Original Author: Paul Perry, Ph.D, BCPP
Latest Revisers: Paul Perry, Ph.D, BCPP, Mitchell
Barnett, Pharm.D.
Creation Date: 1996
Last Revision Date: February 2004
Peer Review Status: Internally Peer Reviewed
A discussion of affective disorder prevention must be prefaced by several definitions, which are described graphically in Figure 1. This schematic can be used to describe the course of either a manic or depressive episode.
Figure 1. Treatment phases in affective illness (Hirschfeld 1994).
The course of an affective episode begins with the development of symptoms, which progress into a defined syndrome. After an effective therapy is initiated, the symptoms gradually improve. A response is defined as the point where a marked improvement is observed, but symptoms are still present. This is roughly analogous to the response definition commonly used in clinical trials of a 50% reduction in the rating scale score (e.g. HAMD - Hamilton Depression Rating Scale, YMRS - Young mania rating scale). In contrast, remission occurs when the patient no longer meets affective syndrome criteria and has no more than minimal symptoms. This is analogous to clinical trials using a threshold response definition such as a HAMD score < 8. The period from the initiation of treatment to the remission of symptoms is referred to the acute treatment phase. The acute treatment of affective illness is discussed at length in other chapters (Pharmacotherapy of Depression, Treatment of Refractory Depression, Antimanics).
Once remission is achieved, treatment is typically continued for a period of 4-6 months. This period is aptly referred to as the continuation phase. The duration of an untreated affective episode is approximately 3 months for mania (Clayton 1992) and 4-13 months (Winokur 1992) for depression. The rationale of continuation treatment is to cover patients for this period during which they are at an increased risk for relapse. Relapse is defined as the return of symptoms meeting the criteria for an affective episode during the continuation phase. The efficacy of continuation treatment in preventing relapse is discussed in subsequent sections. After the completion of continuation treatment, the decision is made to either continue or discontinue treatment. Continuing treatment beyond this point is referred to as maintenance treatment. The return of an affective syndrome beyond this point is defined as a recurrence and is assumed to be a new episode. The efficacy of and criteria for maintenance treatment of affective illness is discussed in subsequent sections. Care must be taken when interpreting clinical studies for "maintenance" treatment as this term is often misused. For example, a 6-month trial investigating the efficacy of Drug X for "maintenance treatment" of depression is likely investigating continuation efficacy rather than maintenance efficacy. Also, the term prophylaxis is not rigorously defined and can be used to describe either continuation or maintenance treatment (or both).
INTRODUCTION
Epidemiology. Unipolar disorder afflicts approximately 5% of the US adult population with a median age at onset of 25 years. A review of naturalistic studies of mood disorders found > 3 episodes occurred in 18% to 80% of patients (Zis and Goodwin 1979). A study of more than 1000 hospitalized patients from five countries, found that the median number of affective episodes was nine for bipolar patients and six for unipolar patients (Angst and Grof 1976). More recently, a NIMH sponsored study of 380 recovered MDD patients found that 50% of the patients relapsed within 132 weeks and the cumulative proportion of recurrence over 15 years was 85% (Mueller TI, Leon AC, Keller MB, et al 1999). These statistics demonstrate the ubiquitous nature of affective disorder in the lives of many bipolar and unipolar patients.
Predictors of Relapse or Recurrence. Numerous factors have been associated with an increased risk of recurrence in patients with unipolar illness. These include: the presence of another mental disorder, a chronic medical disorder, chronic affective symptoms, an older age of onset for the first episode, psychotic affective episodes, a serious suicide attempt, severe functional impairment while depressed, and a positive family history for either suicide and/or bipolar illness (Consensus Development Panel 1985). Of these factors age of onset is the least robust predictor since other studies have found younger age (Georgotas et al 1989) was a predictor while another found that age was not a predictor (Frank et al 1989). However, these consensus findings have become suspect based on data from the NIMH Psychobiology of Depression study (Mueller et al 1999). Based on data from 380 recovered major depressive episode patients followed for up to 15 years, none of these predictors were valid. The recurrence predictors turned out to be female gender, longer depressive episode prior to intake into the study, more prior episodes and never married. However, if the patient recovered and remained well for 5 or more years, no predictors of recurrence could be identified.
DEPRESSION CONTINUATION TREATMENT
Prien and Kupfer (1986) published the results of the NIMH affective disorders collaborative project. This study provided guidelines for duration of continuation treatment in depressive episodes to ensure that the episode is over. The results indicate that withdrawal of continuation therapy is safe only after the patient has been free of significant symptoms for 16 to 24 weeks and that focusing on mild as well as severe symptoms is critical in this decision. Patients are three to five times more likely to relapse during the first 16 symptom-free weeks. Secondly, they showed that patients that discontinue continuation treatment early (i.e., before 16-24 symptom-free weeks) have a relapse rate ranging between 44-53% (Prien and Kupfer 1986).
Maj et al (1992) examined the pattern of recurrence after an episode of major depression. The authors concluded that acute phase response to medication ought to be followed by continuation treatment with the same medication at the same dosage for approximately 4 to 9 months and then tapered over several weeks. Early discontinuation was followed by a roughly 25% relapse rate within 2 months. If a major depressive episode does return after discontinuation of medication, the patent is likely to respond to the same medication at the same dosage effective previously, which should be continued for 4 to 9 months. An increased relapse/recurrence rate in patients discontinuing medication before six months of treatment has also been reported using retrospective Medicaid claims data (Melfi et al 1998). Patients receiving 3 or fewer antidepressant prescriptions in the 6 months after the initial diagnosis of depression were almost twice as likely (RR, 95% CI 1.470-2.137) to experience a relapse or recurrence during the two years after diagnosis.
Hawley et al (1997) conducted a questionnaire in 78 major depressives to evaluate the depression remission rate following six months of treatment. Those patients receiving tricyclics were less likely to be receiving adequate doses than those on SSRIs (mean tricyclic dose was 70 mg) (p<0.001). For the TCAs 31% had a Beck Depression Inventory of < 11 (full remission) versus 43.5% in the SSRI group.
Continuation treatment after electroconvulsive therapy
Lauritzen et al (1996) studied the effects of continuation treatment with an antidepressant after acute phase treatment with ECT. This report combined the results of two randomized double-blind controlled trials. After successful acute treatment with ECT, patients were assessed for electrocardiological impairment. Those without impairment were randomized to receive either paroxetine 30mg/d or imipramine 150mg/d. Patients with electrocardiological impairments (in whom TCA treatment was avoided) were randomized to either paroxetine 30mg/d or placebo. After six months of treatment, the relapse (HAMD ³ 18) rates were 25% (n=36), 36% (n=22), and 65% (n=16) for the paroxetine, imipramine, and placebo groups, respectively. Following successful courses of ECT, Sackeim et al (2001) contrasted the relapse rates of nortriptyline 75-125 ng/ml, nortriptyline 75-125 ng/ml plus lithium 0.5-09 mEq/L and placebo in 84 remitted patients. The respective relapse rates of 84%, 60%, and 39% concluded that the combination therapy was the most effective treatment although the relapse rate was high especially within the first month of continuation therapy.
Continuation Treatment Efficacy
Table 1 shows the results of randomized controlled trials of continuation therapy to prevent relapse. The studies were usually withdrawal studies contrasting withdrawal to placebo after 2-3 months of treatment to continued active treatment for and additional 6-9 months. All studies showed considerable benefit from continuation, with relapse rates at least halved.
|
Table 1. Relapse rates (%) in controlled trials of antidepressant continuation therapy in prevention of relapse. |
||
|
Tricyclics |
placebo |
Active drug |
|
Mindham et al 1973 |
50 |
22 |
|
Paykel et al 1975 |
29 |
12 |
|
Coppen et al 1978 |
31 |
0 |
|
Stein et al 1980 |
69 |
28 |
|
Prien et al 1973a |
73 |
32 |
|
Prien and Kupfer 1986 |
38 |
5 |
|
MAOIs |
|
|
|
Davidson and Raft 1984 |
100 |
14 |
|
Harrison et al 1986 |
100 |
20 |
|
SSRIs |
|
|
|
Montgomery et al1993 |
31 |
11 |
|
Robert and Montgomery 1995 |
24 |
13 |
|
Reimherr et al 1998 (26 weeks) |
23 |
9 |
|
Nefazodone |
|
|
|
Feiger et al 1999 |
33 |
17 |
|
Mirtazepine |
|
|
|
Thase et al 2001 |
44 |
20 |
|
Nortriptyline vs Nortriptyline/Lithium s/p ECT |
|
|
|
Sackeim et al 2001 |
84 |
60/39 |
Continuation Treatment Recommendations
Table 2 summarizes the recommended duration of continuation treatment for patients with major depression. Overall, treatment should be continued for an additional 4 to 6 months beyond the point of remission.
|
Table 2. Continuation Treatment Recommendations |
|
|
Group |
Duration |
|
World Health Organization (1989) |
> 6 months |
|
Royal College of Psychiatry / Royal College of General Practitioners (Paykel and Priest1992) |
4-6 months |
|
American Psychiatric Association (1993) |
4-5 months |
DEPRESSION MAINTENANCE TREATMENT
EFFICACY
Table 3 shows the results of randomized controlled trials of maintenance therapy to prevent recurrences of new depressive episodes. The studies were usually withdrawal studies contrasting withdrawal to placebo after a symptom-free period. All studies showed considerable benefit from maintenance, with their being a mean study 36% difference in the relapse rates between active drug and placebo.
|
Table 3. Relapse rates (%) in controlled trials of antidepressant maintenance therapy in prevention of depression recurrence. |
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|
Lithium |
placebo |
Active drug |
|
Baastrup et al 1970 |
53 |
0 |
|
Coppen et al 1971 |
30 |
5 |
|
Davis et al 1999 (meta-analysis) |
75 |
36 |
|
Tricyclics |
|
|
|
Prien et al 1973b a |
85 |
29 |
|
Kane et al 1982 |
83 |
100 b |
|
Prien et al 1984 a |
71 |
41 |
|
Glen et al 1984 a |
89 |
51 |
|
Rouillon et al 1989 a |
35 |
16 |
|
Georgotas et al 1989 |
63 |
54 b |
|
Frank et al 1990 |
78 |
22 |
|
Old Age Depression Interest Group 1993 a |
61 |
40 |
|
Kocsis et al 1996 c |
52 |
15 |
|
Reynolds et al 1999 |
87 |
32 |
|
MAOIs |
|
|
|
Georgotas et al 1989 |
63 |
13 |
|
Robinson et al 1991 |
81 |
20 |
|
Stewart et al 1997 |
87 |
23 |
|
SSRIs |
|
|
|
Montgomery et al 1988 |
57 |
26 |
|
Doogan and Caillard 1992 a |
46 |
13 |
|
Montgomery and Dunbar 1993 a |
43 |
6 |
|
Franchini et al 1998 d |
52 |
24 |
|
Terra and Montgomery 1998 |
35 |
12 |
|
Hochstrasser et al 2001 |
47 |
18 |
|
Gilaberte et al 2001 |
40 |
20 |
|
a mixed continuation/maintenance design b no benefit a dysthymia d partial reduction from 40 to 20 mg/d |
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Consensus Maintenance Treatment Recommendations
One of the most important decisions a clinician is confronted with in treating patients with recurrent affective illness is when maintenance treatment should be instituted. Angst (1981) analyzed the course of affective illness in 159 unipolar, 95 bipolar, and 150 schizoaffective patients over a period ranging from 19 to 27 years. He found that only 37% of unipolars, 15% of bipolars and 18% of schizoaffective patients had suffered one episode of illness during the follow-up period. As a clinician he decided that it would be desirable to start prophylactic treatment in the patients who were most likely to suffer two additional affective episodes in the subsequent five-year period. His data showed that 40% of the unipolars and 67% of the bipolars and schizoaffectives experienced this outcome. Based on these data the World Health Organization recommends that apart from the present episode, prophylactic treatment should be started in unipolar depression after three episodes, particularly if one discrete episode has occurred within the last five years, apart from the present episode.
Table 4 provides an overview of the recommendation for maintenance medication based on the available maintenance phase studies according four different expert panels. Under ideal conditions, patients can reach full recovery and remain well indefinitely. Unfortunately, inadequate treatment is common, with frequent relapse, and recurrence among patients w=seen in community practice.
|
Table 4. Maintenance Treatment Recommendations. |
||
|
Group |
MDD Episodes |
Duration |
|
WHO (1989) |
> 2 severe |
2 yr |
|
Royal College of Psychiatry (Paykel 1998) |
> 2 severe |
unspecified |
|
APA (1993) |
> 2 |
unspecified |
|
British Association for Psychopharmacology |
> 2 |
Indefinitely |
Clinical Dosing Considerations
Frank et al (1993) studied a group of patients who were assigned to either full-dose or half-dose maintenance treatment for a period of 3 years. Survival analysis suggested that a superior response was achieved with a full-dose as compared to a half-dose maintenance treatment strategy. Mean survival time for the full-dose subjects was 135 weeks as compared to 75 weeks for the half-dose subjects. They conclude that for patients who have suffered several episodes, full-dose maintenance treatment is the more effective prophylactic strategy.
BIPOLAR AFFECTIVE DISORDER
Introduction. Bipolar disorder afflicts approximately 1% of the US adult population with a median age at onset of 19 years. An estimated one-fourth of affected patients attempt suicide and nearly 1 in 10 die by suicide. A US Public Health Service survey reported that without adequate treatment, the average female patients with bipolar disorder with onset at age 25 can expect to lose nearly 9 years of life, 14 years of effective major activity (e.g., work, school, and children), and 12 years of normal health. The disorder is usually comorbid with substance abuse or dependence; more than 60% of bipolar I patients have an alcohol or other drug diagnosis, with an odds ratio of 7.9 (Solomon and Bauer 1993).
INDICATIONS FOR MAINTENANCE
In Bipolar I disorder, maintenance treatment is strongly recommended after two manic episodes and often recommended after one manic episode if the episode was especially severe or destructive or when there is a strong family history of bipolar disorder (Expert Consensus Guideline 1996).
LITHIUM
Berghofer et al (1996) followed 55 bipolar patients for a period that average 8.2 years. All of the patients took lithium at least 3 years. In the 30 patients who received lithium for at least 10 years there was no indication of a loss of the prophylactic effectiveness of the drug. The recurrence rate in the first five years was 34% versus 29% during the second five years.
Fifty bipolar patients completed 3 months of open label lithium and were then randomized to daily or every other day treatment (Jensen et al 1995). Five of 25 patients (20%) receiving daily lithium relapsed (3 mania, 2 depression) vs 12 of 25 patients (48%) on every other day dosing (6 mania, 6 depression). The risk of relapse increased three times when converting from every day to every other day dosing.
Davis et al (1999) performed a meta-analysis to determine the efficacy of lithium in preventing recurrence of bipolar episodes. For bipolar I and II diagnoses (n=514) the reduction in recurrences versus placebo was significant (chi-square = 126, p = 10-29). The lithium recurrence rate was 32% versus 82% for placebo treated paitents.
Lithium vs. Antidepressants
Prien et al (1973b) randomly assigned 35 patients with bipolar affective illness to lithium, imipramine or placebo prophylactic therapy for 5 months to 2 years following discharge from hospitalization for acute depression. In the bipolar group lithium therapy resulted in significantly fewer relapses (3/17) than with either imipramine (6/9) or placebo (6/9). Of the episodes, 69% were manic and 31% depressive. Manic attacks occurred in 12% of the lithium group, 67% of the imipramine group, and 33% of the placebo group. Depression occurred in 12% of the lithium group, none of the imipramine group and 55% of the placebo group. Thus the major difference between lithium and imipramine was due to manic episodes.
Lithium vs Antidepressants vs Combination
Prien et al (1984) studied 117 RDC diagnosed bipolar patients who received either lithium alone (mean = 0.75 mEq/L), imipramine alone (mean = 132 mg/d), or the combination for 2 years or until relapse. Prior to randomization the patients were treated for two months with lithium carbonate (0.6-0.9 mEq/l) and imipramine 75-150 mg/d. Thirty-three percent of the lithium-treated (14/42) and combination-treated (12/36) patients remained well, which was significantly greater than the 8% (3/36) of imipramine treated patients. The high failure rate in the imipramine group was due to a high incidence of manic episodes. Shapiro et al (1989) reanalyzed these data and found that in bipolar patients with manic index episodes both the lithium and the combination were superior to imipramine. However, in patients with depressive index episodes the combination was superior to imipramine while lithium was indistinguishable from imipramine.
LITHIUM AUGMENTATION
Carbamazepine
Fawcett et al (1985) retrospectively reviewed 90 charts of bipolar patients treated with lithium plus in some cases "other drugs" who had not responded to lithium treatment or had significant lithium side effects. Carbamazepine had been added to existing medication "usually" and the author classified a responder as a person who experienced no affective episode after the addition of carbamazepine. According to this criterion 65 of 90 patients responded. Average carbamazepine plasma levels were 8 + 2.6 mcg/ml and the average dose was 790 + 300 mg/d.
Valproate
Emrich et al (1985) reported their experience with the prophylactic use of valproic acid and carbamazepine in patients considered lithium nonresponders. Eleven patients had an unspecified prophylactic dose of valproate added to low levels of lithium (0.4-0.8 mEq/L). The average pre-valproate phase interval was 10 ± 4.3 months (range, 3-19 months) as compared to the average interval after the addition of valproate of 41 ± 19 months (range, 18-78 months, p<.005). Two of the 11 patients relapsed on valproic acid. The 3 carbamazepine treated patients also demonstrated an increase in their phase interval.
Clonazepam
Aronson et al (1989) described the first five patients enrolled in an open clinical trial of clonazepam as a maintenance treatment in lithium-refractory bipolar disorder. All patients relapsed quickly after taking clonazepam. One, rapid cycler on only clonazepam relapsed within 2 weeks and the other four on clonazepam and lithium (0.8-1.3 mEq/l) relapsed within 10-15 weeks. The study was prematurely terminated. The value of clonazepam as a prophylactic agent in the treatment of lithium-resistant bipolar patients who have histories of psychotic mania or delusional depression is questionable.
CARBAMAZEPINE
Carbamazepine vs. Placebo
Seven controlled trials have compared the maintenance treatment efficacy of carbamazepine to lithium and or placebo. These trials are summarized in Table 5. The earlier studies suggested no difference in efficacy while the later studies suggested that lithium is more effective than carbamazepine overall. However, more specifically the largest study of 171 bipolar (DSM-IV) patients (Greil et al 1997, Kleindienst and Greil 2001) suggested a number of important differences between the two treatments. Lithium was more effective for the treatment of "classic" euphoric manic patients while their was no difference in effectiveness in the remaining patients categorized as either mixed or rapid cyclers. Overall, the carbamazepine patients required more medication. Finally, fewer recurrences occurred in the lithium group (p=0.09).
|
Table 5. Controlled carbamazepine studies for bipolar disorder prevention. |
|||
|
Study |
Diagnosis |
Treatment (n) |
Dose or Serum Level |
|
CBZ = lithium > placebo |
|||
|
Okuma et al 1981 |
IDC-9 |
CBZ (12), PLB (10) |
400-1200 mg/d, mean level 5.6 mcg/ml |
|
Placidi et al 1986 |
DSM-III |
LI (20), CBZ (23) |
Li 0.6-1.0 mEq/L; CBZ 7-12 mcg/ml |
|
Lusznat et al 1988 |
DSM-III |
LI (27), CBZ (27) |
Li 0.6-1.4 mEq/L; CBZ 6-12 mcg/ml |
|
Small et al 1991 |
DSM-III-R, RDC |
LI (24), CBZ (24) |
Li 0.6-1.5 mEq/L; CBZ 6.3-12.5 mcg/ml |
|
Coxhead et al 1992 |
DSM-III |
LI (16), CBZ (15) |
Li 0.6-1.0 mEq/L; CBZ 9.5-12.8 mcg/ml |
|
Lithium > carbamazepine |
|||
|
Watkins et al 1987 |
DSM-III |
LI (8) CBZ (12)
|
Li 0.4-0.9 meq/L CBZ 5-12 mcg/ml
|
|
Greil et al 1998 |
DSM-III-R |
LI (86) CBZ (85) |
Li 0.61+0.12 mEq/L; CBZ 6.1+1.3 mcg/ml |
Carbamazepine vs Lithium vs Combination
Denicoff et al (1997) randomized 42 bipolar patients to either lithium or carbamazaine maintenance treatment for one year. Depending upon which occurred first, one year of treatment or relapse, the patient was switched to the other medication. Patients were switched the combination of lithium and carbamazepine in the third year or sooner if a relapse occurred during the second treatment arm of the study. A patient was considered to have relapsed if hospitalization was required or the patient became severely handicapped for at least several days. In either case, the patient was then advanced to the next treatment. The percentage of evaluable patients who had marked or moderate improvement scores on the CGI was 33% for lithium, 31% for carbamazepine, and 55% for the combination. Lithium was more effective than carbamazepine in the prophylaxis of mania. The mean survival time between manic episodes was 90 days for lithium, 66 days for carbamazepine, and 179 days for the combination. Rapid cyclers did poorly on individual drug therapy. The lithium response rate was 28%, 19% for carbamazepine and 56% for the combination.
Carbamazepine dose
In a open design trial by Simhandl et al 1993, 58 outpatient affective disorder patients who had at least one episode of affective illness within the last 2 years received prophylactic treatment with carbamazepine-low serum level (3.5-5.9 ug/ml), carbamazepine-high serum level (6.6-9.4 ug/ml) or lithium (0.6-0.8mEq/L). Eight patients who received the low dose carbamazepine did not relapse vs 11 who did relapse. Seven patients who received the high dose carbamazepine did not relapse vs 11 who did. Twelve patients treated with lithium did not relaspe vs 9 patients who did relapse. Each of these treatments were found to be equally effective in the prophylactic treatment of bipolar affective disorder.
VALPROATE
Valproate vs lithium vs placebo
Bowden et al (2000) randomized 372 recovered bipolar I patients to a 52 week trial of prophylactic treatment with either valproate, lithium, or placebo. The three outcome measures were time to recurrence of any affective episode, manic episode and depressive episode. None of the treatments varied significantly in these three outcomes. The median times to 50% survival without any mood episode were 40 weeks for valproate, 28 weeks for lithium and 24 weeks for placebo.
VALPROATE
BIPOLAR CLINICAL CONSIDERATIONS
The course of affective disorder relapse patterns have been classified in the following manner: MDI (the cycle starts with mania followed by depression and a free interval), DMI (the cycle starts with depression followed by mania and a free interval), CC-LC (continuous circular course with long cycles), CC-RC (continuous circular course with rapid cycles), and IRR (irregular course). Maj (1990) collected 99 patients with recurrent affective illness and classified them as above. Following recovery from an acute episode they were treated prophylactically with lithium carbonate (0.5-1.0 mEq/L) and followed for a period of two years. Lithium significantly reduced the mean number of episodes only in the patients with the MDI (1.7 Æ 0.5) and IRR (1.9 Æ 0.6) courses. The sensitivity of this course marker was 73% (17/23) for the MDI group and 67% (24/36) for the IRR group. The response rate for the DMI group was 37% (7/19), CC-LC 55% (5/9), CC-RC 25% (3/12).
Suppes et al (1991) estimated the risk of episode recurrence in bipolar disorder following discontinuation of stable maintenance treatment with lithium salts from an analysis of 14 studies involving 257 patients with bipolar I disorder. More than 50% of new episodes of illness occurred within 10 weeks of stopping an average of 30 months of treatment. By survival analysis of 124 cases in which the time to a new episode was known, the computed time to 50% failure of remission was 5.0 months after stopping therapy; the time to 25% recurrence of mania was 5.2 times earlier than for depression (2.7 vs 14 months). In 16 patients with a mean cycle length before treatment of 11.6 months, the time to a new episode when off lithium therapy was only 1.7 months. Risk of early recurrence of bipolar illness, especially of mania, evidently is increased following discontinuation of lithium use and may exceed that predicted by the course of the untreated disorder. This relapse risk data should be explained to any patient considering stopping their maintenance therapy. This risk of relapse can be lessened by gradual discontinuation of lithium treatment. The same group (Faedda et al 1993) compared risks of stopping lithium rapidly vs gradually. Sixty-four bipolar (DSM-III-R) outpatients undergoing clinically determined discontinuation of lithium treatment at different rates were followed up prospectively to 5 years. Risks and timing of new episodes were analyzed. The patients who were stable on lithium prophylactic monotherapy for 18 to 120 months (mean, 3.6 years) were followed up clinically after discontinuing lithium. Within 5 years, 75% had a recurrent episode; bipolar I patients were 1.5-times less likely than bipolar II to remain in remission. Polarity of first-recurrent and onset episodes was 80.8% concordant. Overall risk of a new episode of mania was significantly greater after rapid (< 2 weeks) than gradual (2 to 4 weeks) discontinuation (5-year hazard ratio = 2.8); the difference in risk of depression was even greater hazard ratio = 5.4). Recurrence rate was more elevated within months of rapid discontinuation (12-month hazard ratio = 5.4). Recurrence rate was more elevated within months of rapid discontinuation (12-month hazard ratio = 4.3) than at later times (2 to 5 years), when courses of "survival" over time were nearly parallel in both discontinuation groups. Risk of early recurrence of bipolar disorder following discontinuation of lithium maintenance is elevated, but may be both predictable (timing and polarity) and modifiable by gradual discontinuation.
The effect of abruptly discontinuing lithium (over 1-14 days) in bipolar patients can increase the risk of relapse by 5-fold versus gradual discontinuation (over 15-30 days). The times to recurrence in 161 bipolar patients were 20+5.8 vs 4+0.7 months in abrupt vs. gradual discontinuation (p<0.0001) (Baldessarini et al 1996).
It has also been reported that discontinuing previously effective lithium maintenance may place patients at risk for nonresponse to lithium treatment during subsequent manic episodes (Maj et al 1995). While subsequent non-response may be a potential risk of the interruption of lithium maintenance, other investigators have not been able to replicate this finding (Coryell et al 1998).
Ellicott et al (1990) examined the effect of life events on the course of bipolar disorder over a 2-year period in a group of 61 outpatients. The patients were followed prospectively with ongoing assessments of stressful life events, symptoms, levels of maintenance medication, and compliance with treatment regimens. Survival analyses indicated a significant association between life events and relapse or recurrence of the disorder. These effects could not be explained by differences in levels of medication or compliance.
Antidepressant-induced mania. It has become reasonably well accepted in the psychiatric literature that bipolar patients treated with an antidepressant for a depressive episode can be at risk to "switch" into a manic episode. In a naturalistic follow-up of 29 bipolar-I patients Boerlin et al (1998) found switches to occur more frequently with TCA or MAOI treatment (33%) than with fluoxetine (12%). These data suggest that switching to mania may occur less frequently with SSRIs than with TCAs or MAOIs. However, this observed difference was not statistically significant and drug treatment was not administered in a randomized or controlled fashion.
ATYPICAL ANTIPSYCHOTICS
Tohen et al (2001) contrasted the effectiveness of olanzapine cotherapy with lithium or valproate versus lithium or valproate monotherapy in reducing symptomatic recurrences in patients suffering from bipolar disorder. Remitted bipolar patients following 6 weeks of acute therapy with olanzapine plus lithium (0.6&endash;1.2 mEq/L) or valproate (50&endash;125 mg/mL) were randomized to receive olanzapine (5&endash;20 mg/day) or placebo with continued cotherapy for 18 months of double-blind therapy. Among patients who were in a mania remission (YMRS £12) the olanzapine cotherapy-treated patients (n=46) had a significantly longer time to relapse into mania than monotherapy-treated patients (n=48; estimated 25th percentile: 362 vs 63 days, respectively; p=.005). Rates of relapse into mania also significantly favored olanzapine-treated patients (monotherapy, 35.4% vs olanzapine, 15.2%; p=.03). Relapse into depression was evaluated in a set of patients who were in symptomatic remission of mania and depression (HAMD-21 £8) following acute therapy. Time to and rates of relapse into depression were not significantly different between cotherapy (n=30) and monotherapy (n=38) groups, but were numerically favorable for the olanzapine cotherapy group (155 vs 27 days, respectively; p=.07; 23.3% vs 39.5%, respectively; p=.197). Importantly, time to relapse to either pole significantly favored the olanzapine cotherapy group (25th percentile: olanzapine cotherapy, 124 days; monotherapy, 15 days, p<0.03). The results indicate that the combination of olanzapine plus lithium or valproate effectively prolongs time in remission in comparison to lithium or valproate monotherapy. The time to relapse for the patients receiving monotherapy seemed exceedingly short when compared to data from other survival studies (Supples et al 1991 and Faedda et al 1993).
CONCLUSIONS - BAD MAINTENANCE
SUICIDE RISK AND THE PREVENTION OF AFFECTIVE DISORDERS
Mortality is significant in that nearly 20% of patients with major depression attempt and 15% complete suicide. According to 1980 data 15,000 people committed suicide as a result of major depression, and that the economic burden of depression was $16 billion for the year (Solomon and Bauer 1993).
Nilsson et al (1995) studied 362 UAD, BPAD and schizoaffective patients in Sweden. Twenty-two percent were UAD, 66% were BPAD and 12% were schizoaffective. These patients had to have been on at least 2 years of continous prophylactic Li (levels as low as 0.5 mEq/L were allowed if they were clinically acceptable by the psychiatrist) in order to be included in the study. Standarized mortality ratios (SMR) were calculated by taking the number of deaths observed in the study population divided by the number of deaths expected in the general Swedish population on the basis of age- and sex-specific rates. A SMR of > than 1 indicated an excess in mortality. The overall SMR in those patients off Li was 1.6-4.3 higher than when on Li. There was a 4.8 times greater risk of suicide when patients were off Li compared to on Li. Six of 78 patients on Li committed suicide whereas 9 of 51 committed suicide off Li. Those that committed suicide off Li were off Li a mean of 3.6 years.
Muller-Oerlinghausen et al (1996) calculated the SMR values in a group of 273 unipolar, bipolar and schizoaffective patients who discontinued their lithium prophylaxis therapy that averaged 63 months (range 6-259 months). The SMR for the whole group of patients was 2.5, significantly higher than 1.0, the SMR of the general population (p<0.01). These data did not distinguish between different causes of death, e.g. between suicide and natural death.
Thies-Flechtner et al (1996) conducted a randomized prophylactic trial involving 378 UAD, BPAD and schizoaffective patients over 30 months. Ninety-three UAD patients were randomized to receive either Li or AMT, 285 BPAD and schizoaffective disorder patients received either Li or CBZ. None of the patients randomized to treatment with Li attempted or committed suicide. Five that received CBZ attempted suicide and 4 completed suicide. There were no suicide attempts made in those that received AMT or another neuroleptic but there were 5 completed suicides in this group. Half of the suicides were completed within 6 months of starting treatment, which the authors feel strengthens the idea that Li has an antisuicidal effect.
COMPLIANCE
Drug therapy is an important factor in preventing the morbidity and mortality of affective illness in selected patients. The importance of medication compliance was demonstrated in a review by Frank et al (1985). The rates of noncompliance with lithium treatment ranged from just below 20% to as high as 47%. Noncompliance with tricyclic antidepressants varied across studies from 32% to 76%. Lenzi et al (1989) studied 67 females with affective disorder diagnoses that required prophylactic lithium or carbamazepine therapy. In their examination of patient compliance, they concluded that most drug defaulters (19/30, 63%) do so within the first month of treatment. Additionally, noncompliant patients are usually manic rather than depressed, hypochondriacal about the adverse effects of the drugs, and do not live either in their conjugal or parental home.
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