d to values recorded in the literature (20-40%). ANALYSIS In addition to traditional statistical comparative methods, therapeutic groups can also be compared using survival curve analysis (Kaplan-Meier method; Peto et al, 1977). It is necessary to control for differences between groups in risk variables for relapse and to control the duration of
time spent without depression before the onset of the trial (Belsher and Costello, 1988). Furthermore, the drop-out rate should be documented and different c o m p a r i s o n s , including an "intent-totreat analysis", made. CONCLUSION The long-term use of antidepressant treatment is becoming standard clinical practice in the management of patients with depressive disorders, and the demonstration of long-term efficacy in controlled clinical studies is now required for all new experimental antidepressant compounds. Despite the fact that more and more studies on the long-term use of antidepressant treatment are being carried out, and there is now good evidence of long-term efficacy for a range of treatments (Montgomery and Montgomery, 1992), there are few data that can be used as reference values in phase II and I I I clinical trials. It is essential to provide some sort of methodological rationale that can be adopted in future studies on the long-term use of antidepressants, not only to improve the quality of study of potential new treatments, but also to provide accepted standard values for the effectiveness of traditionally used reference products (eg, TCAs). Although there still remain several questions to be resolved (eg, optimal dose of treatment, optimal duration of treatment, inclusion criteria), which could conceivably be the objectives of forthcoming clinical studies, there is now some consensus on important m e t h o d o l o g i c a l a p p r o a c h e s to the long-term study of antidepressants. With the help of these recommendations, a clear concept of study objectives and fimeframe should now allow a m o r e consistent and h o m o g e n o u s approach to be taken for future studies on the longterm efficacy of antidepressants, enabling not only more extrapolable conclusions to be obtained, but also providing data that will be suitable for retrospective meta-analysis in the years to come.
REFERENCES Belsher G, Costello CG. Relapse after recovery from unipolar depression: a critical review. Psychol Bull 1988;104:84-96 Bialos D, Giller F, Jatlow P et al. Recurrence of depression after discontinuation of long-term amitriptyline treatment. Am J Psychiatry 1982;139:325-9 Coppen A, Ghose K, Montgomery Set al. Continuation therapy with amitriptyline in depression. Br J Psychiatry 1978; 133:28-33 Doogan D, Caillard V. Sertraline in the prevention of depression. Br J Psychiatry 1992;160:217-22 Dunbar GC, Mewetts S. A double-blind comparative study of
Methodological approaches to the long-term study of antidepressants paroxetine and placebo in preventing recurrent major depressive episodes, presented at the British Assoc of Psychopharmacology Annual meeting, York, 1991 Frank E, Kupfer DJ, Perel JM et al. Three-year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry 1990;47:1093-9 Glen AIM, Johnson AL, Shepherd M. Continuation therapy with lithium and amitriptyline in unipolar depressive illness: a randomized, double-blind controlled trial. Psychol Med 1984;14:37-50 Grof P. Designing long term clinical trials in affective disorders. J Affect Disord 1994;30:243-55 Harrison W, Rabkin J, Stewart JW et al. Phenelzine for chronic depression: a study of continuation treatment. J Clin Psychiatry 1986;47:346-9 Jonsson B, Bebbington P. Health economics of depression. In: Jonsson B, Rosenbanm J, eds. Perspectives in Psychiatry, Vol 4. Chichester, England: John Wiley 1993;35-48 Kane JM, Quitkin FM, Rifkin A e t al. Lithium carbonate and imipramine in the prophylaxis of unipolar and bipolar I illness. Arch Gen Psychiatry, 1982;39:1065-9 Kay DWK, Fahy T, Garside RF. A seven-month double-blind trial of a m i t r i p t y l i n e and d i a z e p a m in E C T - t r e a t e d depressed patients. Br J Psychiatry 1970; 117:667-71 Klerman GL, Di Mascio A, Weissman MM et al. Treatment of depression by drugs and psychotherapy. Am J Psychiatry 1974;131:186-91 Kraepelin E. Das Manisch-Depressive irresein. In: Psychiatric. Ein Lehrbuch fiir Studierende and Aerzte, vol IN, 2. Leipzig, Germany: Barth, 1913 Kupfer D J, Frank E. The minimum length of treatment for recovery. In: Montgomery SA, Rouillon F, eds. Long-term Treatment o f Depression. London: John Wiley & Sons Ltd 1992;33-52 Kupfer DJ, Frank E, Perel JM et al. Five year outcome for maintenance therapies in recurrent depression. Arch Gen Psychiatry 1992;49:769-73 Lendresse P, Cren MC, Lemarie JC. Traitement prolong6 par nomifensine 75 mg dans les 6tats d6pressifs n6vrotiques et r6actionnels. Psychiatrie Fran~aise 1984; 16 (suppl): 156-8 Loonen AJN, Zwanikken GJ. Continuation and maintenance therapy with a n t i d e p r e s s i v e agents: an o v e r v i e w of research. Phar Weekbl (Sci) 1990;12:128-41 Mindham RHS, Howland C, Shepherd M. An evaluation of continuation therapy with tricyclic antidepressants in depressive illness. Psychol Med 1973;3:5-17
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Montgomery SA, Dufour H, Brion S et al. The prophylactic efficacy of fluoxetin in unipolar depression. Br J Psychiatry 1988; 153 (3 suppl):69-76 Montgomery SA, Green M, Baldwin D, Montgomery D. Prophylactic treatment of depression: A public health issue. Neuropsycholiology 1989;22:214-9 Montgomery SA, Montgomery DB. Prophylactic treatment in recurrent unipolar depression. In: Montgomery SA, Rouilion F, eds. Long-Term Treatment o f Depression. London: John Wiley & Sons Ltd 1992;53-79 Montgomery SA, Rasmussen TGC. Citalopram 20 mg, Citalopram 40 mg and placebo in the prevention of relapses of major depression. Int Clin Psychopharmacol 1991;6 (suppl 5):71-3 NIH/NIMH. Consensus development conference statement. Mood disorders: Pharmacologic Prevention of Recurrences. Consensus Development Panel. Am J Psychiatry 1985; 142/4:469-76 Okuma T, Inanaga K, Otsuki S. A preliminary double blind study on the efficacy of carbamazepine in prophylaxis of manic depressive illness. Psychopharmacology 1981 ;73: 95-6 Pert R, Pike MC, Armitage P e t al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient, II: analysis and examples. Br J Cancer 1977;35:1-39 Prien R, Kupfer DJ, Mansky P A e t al. Drug therapy in the prevention of recurrence in unipolar and bipolar affective disorders. Arch Gen Psychiatry 1984;41 : 1096-104 Rouillon F, Serrurier D, Miller HD, G6rard MJ. Prophylactic efficacy of maprotiline on unipolar depression relapse. J Clin Psychiatry 1991;52/10:423-31 Rouillon F, Lejoyeux M, Filteau MJ. Unwanted effects of long term treatment. In: Montgomery SA, Rouillon F, eds. LongTerm Treatment o f Depression. London: John Wiley & Sons 1992;81-112 Seager CP, Bird RL. Imipramine with electrical treatment in depression: a controlled trial. J Merit Sci 1962; 108:704-7 Stein M, Rickels K, Weise CC. Maintenance therapy with amitriptyline: a controlled trial. Am J Psychiatry 1980;137: 370-1 Thase ME. Relapse and recurrence in unipolar major depression. Short-term and long-term approaches. J Clin Psychiatry 1990;51 ;6 (suppl):51-7 Van Praag H, De Haan S. Depression vulnerability and 5-HT prophylaxis. Psychiatry R es 1980;3:75-83
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© Elsevier, Paris
Methodological approaches to the long-term study of antidepressants F Rouillon 1, L Steru 2, S
Wood 2
I Department of Psychiatry, H3pital Louis-Mourier, University Paris VII, 178 rue des Renouillers, 92701 Colombes cedex; 21TEM (Institute for the Technical Evaluation of Medicines), 93 avenue de Fontainebleau, 94276 Le Kremlin-Bic~tre cedex, France
Summary - It has long been known that most patients with bipolar disorder have a course marked by multiple recurrence of major depressive and manic episodes. More recently, many epidemiological studies have shown that at least 50% of unipolar depressive patients have one or more subsequent episodes of depression in their lifetimes. Likewise, relapse following successful short-term treatment of depression is so common that it is now recommended to prolong treatment in the form of maintenance pharmacotberapy.Interest in preventing the recurrence of depression has been stimulated by the results from long-term trials involving antidepressant drugs and lithium. However, these pharmacologicalstudies suffer somewhat from methodologicaldeficits, making difficult any clear and complete interpretationof their results. While some methodological recommendationshave now been established to compensate for previous deficits (eg, definition of relapse and recurrence, duration of acute and maintenance treatments, statistical analysis of efficacy), unfortunately, many key points still remain to be resolved (eg, selection of patients, dosage in maintenance and prophylacticphases, maximum length of a course of treatment, etc). long-term [ clinical trial / antidepressant / methodology
INTRODUCTION Depression is a c o m m o n l y occurring disorder having a chronic and relapsing course (NIH/NIMH Consensus, 1985). Since the affective disorder can often be severe enough to reduce the patient's w o r k c a p a c i t y and to disrupt social relations, the social and e c o n o m i c consequences can be very important ( J o n s s o n a n d B e b b i n g t o n , 1993). F u r t h e r m o r e , d e p r e s s i v e disorders are associated with increased m o r b i d i t y f r o m a l m o s t all p h y s i c a l i l l n e s s e s a n d with an increased risk o f mortality f r o m these illnesses and from suicide. The l o n g e r the d e p r e s s i v e e p i s o d e persists or the m o r e f r e q u e n t l y r e l a p s e s o c c u r , the g r e a t e r the l o n g - t e r m c o n s e q u e n c e s for the patient are l i k e l y to be. F o r this reason, m a i n t e n a n c e and continuation t r e a t m e n t s are n o w b e c o m i n g the d o m i n a n t s t r a t e g y in the m a n a g e m e n t o f d e p r e s s i o n , thus necessitating the evaluation o f the l o n g - t e r m effic a c y o f antidepressant c o m p o u n d s . This p r o b a b l y explains why European regulatory agencies r e q u i r e p r o o f o f the l o n g - t e r m e f f i c a c y o f n e w antidepressants before a p p r o v i n g t h e m for marketing and use in practice. Unfortunately, our k n o w l e d g e o f the treatment o f recurrent depression consists o f little m o r e than clinical i m p r e s s i o n s from
the treating physicians; to date v e r y few c o n t r o l l e d studies h a v e b e e n p e r f o r m e d (less than 30) on the m a i n t e n a n c e and p r o p h y l a c t i c e f f i c a c y o f antidepressants ( L o o n e n and Z w a n i k k e n , 1990; B e l s h e r and Costello, 1988). In addition, there are multiple m e t h o d o l o g i c a l p r o b l e m s i n h e r e n t in l o n g - t e r m c l i n i c a l t r i a l s in a f f e c t i v e d i s o r d e r s t h a t r e n d e r interpretation o f the results difficult: - M a n y o f the d o u b l e - b l i n d studies carried out to date have no p r e - i n c l u s i o n p e r i o d b e f o r e p r o p h y lactic treatment (table I). - T h e d u r a t i o n o f the p r o p h y l a c t i c p h a s e s t u d i e d varied w i d e l y (ranging f r o m 6 to 36 months), thus confusing analysis o f the prevention o f r e l a p s e (up to six m o n t h s after resolution) and p r e v e n t i o n o f recurrence (more than six months after resolution). - The n u m b e r o f patients was l o w (less than 30 p e r treatment g r o u p ) in m o r e than half the l o n g - t e r m c o n t r o l l e d studies p e r f o r m e d to date (tables I-III). - O n l y two tricyclic antidepressants ( T C A s ) (amitriptyline and i m i p r a m i n e ) , one q u a d r i c y c l i c antid e p r e s s a n t a n d one m o n o a m i n e o x i d a s e i n h i b i t o r (MAOI) have been evaluated under double-blind conditions. In contrast, a l m o s t all the n e w selective serotonin r e u p t a k e inhibitors (SSRIs) (zimelidine, fluoxetine, sertraline, citalopram, paroxetine) have been studied in this w a y (table III).
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Table I. Long-term controlled studies of antidepressant treatments versus placebo (without preinclusion period).
Author
Preinclusion period (months)
Treatment
Number of patients
Duration of prophylactic treatment (months)
Efficacy
Seager & Bird, 1962
0
28
6
I>P
Kay et al, 1970
0
102
7
A > P/D
Mindham et al, 1973
0
92
6
A>P
Klerman et al, 1974
0
92
8
A>P
Van Praag & De Haan, 1980 Stein et al, 1980
0
20
24
5-HTP > P
0
55
6
A>P
Glen et al, 1984
0
Imipramine placebo Amitriptyline placebo/diazepam Amitriptyline imipramine placebo Amitriptyline placebo 5-HTP placebo Amitriptyline placebo Amitriptyline placebo lithium
26
36
A = Li = P A + Li > P
I: imipramine; P: placebo; A: amitriptyline; D: diazepam; Li: lithium.
- The criteria used to describe relapse patterns, the study designs, the population recruited (in- or outpatients) all differed from one study to another, making it very difficult to perform a retrospective meta-analysis of the available results. In order to improve the quality and consistency of the assessment of the long-term use of antidepressants, some consensus approach concerning these methodological problems/discrepancies must be agreed upon. This review suggests some recommendations that should be taken into c o n s i d e r a t i o n in the design of future protocols on the long-term study of antidepressant m o l e c u l e s and discusses the drawbacks and problems inherent in the conception and performance of these trials. SUGGESTED DEFINITIONS Methodological discrepancies between protocols of different long-term studies on antidepressants (eg, duration of treatment/follow-up) have tended to derive from different ideas of what defines the efficacy of a long-term treatment (recovery, prevention of relapse, prevention of remission). While efficacy c r i t e r i a f o r s h o r t - t e r m trials s e e m r e l a t i v e l y straightforward (improvement of depressive symptoms), those of long-term trials seem more obscure. For example, it has not been clear if the disappearance of depressive symptoms during a longterm trial constituted a temporary remission of the
episode or a full recovery, and should new depressive symptoms emerge, whether this should be considered as a reappearance of the previous episode or as a new episode. This confusion of terminology has prevented the conception of protocols having consistent timeframes of patient evaluation. Below we offer several definitions of criteria essential to the study of the long-term efficacy of antidepressant treatment that should be considered when designing protocols for long-term trials.
Evolution of the depressive episode Remission Remission defined as short-term marked improvement of the patient, having a symptom score on current established rating scales within the range for non-depressed individuals (eg, H A M D < 7). Some authors suggest that full and partial remission should be distinguished according to the degree of improvement attained (Kupfer and Frank, 1992). Full recovery Full recovery is considered to have been obtained if the level of improvement persists for at least six months.
Relapse Exacerbation of an ongoing depressive episode after an initial brief suppression of symptoms (not
Methodological approaches to the long-term study of antidepressants
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Table II. Long-term controlled studies of antidepressant treatments versus placebo (with preinclusion period).
Author
Preinclusion period (months)
Treatment
Coppen et al, 1978
1.5
Amitriptyline placebo
Kane et al, 1982
6
Bialos et al, 1982
44.4
Imipramine lithium placebo Amitriptyline placebo Nomifensine placebo Imipramine lithium placebo Phenelzine placebo Imipramine and/or placebo Maprotiline (75 mg) maprotiline (37.5 mg) placebo
Lendresse et al, 1984
2
Prien et al, 1984
2
Harrison al, 1986
1.5
Frank et al, 1990
5
Rouillon et al, 1991
2
Number of patients
Duration of prophylactic treatment (months)
Efficacy
29
12
A>P
18
24
I=P Li > I or P
17
6
A>P
303
6
N >P
110
24
I>P Li = P
12
6
Phen > P
128
36
I>P
1,t 41
12
M (75) > M (37.5) > P
A: amitriptyline; P: placebo; I: imipramine; Li: lithium; N: nomifensine; Phen: phenelzine; M: maprotiline.
T a b l e III. Long-term controlled studies of SSRIs.
Author
Preinclusion period (months)
Treatment
Number of patients
Duration of prophylactic treatment (months)
Efficacy
Montgomery et al, 1988
6
220
12
F>P
Dunbar & Mewett, 1991
2
135
12
Pa > P
Montgomery & Rasmussen, 1991
1.5
Fluoxetine placebo Paroxetine placebo Citalopram placebo
147
6
C>P
Doogan & Caillard, 1992
2
Sertraline placebo
480
11
S>P
F: fluoxetine; P: placebo; Pa: paroxetine; C: citalopram; S: sertraline.
lasting for a sufficient amount of time to be considered as a r e c o v e r y ) defines relapse. Several e x p e r t s h a v e s u g g e s t e d that any d e t e r i o r a t i o n occurring within six months of response to treatment should be considered as relapse. Thus relapse represents a re-emergence of the initial depressive episode, not the occurrence of an independent secondary episode (see recurrence below). Recurrence A new episode of depression after a full recovery from the prior episode had been established, ie, an
episode of depression emerging at least six months after the improvement of the patient. These definitions are partially arbitrary, deriving from the medical model where relapse and recurrence of a disease are distinguished by the causes of the two episodes (eg, whether two episodes of fever result from the same or different bacterium). When Klerman et al (1974) initially suggested the distinction between relapse and recurrence of depression should be based on a time criterion (six months), they based this proposition on the fact that the likelihood of reappearance of depressive symptoms is
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greatest in the four to six months following initial symptomatic recovery. Furthermore, according to Kraepelin (1913), the average length of a depressive episode is approximately six months when no pharmacological treatment is administered. Nevertheless, despite the arbitrary nature o f these definitions, their use as conventions should help to organise the study o f relapse and recurrence of depression into clinically meaningful, and consistent, timeframes (Thase, 1990). Treatment
phase
Acute phase This includes the initiation of the antidepressant drug, either administered alone or associated with psychotherapeutic treatment, and alternate therapies for treatment non-responders. An acceptable improvement usually appears in three to six weeks. Continuation therapy This aims to prevent relapse and to maintain optimum clinical effects over four to six months using a stable dose of medication. Maintenance therapy This is prescribed over a period of one or more years to avoid recurrence of depression. STUDY DESIGNS Studies on the long-term use of antidepressants take their major strategic points from short-term studies and can be conceived in either open or double-blind settings. Open studies, while easier to perform, can not be used to provide statistical evaluation of the prophylactic efficacy of an antidepressant treatment. Such long-term studies can be carried out using various protocols: - as an open trial c o m p a r i n g two r a n d o m i s e d groups of patients, one treated by the experimental antidepressant, the other by a reference compound (randomised, open comparative study); - in single-blind versus placebo; and - by comparing for each patient the number of depressive episodes emerging in a patient during a period of treatment by a new antidepressant to the number of previous episodes occurring during the same length of time when untreated (one group, non-blind, mirror design). Mirror design studies have the advantage o f being pragmatic, avoiding the need for placebo, but do not take into account numerous non-specific factors. Even if these studies give a good indication of efficacy, their results must be interpreted with
caution. Only controlled trials carried out in double-blind conditions can be used to draw any definitive conclusions, but suffer from the fact that they can be very demanding on resources and pose ethical problems w h e n placebo is a d m i n i s t e r e d to depressed patients over a long period of time. Two types of long-term controlled trials can be conceived: - Start trials are similar in their c o n c e p t i o n to short-term studies, if not in duration, and can be carried out versus placebo or against a reference compound. The problems here are that no recognised antidepressant can be assumed to be a 'reference' in the normal sense of the word in the prev e n t i o n o f r e l a p s e or r e c u r r e n c e , and, w h i l e requiring large numbers of patients, such trials can only provide a relative estimation of efficacy. - Discontinuous studies include in the comparative blind phase only those patients responding to the experimental antidepressant during an open preinclusion phase. Their design has the advantage of reducing the period during which patients receive placebo compared to that in the start-trials and increases the likelihood of distinguishing a difference between study product and placebo. Furthermore, such trials correspond better to actual clinically accepted regimens for antidepressant therapy, which separate the acute treatment phase from phases of relapse and recurrence. However, these trials risk having an over-representation of patients who r e s p o n d to the study p r o d u c t and c o n s e quently exposing these to a risk o f withdrawal problems at the brutal change of prescribed treatment at the end of the pre-inclusion period when run-in (active) treatment is changed to placebo for those studies using placebo control in double-blind conditions (Grof, 1994). INCLUSION CRITERIA When designing a comparative long-term trial, it is suggested that the following criteria be met in a study population. Recognition
The illness should be syndromically defined using recognised diagnosis criteria (DSM-III-R, DSMIV, ICD-10, etc) and/or a score above a pathological threshold on a recognised depression scale. Recurrence
The usual practice has been to study patients with an established history of at least one previous epi-
Methodologicalapproachesto the long-termstudy of antidepressants sode of depression during the five years immediately prior to the trial (Montgomery et al 1989). This establishes a control rate of recurrence for each patient that enables the potential agent to be tested over the study period in this respect. Resolution The use of a symptom-free period helps to establish that an episode o f depression has properly resolved. Thus, this third criterion reduces a source o f confusion between relapses o f inadequately treated depression and the occurrence of a new depressive episode. The s y m p t o m - f r e e period before randomisation at the end of the open preinclusion phase can be defined by a good improvement (> 50% reduction in depressive symptoms) and/or an absolute score on a standardised rating scale that falls outside the range of clinical depression (eg, < 10 on the Hamilton Depression Scale). The diagnosis of the patient population should be c h o s e n a c c o r d i n g to the m e d i c a t i o n u n d e r study; for studies of bipolar patients - lithium, carbamazepine, valproate, clonazepam, etc; and for studies on unipolar patients - antidepressants (TCAs, SSRIs). Some co-morbid conditions (non-affective psychiatric disorders, chronic medical illnesses, personality disorders, alcoholism, chronic history, drug resistance, etc) are often exclusion criteria in short-term studies. However, these are also risk factors for relapse of depression, making such populations interesting for long-term study. Thus there is some discrepancy between the criteria required so as to include patients with high risk of relapse and recurrence of depression important in a study of the prophylactic efficacy of a drug and those criteria required to ensure good study reliability. ASSESSMENT The depression scales used in l o n g - t e r m antidepressant studies are the same as those used in short-term studies (eg, M A D R S , HAMD, etc); nevertheless, other semi-logistic measurements can be useful, such as social adjustment or quality of life, particularly for a long-term study design. In addition, a pharmaco-economic approach can be interesting, evaluating the direct costs (eg, number of consultations in addition to those necessary for clinical surveillance, length of hospitalisation, cost of side-effects, suicide attempts, physical illness in case of drop-out) and the indirect costs (eg, the reduction of work capacity) to give an estimation of the cost-benefit relation of the product.
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S o m e indicators seem to be more s p e c i a l l y suited for use in long-term studies than short-term trials. For example, the likelihood of suicide is obviously greater in a follow-up period of one year, than in one of just six weeks. Thus, in longterm trials, parameters such as suicide, attempted suicide, mania or hypomania, and impulsive obsessional behaviour requiring additional treatment should be monitored. Since patients with intolerance to an antidepressant are excluded from long-term trials during the pre-inclusion phases, the assessment of tolerability is inevitabily different in these trials from that in short-term studies. Side effects are less frequent, but they could be more severe. M o r e o v e r , the longer the duration of the study, the worse the patient compliance. Nevertheless, the annual mean drop-out rate due to side effects in long-term studies is only 10-15% (Rouillon et al, 1992). Finally, some authors have suggested that biological markers, thought to be related to relapse or recurrence of depression, should be e v a l u a t e d (Thase, 1990). For example, it seems that abnormal results in the dexamethasone suppression test are predictive of relapse despite clinical remission. Similarly, a decrease in the latency of rapid eye movement (REM) in electroencephalographic sleep or a decrease in the proportion of slow-wave sleep are proposed to be correlated with a higher risk of relapse (Thase, Simons and Monroe, 1990, u n p u b l i s h e d results). It c o u l d be advisable to maintain prophylactic therapy for as long as a patient continues to present such abnormal biological markers. TREATMENT There are many treatments that could be used as potential reference compounds in long-term prophylactic studies. Lithium salts are usually prescribed for bipolar disorders, but can be given alone or in association with antidepressants for unipolar disorders as well. Carbamazepine is useful in bipolar disorders but seems to be better than lithium in the treatment of rapid cyclers disease and in schizo-affective disorders (Okuma et al, 1981). In short-term trials in depression, TCAs have generally been the products of choice when selecting a reference compound. However, the long-term efficacy of these treatments has been very poorly studied, thus rendering their suitability as "reference" compounds in long-term trials somewhat doubtful. Controlled studies against placebo of the long-term treatment with TCAs are required in
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order to produce satisfactory accepted standards against which the effectiveness of new experimental drugs can be compared. The duration of treatment in a long-term prophylactic study should be planned so as to separate the acute phase o f treatment ( 6 - 8 weeks) f r o m the continuation phase (4-6 months) and the preventative t r e a t m e n t o f r e c u r r e n c e ( o v e r a period o f years). What the optimal length of treatment in such a study should be is not clear, there being only one double-blind study with antidepressant (imipramine versus placebo) that has assessed efficacy up to five years (Kupfer et al, 1992). However, it is clear that treatment must be tapered off gradually over a period of several months (25-33% monthly decrements as proposed by Loonen and Z w a n i k k e n , 1990) in order to prevent withdrawal problems and to minimise recurrence after long-term administration of antidepressant. Similarly, there is no scientific proof of the best dose o f antidepressant to be used in l o n g - t e r m treatment, although two opposing strategies concerning this point have been proposed: i) the dose of drug administered during the continuation phase should be reduced to no less than approximately 50-66% of that necessary for acute treatment. This proposition for a minimal effective dose is substantiated by clinical practice. The only double-blind c o m p a r i s o n between two doses of antidepressant performed to date (Rouillon et al, 1991) demonstrated that a m e d i u m reduction of the active dose of maprotiline (150 mg/day) to 75 mg/day was better at preventing recurrence of depression than a large reduction in dose to just 37.5 mg/day; ii) the results from a recent Pittsburgh study (Kupfer et al, 1992) now suggest that it is advisable to maintain the full dose of treatment in the continuation phase. In this study, a full dose of imipramine appeared better than a medium dose of this drug in the long-term treatment of depression. The mean daily dose administered was around 250 mg and a low rate of relapse was observed (7.6% in six m o n t h s with i m i p r a m i n e and interpersonal psychotherapy) c o m p a r e d to values recorded in the literature (20-40%). ANALYSIS In addition to traditional statistical comparative methods, therapeutic groups can also be compared using survival curve analysis (Kaplan-Meier method; Peto et al, 1977). It is necessary to control for differences between groups in risk variables for relapse and to control the duration of
time spent without depression before the onset of the trial (Belsher and Costello, 1988). Furthermore, the drop-out rate should be documented and different c o m p a r i s o n s , including an "intent-totreat analysis", made. CONCLUSION The long-term use of antidepressant treatment is becoming standard clinical practice in the management of patients with depressive disorders, and the demonstration of long-term efficacy in controlled clinical studies is now required for all new experimental antidepressant compounds. Despite the fact that more and more studies on the long-term use of antidepressant treatment are being carried out, and there is now good evidence of long-term efficacy for a range of treatments (Montgomery and Montgomery, 1992), there are few data that can be used as reference values in phase II and I I I clinical trials. It is essential to provide some sort of methodological rationale that can be adopted in future studies on the long-term use of antidepressants, not only to improve the quality of study of potential new treatments, but also to provide accepted standard values for the effectiveness of traditionally used reference products (eg, TCAs). Although there still remain several questions to be resolved (eg, optimal dose of treatment, optimal duration of treatment, inclusion criteria), which could conceivably be the objectives of forthcoming clinical studies, there is now some consensus on important m e t h o d o l o g i c a l a p p r o a c h e s to the long-term study of antidepressants. With the help of these recommendations, a clear concept of study objectives and fimeframe should now allow a m o r e consistent and h o m o g e n o u s approach to be taken for future studies on the longterm efficacy of antidepressants, enabling not only more extrapolable conclusions to be obtained, but also providing data that will be suitable for retrospective meta-analysis in the years to come.
REFERENCES Belsher G, Costello CG. Relapse after recovery from unipolar depression: a critical review. Psychol Bull 1988;104:84-96 Bialos D, Giller F, Jatlow P et al. Recurrence of depression after discontinuation of long-term amitriptyline treatment. Am J Psychiatry 1982;139:325-9 Coppen A, Ghose K, Montgomery Set al. Continuation therapy with amitriptyline in depression. Br J Psychiatry 1978; 133:28-33 Doogan D, Caillard V. Sertraline in the prevention of depression. Br J Psychiatry 1992;160:217-22 Dunbar GC, Mewetts S. A double-blind comparative study of
Methodological approaches to the long-term study of antidepressants paroxetine and placebo in preventing recurrent major depressive episodes, presented at the British Assoc of Psychopharmacology Annual meeting, York, 1991 Frank E, Kupfer DJ, Perel JM et al. Three-year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry 1990;47:1093-9 Glen AIM, Johnson AL, Shepherd M. Continuation therapy with lithium and amitriptyline in unipolar depressive illness: a randomized, double-blind controlled trial. Psychol Med 1984;14:37-50 Grof P. Designing long term clinical trials in affective disorders. J Affect Disord 1994;30:243-55 Harrison W, Rabkin J, Stewart JW et al. Phenelzine for chronic depression: a study of continuation treatment. J Clin Psychiatry 1986;47:346-9 Jonsson B, Bebbington P. Health economics of depression. In: Jonsson B, Rosenbanm J, eds. Perspectives in Psychiatry, Vol 4. Chichester, England: John Wiley 1993;35-48 Kane JM, Quitkin FM, Rifkin A e t al. Lithium carbonate and imipramine in the prophylaxis of unipolar and bipolar I illness. Arch Gen Psychiatry, 1982;39:1065-9 Kay DWK, Fahy T, Garside RF. A seven-month double-blind trial of a m i t r i p t y l i n e and d i a z e p a m in E C T - t r e a t e d depressed patients. Br J Psychiatry 1970; 117:667-71 Klerman GL, Di Mascio A, Weissman MM et al. Treatment of depression by drugs and psychotherapy. Am J Psychiatry 1974;131:186-91 Kraepelin E. Das Manisch-Depressive irresein. In: Psychiatric. Ein Lehrbuch fiir Studierende and Aerzte, vol IN, 2. Leipzig, Germany: Barth, 1913 Kupfer D J, Frank E. The minimum length of treatment for recovery. In: Montgomery SA, Rouillon F, eds. Long-term Treatment o f Depression. London: John Wiley & Sons Ltd 1992;33-52 Kupfer DJ, Frank E, Perel JM et al. Five year outcome for maintenance therapies in recurrent depression. Arch Gen Psychiatry 1992;49:769-73 Lendresse P, Cren MC, Lemarie JC. Traitement prolong6 par nomifensine 75 mg dans les 6tats d6pressifs n6vrotiques et r6actionnels. Psychiatrie Fran~aise 1984; 16 (suppl): 156-8 Loonen AJN, Zwanikken GJ. Continuation and maintenance therapy with a n t i d e p r e s s i v e agents: an o v e r v i e w of research. Phar Weekbl (Sci) 1990;12:128-41 Mindham RHS, Howland C, Shepherd M. An evaluation of continuation therapy with tricyclic antidepressants in depressive illness. Psychol Med 1973;3:5-17
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Montgomery SA, Dufour H, Brion S et al. The prophylactic efficacy of fluoxetin in unipolar depression. Br J Psychiatry 1988; 153 (3 suppl):69-76 Montgomery SA, Green M, Baldwin D, Montgomery D. Prophylactic treatment of depression: A public health issue. Neuropsycholiology 1989;22:214-9 Montgomery SA, Montgomery DB. Prophylactic treatment in recurrent unipolar depression. In: Montgomery SA, Rouilion F, eds. Long-Term Treatment o f Depression. London: John Wiley & Sons Ltd 1992;53-79 Montgomery SA, Rasmussen TGC. Citalopram 20 mg, Citalopram 40 mg and placebo in the prevention of relapses of major depression. Int Clin Psychopharmacol 1991;6 (suppl 5):71-3 NIH/NIMH. Consensus development conference statement. Mood disorders: Pharmacologic Prevention of Recurrences. Consensus Development Panel. Am J Psychiatry 1985; 142/4:469-76 Okuma T, Inanaga K, Otsuki S. A preliminary double blind study on the efficacy of carbamazepine in prophylaxis of manic depressive illness. Psychopharmacology 1981 ;73: 95-6 Pert R, Pike MC, Armitage P e t al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient, II: analysis and examples. Br J Cancer 1977;35:1-39 Prien R, Kupfer DJ, Mansky P A e t al. Drug therapy in the prevention of recurrence in unipolar and bipolar affective disorders. Arch Gen Psychiatry 1984;41 : 1096-104 Rouillon F, Serrurier D, Miller HD, G6rard MJ. Prophylactic efficacy of maprotiline on unipolar depression relapse. J Clin Psychiatry 1991;52/10:423-31 Rouillon F, Lejoyeux M, Filteau MJ. Unwanted effects of long term treatment. In: Montgomery SA, Rouillon F, eds. LongTerm Treatment o f Depression. London: John Wiley & Sons 1992;81-112 Seager CP, Bird RL. Imipramine with electrical treatment in depression: a controlled trial. J Merit Sci 1962; 108:704-7 Stein M, Rickels K, Weise CC. Maintenance therapy with amitriptyline: a controlled trial. Am J Psychiatry 1980;137: 370-1 Thase ME. Relapse and recurrence in unipolar major depression. Short-term and long-term approaches. J Clin Psychiatry 1990;51 ;6 (suppl):51-7 Van Praag H, De Haan S. Depression vulnerability and 5-HT prophylaxis. Psychiatry R es 1980;3:75-83