Discontinuation trials relapse

Nevertheless, some long-term efficacy trials have been conducted. These continuation studies are different from relapse-prevention or discontinuation trials in some very important ways. Instead of just looking at patients who have responded... 

Discontinuation trials, either controlled or open, usually are not likely to have any direct benefit and may well have real risks, such as relapse, suicide, and loss of employment. Such studies need additional scrutiny and safeguards to minimize risk and to strengthen consent procedures. There are some situations in which a discontinuation study may be considered. For example, to determine whether long-term treatment is needed, a study design might randomly assign patients who have responded successfully to a particular treatment to either a continuation or discontinuation of that treatment. Relapse rates across these two conditions could... 

The risk of relapse in discontinuation trials depends on many non-pharmacological, often poorly controllable factors, notably the expectations of the patients, doctors and nurses, other environmental factors, the duration of hospitalization and prior treatment, and the time interval since the last acute psychotic episode. On the basis of an analysis of 14 discontinuation trials, Kane and Lieberman (1987) found that the relapse rate varied greatly from study to study depending on the trial, relapse rates of 30 86% with clustering around 60 70% have been reported in the first 12 months after placebo substitution. According to Kane and Lieberman, this scatter is a result of the different inclusion criteria applied and the different definitions of relapse . 

Controlled discontinuation trials show that about half of all depressive patients suffer a serious relapse within 6 months if their antidepressant medication is withdrawn shortly after the disappearance of acute symptoms with continuation therapy, only about one-fifth of patients experience a relapse in the same period. The difficulty for the treating doctor is to estimate reliably how long he should continue to prescribe antidepressants for patients who have overcome depression. Consensus groups suggest that this period should be between four and six months after the symptoms of depression have resolved (Montgomery, 1997) even mild continuing symptoms may indicate that a depressive episode has not ceased completely and that the treatment should be continued further (Lader, 2001). 

Although clinical experience indicates tranylcypromine may be an effective antipanic agent, there are no controlled trials confirming this observation. Phenelzine, however, has been found to be very effective in both open and controlled designs ( 21, 116, 117). Onset of action is similar to that of other antidepressants, and although adverse effects tend to be less troublesome than with tricyclics, dietary restrictions may limit the usefulness of MAOIs in some patients. Unfortunately, the relapse rate may be comparable to that seen with BZDs and TCAs. For example, Kelly et al., in a follow-up of 246 patients, found that 50% who had discontinued MAOIs relapsed within 1 year (118). 

A review of 18 controlled studies in otherwise typically developing children (Moffatt et ah, 1993) demonstrated that only about 24% of children were completely dry while on medication and that 94% relapsed after medication was discontinued. In the Swedish Enuresis Trial (SWEET), 399 children aged 6-12 years with primary enuresis participated in an open, multicenter trial of DDAVP (Tullus et ah, 1999). Subjects were observed for 4 weeks and had their DDAVP dose titrated over 6 weeks (20 0 pg), followed by a 1-year long-term treatment period. A total of 245 children (61%) experienced a 50% or more reduction in the number of wet nights, with resolution of enuresis in 77 children. The greatest therapeutic effect was observed in children 6-7 years of age. There were no studies on the effectiveness of DDAVP in children with MR. 

For women who are planning to become pregnant and who have had mild to moderate depression, a trial of medication taper and discontinuation is appropriate. Plans for relapse should be discussed prior to the trial. This strategy may not be appropriate for women who have had severe or multiple episodes of depression, as a recent study reported that pregnant women with a history of recurrent depression were at significant risk for relapse when medication was discontinued (Cohen et ah, 1997). 

Although ABA designs are only marginally better than open trials, they may be somewhat relevant to another scientific question (i.e., once the disease process is turned off, will patients relapse when placebo is substituted ). For most psychotropics, we do not know whether relapse will occur immediately after a drug is stopped within a few days of achieving remission. The active disease may only have been suppressed, with relapse likely after discontinuation. 

The durability of naltrexone s effect in alcoholism is not clear, since the initial clinical trials were only for 12 weeks. In a follow-up study, the decrease in relapse after 12 weeks of treatment continued for only one month after discontinuation of the naltrexone (O Malley et al, 1996). 

The efficacy of imipramine has been repeatedly demonstrated in controlled trials about 85% of children treated within a week of the start of medication, but tolerance frequently develops after a number of weeks and relapse is high after discontinuation of the treatment. Relatively low doses of imipramine only are needed, but the typical side effects of tricyclic antidepressants limit the prolonged use of the drug. The mechanism of action of imipramine in the treatment of nocturnal enuresis is unclear but one possible action is through a direct anticholinergic action on the bladder wall. 

Trials that compare the relapse rate among people treated with lithium and people treated with placebo are thought to have established the efficacy of lithium for the prevention of recurrence in manic depression. However all these studies were actually discontinuation studies or involved discontinuing lithium in at least some subjects. Many earlier studies especially involved people who had taken lithium for many... 

Several trials of olanzapine for prophylaxis of manic depression have now been conducted, funded by Eli Lilly, and claim to show positive evidence of efficacy. A comparison with lithium demonstrated little difference between the two treatment groups overall, although olanzapine appeared to be better at preventing recurrence of mania (Tohen et al. 2005). The only placebo-controlled trial that has been published showed superiority of olanzapine, but there was evidence of a discontinuation effect. Fifty per cent of the placebo group relapsed within 22 days of randomisation and almost all the excess risk of relapse was confined to the first three months of the study (Tohen et al. 2006). All patients were treated with olanzapine initially and since no gradual discontinuation schedule was mentioned, it appears that it was stopped abruptly at the point of randomisation for patients allocated to placebo. 

Atovaquone suspension (1500 mg orally bd) plus either pyrimethamine (75 mg/day after a 200 mg loading dose) or sulfadiazine (1500 mg qds), as treatment for acute Toxoplasma encephalitis (for 6 weeks) and as maintenance therapy (for 42 weeks), has been studied in a randomized phase II trial in HIV-positive patients (17). There were good responses in 21 of 28 patients who received pyrimethamine and nine of 11 who received sulfadiazine. Of 20 patients in the maintenance phase, only one relapsed. Of 40 eligible patients, 11 discontinued treatment as a result of adverse events, nine because of nausea and vomiting or intolerance of the taste of the atovaquone suspension. 

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