A Stony Brook University-led study reveals that, despite the common view that early intervention in schizophrenia slows or stops mental decline, those who receive early intervention eventually experience the same declines as those whose treatment started later.
The finding, published online in The American Journal of Psychiatry, suggests that studies of schizophrenia should take into account how long study participants have been symptomatic, otherwise treatments may appear more effective than they actually are.
“Our finding is somewhat counterintuitive. There has been a good amount of evidence suggesting that if you get people who are having their first psychotic episode into treatment as soon as possible, you can avert irreversible declines,” said Lead Author Katherine Jonas, PhD, Postdoctoral Fellow in the Department of Psychiatry in the Renaissance School of Medicine at Stony Brook University.
“We found that if you compare people who got into treatment early with those who did not, the early treatment group only appears to have better outcomes because they are often younger, and haven’t been sick as long.”
Jonas and colleagues point out that comprehensive pharmacological and psychosocial treatment has shown to be effective in reducing symptoms and improving quality of life in schizophrenia.
However, many patients in the US do not get these treatments.
Most receive only antipsychotic medications, which help with hallucinations and delusions but not with other symptoms.
Therefore, they caution that “while starting ‘treatment as usual’ earlier may not halt the disease process, comprehensive and sustained care has been shown to improve overall mental health for those with schizophrenia.”
The study evaluated duration of untreated psychosis (DUP) – defined as the amount of time that elapses between psychosis onset and treatment initiation.
Data came from the Suffolk County Mental Health Project and included 287 individuals with schizophrenia or schizoaffective disorder.
More than 2,000 patient observations spanning from childhood to 20 years after first hospital admission are included in the dataset. Overall mental health was evaluated at multiple points and related to DUP.
The association between long DUP and poor outcomes is well known in the treatment of patients with schizophrenia.
Yet Jonas and colleagues found that in this study the association can be explained by lead-time bias.
Early intervention in schizophrenia has been thought to slow or stop further declines. This study, however, suggests that typical interventions do not improve long-term outcomes, even if administered early.
“Lead-time bias is a phenomenon in which early detection – such as early screening for breast cancer or another disease – appears to improve outcomes because it enlarges the observation window of the disease,” she explained.
The authors conclude in their study that the association between DUP and psychosocial function in schizophrenia may be an artifact of early detection, creating the illusion that early detection is associated with improved outcomes.
Given this finding, they emphasize that shortening DUP does not necessarily change long-term illness course. DUP may be more of an indicator of illness stage than a predictor of course.
Co-authors include faculty from the Department of Psychiatry at the Renaissance School of Medicine and in the Department of Applied Mathematics and Statistics at Stony Brook University, and from the Feinstein Institute for Medical Research.
Funding: The research was supported in part by the National Institutes of Health (grant numbers MH44801 and MH094398).
Schizophrenia and related conditions affect up to 1% of the population,1 and are associated with long-term suffering and disability, premature death, physical illness and high costs to individuals and society.2 Recommended treatment for people with recurrent episodes consists of continuing antipsychotic medication.3 4
Current guidelines do not recommend attempts at reduction or discontinuation of antipsychotics after the first episode, and in practice, antipsychotic treatment is often ‘for life’. In spite of ongoing treatment, many people remain functionally impaired. In one study 25% of people with schizophrenia had severe social disabilities after 15 years, and only 14% had none.5
The evidence base for long-term antipsychotic treatment consists of studies showing lower relapse rates with maintenance treatment compared with discontinuation.6 However, there are acknowledged methodological problems with these studies.7
In addition, several long-term non-randomised cohorts studies find worse outcomes in people who take continuous treatment compared with those who do not, although confounding by indication is likely to be relevant.8 9
Criticism of randomised controlled trials includes the fact that most focus on relapse and neglect other outcomes. Follow-up is generally short; only six of 65 studies included in a recent meta-analysis by Leucht et al6 had followed the participants up for more than a year, and longer duration of follow-up was found to be associated with less difference between maintenance and discontinuation.6 10
Moreover, relapse rates may have been inflated by abrupt discontinuation and misidentification of withdrawal-related adverse effects.11 12
Some evidence suggests gradual discontinuation may reduce risk of relapse compared with abrupt discontinuation,13although this difference was not confirmed in the analysis by Leucht et al.6
However, the average taper of 28 days for gradual medication withdrawal may not have prevented discontinuation-related effects in those people who had been taking antipsychotics for many years.
Long-term antipsychotic medication is associated with potentially serious physical complications, including diabetes, tardive dyskinesia and cardiovascular disease.14–17 Other adverse effects, such as sexual dysfunction, sedation, emotional blunting and akathisia may be debilitating and unpleasant.18–20
Previous research has found that many patients find the adverse effects of antipsychotics burdensome, and would like to try and discontinue the treatment at some stage.21–23
There are few long-term follow-ups of people from randomised studies of antipsychotic discontinuation. A 7 year follow-up of an 18 month open trial conducted with people with first episode psychosis found that assignment to a gradual antipsychotic reduction programme was associated with better rates of social recovery and equal rates of relapse compared with maintenance treatment.24
Improved levels of neurocognitive performance exhibited by those randomised to antipsychotic reduction at 18 months suggest a possible mechanism for the long-term differences in functional outcome.25
In contrast, recent data from a 10 year follow-up of a 1 year, placebo-controlled trial of quetiapine in people with first-episode psychosis reported higher rates of a composite ‘poor outcome’ in people originally randomised to placebo. There were no differences, however, in overall symptom measures, social functioning or quality of life.26
Therefore, although continuing antipsychotic treatment has become the norm, it remains unclear whether it has an optimal risk-benefit balance for all people with psychosis or schizophrenia. In particular, more evidence on the effects of gradual reduction of antipsychotics on short and longer-term outcomes could inform practice in this area.
Effects on social functioning are particularly important to study because of evidence that long-term antipsychotic treatment may impair social functioning, despite improving symptoms or reducing relapse in the short-term.24 27
Further studies are currently being conducted in the first-episode psychosis population.28 To date, however, there is no study using gradual and flexible reduction with long-term follow-up in people with more than one episode.
Aims of trial
The current trial was designed to compare the benefits and harms of a gradual programme of dose reduction and discontinuation of antipsychotic treatment, under clinician guidance, with maintenance treatment in people with a diagnosis of schizophrenia or a related disorder.
In particular, the study was set up to test whether such a strategy can improve functional outcomes in people with recurrent or chronic psychosis while minimising the risk of worsening symptoms or relapse.
Better evidence is required about the balance of risks and benefits of a supported programme of antipsychotic reduction and discontinuation under the guidance of a clinician for the many people who have a diagnosis of schizophrenia or recurrent psychoses.
The current study will be the first study conducted with people with more than one psychotic episode to employ a gradual and supported method of antipsychotic reduction, to look at a wide range of outcomes giving priority to social functioning and to follow people up for a reasonable duration. Further follow-ups are envisaged after the official end of the trial in order to provide data on longer-term outcomes.
The Dutch first-episode study suggested that long-term outcomes after a period of antipsychotic dose reduction differ from short-term outcomes.24 54 Although relapse rates are increased initially compared with maintenance treatment, over time these equalise. Social functioning, which was not affected in the short-term, was considerably improved by the time of the 7 year follow-up assessment.
Social functioning is a measure of independence and personal efficacy. If the current trial results in improvements in social functioning this could reduce an individual’s reliance on services and produce significant economic benefits.
From the individual’s point of view, better social functioning reflects a more fulfilling and socially integrated life.
A strategy that can successfully reduce the use of antipsychotic medication is also likely to be associated with health benefits and improvements in quality of life secondary to the reduction of adverse effects.
The outcomes of the current trial will provide good evidence to inform patients and clinicians about the likely consequences of reducing and discontinuing long-term antipsychotic treatment in a gradual manner in a clinical setting.
Many patients currently want to consider this option, but existing data on the range of relevant outcomes is limited. Providing further information will facilitate a more collaborative approach to long-term antipsychotic treatment.
Stony Brook University