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Antipsychotic Maintenance Treatment: Must It Be Forever?

30 May 2007. Antipsychotic drugs are highly effective treatments for the positive symptoms of schizophrenia, but the serious and sometimes permanent side effects of these medications make successful long-term maintenance treatment challenging for both patient and clinician. Although newer “atypical” medications such as risperidone appear to present less risk of tardive dyskinesia and other extrapyramidal symptoms than first-generation drugs, second-generation agents have troublesome side effect profiles of their own, including disturbances in glucose metabolism, weight gain, and a heightened risk of diabetes (see American Diabetes Association et al., 2004; Haddad, 2004).

These side effects have led to the development of low-dose maintenance treatment protocols, but they have also prompted some researchers to ask whether there may be subgroups of people with schizophrenia who can eventually do well without taking any antipsychotic medications—and if so, whether this population has distinctive characteristics that would make these individuals easier to identify. The ethics of placebo-controlled studies of schizophrenia treatment remain highly controversial (see SRF related news story), but three recent prospective studies used other research designs to address these questions.

Who Succeeds Without Antipsychotics?
It is well-known that many people with schizophrenia stop taking antipsychotic medications after acute hospital treatment (see Fenton and McGlashan, 1987; Lieberman et al., 2005; also see SRF related news story). Martin Harrow and Thomas H. Jobe of the University of Illinois College of Medicine undertook a prospective 15-year follow-up study of 145 psychosis patients, including 64 who eventually received a diagnosis of schizophrenia, to see what types of schizophrenia patients discontinued medications—whether on their own initiative or with the guidance of a physician—and how they fared over the long term.

In particular, Harrow and Jobe were interested in whether patients’ past developmental achievements and their prognostic potential, as assessed during the index hospitalization, were predictive of their success off medication. In addition, the researchers used locus-of-control (LOC) and self-esteem scales at 4.5-year follow-ups to determine whether these personality measures correlated with patients’ medication status and well-being in later years.

As reported in the May 2007 issue of the Journal of Nervous and Mental Disease, Harrow and Jobe found in follow-up assessments at 2, 4.5, 7.5, 10, and 15 years that up to 41 percent of the patients with schizophrenia in the study sample had stopped taking antipsychotic medications, and as many as 25 percent were receiving no mental health treatment whatsoever. However, from the 4.5-year mark to the conclusion of the study, the patients with schizophrenia not taking antipsychotic drugs scored significantly better than those still taking medications on measures of global functioning and adjustment (p <.001). At 15 years, 64 percent of those on antipsychotic medications had psychotic activity, versus 28 percent of the group off medications. Moreover, 83 percent of the subjects with schizophrenia (19 of 23 patients) with a uniformly poor outcome at the 15-year follow-ups were on antipsychotic medications.

Harrow and Jobe found a strong correlation between the 4.5-year LOC and self-esteem scores and the likelihood that a patient would be using antipsychotic medications at each subsequent follow-up. Those patients whose results indicated an “internal” LOC—reflecting a belief that the course of their life is mostly influenced by their own skills and efforts rather than by chance, fate, or other powerful individuals—and those who scored higher in self-esteem were far less likely to be taking antipsychotic drugs at 15 years. Patients who had more significant developmental achievements prior to hospitalization and those deemed during hospitalization to have good prognostic potential were also far less likely to use antipsychotic drugs.

The researchers stress that, overall, schizophrenia has a poor outcome: compared to the control group of patients who had been treated for psychosis but did not have schizophrenia, those with schizophrenia functioned less well at all stages of the study. However, Harrow and Jobe say that their data provide evidence that specific subgroups of patients with schizophrenia with measurable personality traits and prognostic factors may not immediately relapse and may function quite well for a considerable period of time without antipsychotic drugs.

Harrow and Jobe point out that a trend toward better functioning without medications only began to emerge 4.5 to 7.5 years after their patients were discharged from the hospital, and that their long-term, “naturalistic” study design may avoid the inevitable observer bias of clinically based studies. “The controlled trials data on clinic populations of patients suggest that among the patients with schizophrenia who stay in clinic treatment settings for years after the acute phase there is increased risk of relapse when going off antipsychotics,” the authors write. “However, the current data suggest that for the select subgroup of patients with schizophrenia who are not in clinic settings, who have gone off antipsychotics and did not immediately relapse, and stayed off them for a period of time, a surprising number experienced periods of recovery and continued to function well for a considerable period without antipsychotics. Clearly, the present longitudinal data suggest that not all patients with schizophrenia need to use antipsychotic medications continuously throughout their lives.”

If at First You Don’t Succeed . . . .
Another naturalistic follow-up study by Tadashi Nishikawa and colleagues at Seiwakai Nishikawa Hospital in Hamada, Japan, and at the National Institutes of Health in Baltimore, Maryland, also provides evidence that discontinuation of antipsychotic medications is a viable option for some patients with schizophrenia.

In an analysis accompanied by eight case reports in the spring 2007 issue of Psychiatry, Nishikawa and colleagues report that eight out of 30 remitted patients (26.7 percent; selected from a total population of 300 +/- 20) followed for an average of 10.7 years in a five-step drug withdrawal program were able to forego antipsychotic drugs for more than 2 years, even after multiple psychotic episodes. In one case, a patient did not take antipsychotic drugs for 15 years, until a relapse required a brief course of drug therapy.

Remission was defined as follows: "(a) total scores in each of nine clinical dimensions of Positive and Negative Syndrome Scale, including the positive and negative syndrome and depression, were either 1 or 2, (b) patients kept up normal social and occupational functioning, and (c) the same condition lasted at least 3 months under neuroleptic medication."

The team emphasizes that in half of these eight cases patients needed two or more attempts at antipsychotic withdrawal to reach a drug-free state, an outcome that could be obscured by more standard study designs. “These cases would be counted as ‘relapse’ or ‘dropouts’ in short-term randomized control studies,” the Nishikawa team writes. The researchers argue that with intensive follow-up care, minor relapses and repeated withdrawal programs may help patients to achieve a drug-free state in the long term, especially if withdrawal is accompanied by social-skills training.

The Nishikawa group’s data show that younger patients with acute onset of symptoms, as well as those who receive antipsychotics at lower doses or for a shorter period of time, are most likely to successfully withdraw from the drugs for extended periods. The authors argue that high-dose maintenance regimens may induce neuronal adaptations that make withdrawal more difficult (see Lieberman et al., 1994). “Even though this is an open study with a limited number of patients,” the Nishikawa team writes, “our results suggest that approximately one fourth of remitted schizophrenics could discontinue maintenance neuroleptic medication even after multiple episodes.”

Relapse: Too High a Risk?
A more cautious conclusion emerged from a shorter-term clinical study published in the May issue of the Journal of Clinical Psychiatry by Lex Wunderink and colleagues at the University Medical Center in Groningen, The Netherlands. In this work, researchers compared antipsychotic maintenance treatment to “guided discontinuation” of the drugs in 131 schizophrenia patients in remission after a first episode of psychosis. For the purposes of the study, the researchers defined remission as a sustained improvement in positive symptoms for 6 months; negative and disorganizational symptoms were not considered in admission criteria.

The patients, who were randomly assigned to receive maintenance treatment or guided discontinuation, were followed for 2 years following their first response to drug treatment, and were assessed using the Positive and Negative Syndrome Scale (PANSS) after the required 6-month remission, at 15 months, and at 24 months. Measures of drug side effects, social functioning, and quality of life were also taken at some of these same intervals.

The 63 patients in the maintenance group received treatment according to American Psychiatric Association guidelines, with preference given to low doses of second-generation antipsychotics, while in 65 patients the dosage was gradually tapered off and discontinued if possible. If signs of relapse or positive symptoms occurred, clinicians were instructed to restore the dosage to its previous effective level.

The Groningen team found that relapse rates were twice as high in the discontinuation group (43 percent vs. 21 percent, p = .011), and only about 20 percent of the group was successful in discontinuing the drugs. The PANSS scores, hospitalization time, and side effects were virtually identical in both groups, leading the researchers to conclude that the risk of relapse outweighs any other benefit that might come from universally tapering off medication in first-episode patients: “Given the relatively small number of patients who were successfully discontinued (21.5 percent), the twice-higher relapse rates with the discontinuation strategy, the selected patient sample of stably remitted and cooperative patients included in the trial, and the lack of substantial advantages of the discontinuation strategy over maintenance treatment, the discontinuation strategy does not seem to offer sufficient benefits over maintenance treatment to implement the strategy in regular practice for all remitted first-episode patients,” Wunderink and colleagues write.—Peter Farley.

Harrow M, Jobe TH. Factors involved in outcome and recovery in schizophrenia patients not on antipsychotic medications: a 15-year multifollow-up study. J Nerv Ment Dis. 2007;195(5):406-414. Abstract

Nishikawa T, Hayashi T, Koga I, Uchida Y. Neuroleptic withdrawal with remitted schizophrenics: a naturalistic follow-up study. Psychiatry. 2007;70(1):68-79. Abstract

Wunderink L, Nienhuis FJ, Sytema S, Slooff CJ, Knegtering R, Wiersma D. Guided discontinuation versus maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome. J Clin Psychiatry. 2007;68(5):654-661. Abstract

Comments on News and Primary Papers
Comment by:  Sarah Yates
Submitted 1 June 2007 Posted 1 June 2007

Discontinuation studies like Wunderink's are problematic because it is difficult to tell whether relapse is due to genuine recurrence reflecting original natural history, or drug withdrawal. There is little evidence to show what length of tapering protocol might be most appropriate.

To illustrate the difficulty, consider what happens in Tourette syndrome:

"Rapid discontinuation from drugs such as haloperidol, pimozide, and fluphenazine may lead to severe withdrawal effects. In general, discontinuation of medication may lead to 2 to 3 months of increased symptoms. Thus, if those medications are withdrawn, it cannot be expected that the patient's "real" status will be visible for quite a while. Some patients may improve for a few weeks after neuroleptic discontinuation and then worsen after an additional week or so, remain worse for a while, and then gradually improve. Side effects such as cognitive blunting, troubles with memory, feelings of dullness, poor motivation, school and sociable phobias, excessive appetite, and sedation may lift rather...  Read more

View all comments by Sarah Yates

Comment by:  Marvin Herz
Submitted 4 June 2007 Posted 4 June 2007
  I recommend the Primary Papers

It is clear that some patients with schizophrenia can do well off antipsychotic medication most of the time. The challenge is how to identify them and develop strategies to minimize the possibility of full relapse. The Harrow study is very helpful in that regard. A small percentage of first break patients will not have another relapse after recovering from the episode even if they are off medication. The benefits and risks should be discussed with the patient if he/she wants to be off medication.

In my studies, I have identified patient characteristics that help identify which patient might succeed off medication, including first break. They should have insight into their illness and not lose it if they begin to relapse; be capable of recognizing their early warning signs of impending relapse and be willing to take APDs when this occurs (having a cooperative family helps); no history of violence or suicidality during prior psychotic episodes; no history of rapid decompensation in prior episodes; and not a drug abuser. Patients should be taught to recognize early signs of...  Read more

View all comments by Marvin Herz

Comment by:  Sarah Yates
Submitted 6 June 2007 Posted 8 June 2007

Marvin Herz writes, "A small percentage of first break patients will not have another relapse after recovering from the episode even if they are off medication. The benefits and risks should be discussed with the patient if he/she wants to be off medication."

But surely the bigger issue is that patients can have relapses whether on antipsychotics or not. The real question is who will, taking into account serious physical side effects, significant increased mortality, and cognitive effects, benefit overall and long term from antipsychotics.

Well, maybe not the 20 percent or so who show little or no functional response; they are getting a heap of side effects for minimal benefit. And for those in the middle, i.e., excluding those 20 percent who would have gotten better anyway—leaving 60 percent of the total—well, we do not know, because discontinuation effects fatally flaw the maintenance studies. It is impossible to accurately judge the impact of discontinuation on relapse rates (see previous post). Discontinuation studies also miss out those who are...  Read more

View all comments by Sarah Yates

Comment by:  Marvin Herz
Submitted 12 June 2007 Posted 13 June 2007

Sarah Yates dismisses the importance of maintenance medication in preventing relapse, because patients relapse on or off medication. It is known that the majority of patients alternate between acute episodes (relapse) and periods of full or partial remission. There have been randomized controlled studies comparing an intermittent (targeted) medication strategy with maintenance medication which have all found that intermittent medication results in much higher relapse rates over 2 years. In our study, it was 30 percent for intermittent and 16 percent for those on maintenance (Herz et al., 1991). Other studies have found even larger differences favoring maintenance.

Relapses are highly undesirable for patients and their families. After each relapse, re-hospitalizations are lengthier and patients may not recover to their previous level of symptoms and functioning. However, a German study found no benefit in maintenance medication for first break patients (Gaebel et al., 2002). My...  Read more

View all comments by Marvin Herz

Comment by:  Patricia Estani
Submitted 13 June 2007 Posted 18 June 2007
  I recommend the Primary Papers

I think that the question of this research news—must the administration of antipsychotic drugs be forever?—is one of the most important questions that really began an excellent debate among the scientific community.

The article by Dr. J. Bola (Bola, 2006; also see SRF related news story) is a really excellent article in this regard, not only for a clinical discussion but also for a research discussion. I think that the scientific community must take these ideas as one of the most important issues for future discussion in the field of schizophrenia research.

View all comments by Patricia Estani

Comment by:  Vittorio Di Michele
Submitted 20 June 2007 Posted 20 June 2007
  I recommend the Primary Papers

In my opinion, these papers confirm and disclose, with stringent scientific methodology, a wide range of phenomena, until now not adequately investigated and understood, observed in countries with a very strong commitment to community-based mental health care, like Italy. The following phenomena listed are typical of a community-based mental health system, which is specifically organized by rules and recommendations of the National Plan of Italian Government:

1. A large proportion of schizophrenia-schizoaffective patients isn’t ever admitted in a psychiatric inpatient unit.

2. The antipsychotic mean doses are lower in Italy than in the U.S., and many patients show a “satisfactory” response at dosage much lower than expected.

3. Many patients and their caregivers (usually parents or partner) manage their antipsychotic daily dosage by themselves, adjusting the dosage according to their needs. Surprisingly, very often this management works!

4. Psychosocial interventions reduce the need for antipsychotics and are currently delivered in a special unit of Mental...  Read more

View all comments by Vittorio Di Michele

Comment by:  Sarah Yates
Submitted 22 June 2007 Posted 22 June 2007

I am not dismissing the importance of maintenance medication; I am saying that the randomized controlled studies quoted by Marvin Herz, which show advantages of maintenance over intermittent medication, are so fundamentally flawed by inadequate tapers and potential discontinuation effects that it is difficult to interpret the results (see my previous posts).

In addition, design of the studies gives an apparently distorted effect, because significant numbers of patients, up to 40 percent, who continue to experience psychotic symptoms whilst taking antipsychotics are not included in the trial, so one is examining a subset of “good” drug responders, giving a false picture of antipsychotic efficacy. The evidence shows that a significant proportion of “good” responders would have recovered without drug treatment in the first place. No drug treatment is not equivalent to treatment and withdrawal.

For these reasons the clearest way to truly assess the benefit of long-term maintenance medication is to use placebo-controlled RCTs (Bola,...  Read more

View all comments by Sarah Yates

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 22 June 2007 Posted 22 June 2007
  I recommend the Primary Papers

I have been interested in this issue for a long time, first as a treatment issue and later as an ethics problem. Key aspects of the discussions are often misconceptualized. My view is as follows:

1. The issue is never drugs or no drugs, but rather how to integrate therapies.

2. Continuous medication is not the only active pharmacotherapy strategy. Targeted antipsychotic treatment is effective (less so than continuous for relapse prevention, but perhaps better for negative symptoms and similar to overall outcome measures). A targeted approach may be optimal for patients who refuse continuous medication, for patient subjects in off-medication protocols for research, and for a subgroup with good prognostic indicators who want to consider managing their recovery process off medication. The targeted approach addresses relapse prevention by intervening early in exacerbation and by assuring continuity of clinical care (see Buchanan and Carpenter, 1996, for overview).

3. Off-medication research is feasible and ethically defensible. The Helsinki Declaration was a flawed...  Read more

View all comments by William Carpenter

Comment by:  Shitij Kapur (Disclosure)
Submitted 28 June 2007 Posted 28 June 2007

Have followed the comments above with great interest. I come to this from the perspective of someone who studies the mechanisms of antipsychotics—usually focusing on the acute and the shorter-term, but find myself increasingly getting interested in the longer-term issues.

I think there can be little denying that antipsychotics administered to those acutely psychotic lead to less distress for those treated and better ability for the rest of us to work with them. The short-term mechanism (D2 blockade) and short-term gains are rather undeniable.

The question is, what are the longer-term trade-offs? This remains a complex question. From a biological perspective the introduction of any drug, including antipsychotics, is an external challenge for the body. The body responds by trying to establish homeostasis and compensate for this challenge. We have shown both in animals (Samaha et al., 2007) and in humans (Silvestri et al., 2000) that, in certain situations and certain...  Read more

View all comments by Shitij Kapur

Comment by:  James C. Matthews
Submitted 28 June 2007 Posted 29 June 2007

The whole idea of "to drug or not to drug" is rather new to me. As a schizoaffective patient for many years who has been mostly compliant with my psychiatrist's direction, I can only say that this might only add confusion to the issue. I attend a lot of discussion and support groups for people with bipolar disorder and schizophrenia. The message I hear the most is to keep taking one's meds. The reason that this message is so often repeated is simply that it is so frequently rejected or ignored by so many patients. The biggest reason for relapse and continued problems is noncompliance. Once patients learn that other patients are experimenting with discontinuing medication, you will simply have more cases of noncompliance. Most patients don't live in a vacuum and most don't necessarily do what they are told. While many lack insight, they do not lack free will.

View all comments by James C. Matthews

Comment by:  Sarah Yates
Submitted 2 July 2007 Posted 2 July 2007

Thanks to all for an interesting debate.

William Carpenter writes, "The issue is never drugs or no drugs, but rather how to integrate therapies."

The therapeutic issue remains drug or no drug if one assumes appropriate social and emotional support will be available to all from diagnosis. At any given point in management the decision that really matters, and is directly influenced by the psychiatrist, is drug or no drug. All other specific therapies are of unproven utility (with the possible exception of cognitive behavior therapy), and can be administered concurrently with drugs. So what therapy is it one is integrating drug use with? I think the issue is whether the long-term goal is to maximize drug use, or minimize drug use, both in terms of numbers of individuals treated, and dose (including number of antipsychotics prescribed concurrently), and duration once treated.

My fundamental position is that careful assessment of long-term data suggests that the goal should be to minimize use of antipsychotics for psychosis including schizophrenia, and in most cases...  Read more

View all comments by Sarah Yates

Comment by:  Wolfgang Gaebel
Submitted 13 July 2007 Posted 13 July 2007
  I recommend the Primary Papers

Efficacy of Treatment Has to Be Related to Safety
The three articles and their summary provided by the Schizophrenia Research Forum address very important questions in long-term treatment of schizophrenia. Due to the efficacy of (first- and second-generation) antipsychotics (FGAs, SGAs) florid psychotic symptoms mostly remit under initiated and maintained treatment in the acute and stabilization phase. However, this mental illness is in most cases (about 80 percent) characterized by symptom recurrence or relapse, and long-term (low-dose) maintenance treatment is indicated to prevent relapse and maintain or improve patients' level of functioning. Like nearly all drugs, antipsychotics can also cause side effects, like extrapyramidal reactions, tachycardia, hypotension, lethargy, impotence, or hyperprolactinaemia (mainly by FGAs), agranulocytosis (Clozapine), weight gain, or metabolic effects (mainly discussed for the newer SGAs). However, contrary to the SRF summary, serious side effects are rather infrequent and uncommon. Nevertheless, to avoid (potential) harm for...  Read more

View all comments by Wolfgang Gaebel

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 14 July 2007 Posted 16 July 2007
  I recommend the Primary Papers

Sarah Yates provides an interesting and informative comment touching on many relevant issues—please read. My thoughts on a couple of these issues are as follows:

1. Minimizing or maximizing antipsychotic drug administration may be a public health issue, but it is not the concept for treating an individual. The issue is optimizing drug therapy (as well as other therapies). In this regard, the evidence base is very weak and practice is probably very bad. Drugs do not come to market with good evidence for optimal dosing even in the acute situation. The doctor's responsibility will be to develop recommendations at each phase of illness based on relatively little information. And the available data will be on groups of patient subjects in illness phase and other circumstances different from the individual being treated.

2. Optimizing will depend on many things, but decisions on how to approach this are developed in the doctor/patient relationship in the broad context of the recovery process. Here an appreciation of risks and benefits is ascertained with attention to...  Read more

View all comments by William Carpenter

Comment by:  Sarah Yates
Submitted 17 July 2007 Posted 18 July 2007

I welcome much of what William Carpenter has to say, though, as he points out, all of it is up for debate, as there are no certainties. However, I think it a little harsh to state, "As a clinical concept, the ‘no drug’ proposition is applicable only if based on an anti-drug ideology." No drug ever, for anyone under any circumstances, yes: this is an ideology. To raise the legitimate concern that once an individual is started on drugs it may be very hard to ever stop them, at least for some individuals, is not an ideology. It is a pragmatic concern, from which follows the premise that if it is possible to avoid drugs, it might well be a good idea to do so, and the long-term outcome might be better. As discussed previously, there is evidence to suggest this is not such a silly idea as many suppose. Seikkula is not an ideologist in the sense that patients sometimes do go on antipsychotics, on a needs basis.

In my own case, I tapered from 1.5 mgs risperidone to 0.25 mgs every third day, over nearly a year, although clearly I was on a very low dose for most of that time. (You...  Read more

View all comments by Sarah Yates

Comment by:  Cenk Tek
Submitted 26 July 2007 Posted 26 July 2007
  I recommend the Primary Papers

I believe the jury is out to decide if long-term antipsychotic treatment is hazardous or not in terms of brain biology. The new generation of antipsychotics clearly increases the risk for other medical problems, thus the re-emerging interest in targeted antipsychotic treatments.

Nobody likes to use a medication all the time. I found most of my patients to be reluctantly compliant on their medications after many self-trials of no medication periods with fairly dramatic psychosocial consequences.

In my experience, the main determinant of success of targeted antipsychotic treatment is not the severity of symptoms such as delusions, but if and how fast insight is lost. There are clear subgroups where the first sign of a relapse is quick loss of insight, while others may keep partial insight throughout relapse of other symptoms. If the desire, and origins of the desire to go off medications, are well addressed in therapy, the second group does enjoy medication-free periods, if not complete medication-free life, albeit almost always with residual symptoms.

Please note...  Read more

View all comments by Cenk Tek
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