In the wake of the new study by Dutch researcher Lex Wunderink, it is time for psychiatry to do the right thing and acknowledge that, if it wants to do best by its patients, it must change its protocols for using antipsychotics. The current standard of care, which—in practice—involves continual use of antipsychotics for all patients diagnosed with a psychotic disorder, clearly reduces the opportunity for long-term functional recovery. (MIA writer Sandy Steingard recently wrote about the Wunderink study, which was published on July 3 in JAMA Psychiatry online.)
The Wunderink study, precisely because it had a randomized design, complements Martin Harrow’s study of long-term outcomes in a very compelling way. In addition, the results reported by Open Dialogue practitioners in northern Finland provide a data-based sense of what would be possible if psychiatry amended its protocols for using antipsychotics based, in large part, on the findings in the Harrow and Wunderink studies.
Here is how the three studies fit so nicely together to form a compelling evidence-based rationale for changing prescribing standards.
Martin Harrow, a psychologist at the University of Illinois Medical School, followed 145 people diagnosed either with schizophrenia or a milder psychotic disorder for 15 years. His was a prospective, naturalistic study. All of the patients were initially treated with antipsychotics and then Harrow followed up at regular intervals to assess how they were doing, and whether they were using antipsychotics. Among his many findings, there were these three key results related to schizophrenia patients:
- At the end of 15 years, the recovery rate for the schizophrenia patients off antipsychotics was 40%, versus 5% for those on antipsychotics. Harrow’s definition for recovery included a functional component (whether they were working, had a decent social life, etc.) and this functional component was a primary reason for the much higher recovery rate for the off-antipsychotic group. Those on antipsychotics might experience clinical remission of their symptoms, but still not be able to function well in society.
- The divergence in outcomes between the two groups (the schizophrenia patients on and off antipsychotics) occurred between the two-year and five-year follow-up assessments. At the two-year assessment, the difference in outcomes was not so notable.
- Once patients off medications became stable, they had very low relapse rates. At both the 10-year and 15-year followup, those off antipsychotics were much less likely to be experiencing psychotic symptoms than those on the drugs.
After Harrow published his 20-year results, he raised the obvious question. Do antipsychotics worsen long-term outcomes? At the very least, Harrow concluded, it is clear that some schizophrenia patients can do well off medication over the long term, and that drug-use protocols need to allow for that possibility.
Harrow’s study presented an obvious challenge to current standards of care for schizophrenia patients. However, those who were eager to defend the common wisdom and common prescribing standards dismissed his findings in this way: His was a naturalistic study, rather than randomized. Thus, there may have been some internal characteristic in those who took themselves off medication that accounted for their better outcomes. The divergence in results wasn’t due to any “harm” being done by the antipsychotics.
Now, I personally think that Harrow’s findings can’t be explained away in that manner, because in every subset of patients in his study, those who got off antipsychotics had markedly better outcomes (in the aggregate.) If the drugs were truly helpful, you simply wouldn’t see such outcomes, but if the drugs did worsen outcomes over the long-term, that is precisely the results you would expect. But it was the lack of randomization that provided an intellectual out for those who would defend current prescribing practices. Randomization is the gold standard for evidence-based medicine, and thus Harrow’s results could be dismissed.
Wunderink has now provided psychiatry with a randomized study of long-term outcomes. In his study of adults with a first episode of psychosis, all patients were stabilized on antipsychotics for six months (n=128), and then they were randomized either to a “drug discontinuation/drug reduction” arm (the DR group), or to standard drug maintenance (the MT group.) In other words, this was a randomized study designed to see which treatment protocol produced better outcomes: tapering first-episode patients from their antipsychotics (or down to a low dose), or standard drug maintenance, at usual doses.
Wunkerink had 103 patients in his study at the end of seven years. Here are his salient findings:
- At the end of seven years, those in the DR group had a much higher recovery rate (40.4% versus 17.6%.) The difference in recovery rate was due to the fact that those in the DR group had much better functional outcomes.
- At the end of 18 months, there was little difference in functional outcomes. The divergence in functional outcomes began to appear after that point (as was the case in the Harrow study.)
- In terms of risk of relapse (control of clinical symptoms), the relapse rate at 18 months was in fact higher for the DR group (43% vs 21% for the MT group.) But from that point on, relapses occurred at a greater rate in the MT group, such that by the end of three years, the relapse rate was roughly the same for the two groups. At the end of seven years, the relapse rate was slightly lower for the DR group (61.5% versus 68.6% for the MT group.)
Thus, this randomized study found that a dose-reduction protocol, which allowed for the possibility that some patients could successfully go off their antipsychotic medications, produced superior overall results to the standard protocol of care, which emphasizes continual drug maintenance at higher dosages.
Now some of the patients in the MT group took themselves off antipsychotics during the seven years, which enabled a second comparison. Wunderink reported results for all of the patients in the study who discontinued antipsychotics or took a very low dose, regardless of which group they were randomized to, and compared their outcomes to those who ended up on standard doses of antipsychotics.
Twenty-two patients in the DR group ended up in this off-drug/low-dose category, while 12 in the MT group did. When Wunderink compared these 34 patients to the 69 patients who ended up on standard doses of antipsychotics, he found a marked difference in outcomes. The discontinued/low dose groups were more likely to achieve symptomatic remission (85.3% versus 59.4%), functional remission (55.9% versus 21.7%) and full recovery (52.9% versus 17.4%.)
In conclusion, Wunderink and his colleagues made two important points. The first was that antipsychotics could be hampering long-term functional recovery. “Antipsychotic postsynaptic blockade of the dopamine signaling system, particularly of the mesocortical and mesolimbic tracts, not only might prevent and redress psychotic derangements but also might compromise important mental functions, such as alertness, curiosity, drive, and activity levels, and aspects of executive functional capacity to some extent.”
Second, they noted that the usual methods for assessing the merits of antipsychotics, which have focused on control of psychotic symptoms over shorter periods, were flawed, and that psychiatry needed to adopt a new perspective in order to best assess the merits of antipsychotics. “The results of this study lead to the following conclusions: schizophrenia treatment strategy trials should include recovery or functional remission rates as their primary outcome and should also include long-term follow-up for more than 2 years, even up to 7 years or longer. In the present study, short-term drawbacks, such as higher relapse rates, were leveled out in the long term, and benefits that were not evident in short-term evaluation, such as functional gains, only appeared in long-term monitoring.”
In sum, both Harrow and Wunderink provide evidence, of a complementary type, for a drug use protocol that would involve tapering first episode patients from their antipsychotics, and, in that manner, identify a subset of patients who could do well off the drugs long-term (or on very low doses.) In the Wunderink study, slightly more than 40% of the patients randomized to the DR group did well off the drugs or on a very low dose over the long term.
If you then wanted to have a next step in the “evidence base” for changing antipsychotic protocols, you would want to have a study in which a provider of psychiatric care had routinely utilized antipsychotics in this way, and had followed patients for a longer period of time. A study of that sort would reveal whether the research findings held up when incorporated into regular care.
The reports by the practitioners of Open Dialogue therapy in northern Finland provide that evidence, and also take the research findings one additional step. In Open Dialogue therapy, there is a delay in the use of antipsychotics in first-episode patients, with the hope that patients, with the proper psychosocial support and selective use of benzodiazepines, can get through their first crisis without ever going on antipsychotics. But if patients need to go on antipsychotics, then the open-dialogue protocol also allows for them to subsequently try to taper from the drugs.
With this selective use of antipsychotics, Open Dialogue has produced the best long-term outcomes in the developed world. At the end of five years, 67% of their first-episode patients have never been exposed to antipsychotics, and only 20% are maintained regularly on the drugs. With this drug protocol, 80% of first episode patients do fairly well over the long-term without antipsychotics.
Thus, together the three studies provide a clear mandate for change. They provide convincing evidence that if psychiatry wants to promote the best possible functional outcomes, it needs to adopt protocols that will maximize the percentage of patients who are able to do fairly well off antipsychotics (or on a very low dose.) The one remaining question is this: how large is this subset of patients? Harrow and Wunderink suggest that at least 40% of all patients fall into this category, while the Open Dialogue studies indicate that, if you have that first step of avoiding initial use of antipsychotics, it may be 80% of all patients.
In a remarkable editorial in JAMA Psychiatry accompanying the Wunderink report, Patrick McGorry and his co-authors argue that psychiatry needs to respond to this data and adopt new drug-use protocols, and if you read their editorial carefully, they are embracing both elements of the Open Dialogue protocol for prescribing antipsychotics. They wrote:
“In moving to a more personalized or stratified medicine, we first need to identify the very small number of patients who may be able to recover from first episode psychosis with intensive psychosocial interventions alone. For everyone else, we need to determine which medication, for how long, in what minimal dose, and what range of intensive psychosocial interventions will be needed to help them get well, stay well, and lead fulfilling and productive lives. These factors have rarely been the goal in the real world of clinical psychiatry—something we must finally address now that we are armed with stronger evidence to counter poor practice.”
That was the argument made in JAMA Psychiatry. There is new evidence to counter current poor practice standards. Try to get people through a first episode with “psychosocial interventions alone,” and for the rest of the patients, adopt protocols that help people get on minimal doses or off the drugs altogether over the long-term. Psychiatry has an evidence-based mandate to change.
In my opinion, this represents a defining moment for the profession. If it changes its protocols for prescribing antipsychotics, in the manner set forth in the JAMA Psychiatry editorial, then “hats off” to the profession. It will have responded to evidence that didn’t show up in shorter withdrawal studies, and changed its ways in response to new evidence, even though that will surely be a difficult thing to do. This would be a beautiful—and inspiring—change to watch.
But, if psychiatry doesn’t amend its protocols, and if psychiatry doesn’t sponsor new research to best reach these goals, then—and I know no other way to say this—then I think psychiatry will have to be seen, by mainstream society, as a failed medical discipline. Psychiatry will no longer be able to claim that its practices are evidence-based and driven by a desire to achieve the best possible outcomes for its patients. Instead, the lack of change will be evidence that its prescribing practices are, in fact, driven by an ideology, which is to maintain a societal belief that antipsychotics are a necessary long-term treatment for psychotic disorders, and that it is more important for the profession to maintain that belief than it is to help those it treats to have the best chance possible to achieve a good functional outcome, which is the outcome that counts.
Which will it be? My optimistic self hopes for the first outcome, while my realistic self expects the latter. And if it proves to be the latter, this will be a medical story of continuing harm done, and, I would argue, it would be reason for our society to conclude that the care of “psychotic” patients can no longer be entrusted to the psychiatric profession.
