Long-term Antipsychotic Treatment: Effective and Often Necessary, with Caveats

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COMMENTARY

Recently, the blogosphere has been buzzing with controversy about maintenance antipsychotic treatment.^1,2 On the one hand, most psychiatrists who have treated severely impaired patients with schizophrenia have little doubt that long-term antipsychotic treatment is both effective and necessary to avoid relapse of psychotic illness. On the other hand, a few recent studies seem to cast doubt on this belief, and a number of psychiatry’s critics have seized on these studies to argue against long-term antipsychotic use-even declaring that in the long run antipsychotics worsen psychosis and clinical outcome for those with schizophrenia.^1,2

This article is by no means a comprehensive review of the voluminous, decades-old literature on antipsychotic maintenance; rather, it is a commentary on some recent studies and their sometimes controversial interpretation. I would argue that interpreting these complex studies requires an in-depth understanding of medical research design, psychopharmacology, and the numerous confounding factors that can affect treatment outcome. Unfortunately, a lack of medical training has not stopped a few critics from confidently charging that psychiatrists are harming their patients by prescribing long-term antipsychotic treatment.^1,2

What does the recent  literature say?

We need to make modest claims-not sweeping generalizations-about the literature on long-term use of antipsychotic medication. “Gold-standard,” randomized, placebo-controlled studies are fewer than we would like, and existing studies are always subject to different interpretations.

“There is no convincing evidence that maintenance treatment causes worsening of schizophrenia or related psychotic illnesses, or leads to poorer outcomes, when compared with discontinuation of the antipsychotic.”

Nonetheless-to prefigure my main arguments-I believe that most randomized, long-term studies of schizophrenia support the net benefit of antipsychotics in preventing relapse of the illness. Some data also show better “quality of life” with maintenance antipsychotic treatment, compared with drug discontinuation. There is no convincing evidence that maintenance treatment causes worsening of schizophrenia or related psychotic illnesses or leads to poorer outcomes, when compared with discontinuation of the antipsychotic.

That said, data from Dr Lex Wunderink and colleagues³ suggested to some that long-term antipsychotic treatment may do more harm than good. Essentially, these researchers compared rates of recovery in patients with remitted first-episode psychosis after 7 years of follow-up of a dose reduction/discontinuation versus maintenance treatment trial. After 6 months of remission, patients were randomly assigned to a dose reduction/discontinuation strategy or maintenance treatment for 18 months. After the trial, treatment was at the discretion of the clinician.

The primary outcome was rate of recovery, defined as meeting the criteria of symptomatic and functional remission. At the 18-month mark, dose reduction/discontinuation resulted in significantly greater relapse rates compared with medication maintenance, as many psychiatrists would have expected. However, at 7 years, the dose reduction/discontinuation group showed unexpectedly higher recovery rates than the maintenance treatment group-40.4% versus 17.6%. This finding seemed to suggest that long-term antipsychotic maintenance worsened outcome after first-episode psychosis.

But as schizophrenia specialist Dr Joseph M. Pierre² has pointed out, this conclusion is unwarranted. First of all, most of the subjects in the dose reduction/discontinuation arm of the study actually remained on antipsychotic medication, although at a reduced dose. Second, as Dr Pierre notes, “. . . while the initial treatment group allocation was randomized, the subsequent dose changes in both treatment groups were based on clinical response and occurred at the whim of the treating psychiatrists.”² Thus, this was not really a randomized study. And rather than antipsychotic treatment worsening outcome, it seems more likely that patients perceived by their doctors as doing relatively well were, understandably, given lower doses of medication. Conversely, patients perceived as doing worse were likely maintained on higher doses.

As Dr Pierre notes, “. . . the study was not so much a comparison of being on or off medications, [as] a comparison of being on higher versus lower antipsychotic doses.”2 At most, the Wunderink study³ might suggest that for some people who experience their first psychotic episode, “less is more”; that is, lower doses of antipsychotics may lead to better long-term recovery rates and social functioning than higher doses. The study does not support the claim that long-term antipsychotic maintenance is causally related to poorer outcome.

Furthermore, in a recent open- label, non-randomized, prospective study of antipsychotic discontinuation in patients who fully recovered from their initial episode of psychosis, Spanish researchers found that discontinuation was associated with a high risk of symptom recurrence.⁴ Persons who experienced relapse had more severe symptoms and lower functional status after 3 years. The rates of relapse over the 3-year period were 67.4% (31 of 46) in the discontinuation group and 31.8% (7 of 22) in the maintenance group.

The resumption of antipsychotic medication after relapse was associated with clinical stability and lack of further relapses. To be sure, the lack of a randomized study design, the relatively small sample size, and the fact that assessors were not blind to medication status are major limitations of this study-but the results provide no support for the claim that antipsychotic maintenance worsens outcome after a single episode of psychosis.

It is important to understand that only a portion of people with a first psychotic episode have schizophrenia, which is usually a very chronic illness. Many have brief bouts of psychosis that never return, making long-term antipsychotic treatment unnecessary. So what does the recent literature tell us about antipsychotic treatment and relapse rates in patients with schizophrenia?

Schizophrenia and long-term antipsychotic treatment

Critics of long-term antipsychotic treatment often cite studies by Dr Martin Harrow and colleagues.⁵ Over a 20-year period, these researchers looked at 139 patients with schizophrenia who were either on or off antipsychotic medications. Surprisingly, patients who were not taking antipsychotics had a lower severity of psychosis and significantly greater rates of recovery than those who were receiving antipsychotics.

Specifically, more than 70% of patients with schizophrenia to whom antipsychotics were continually prescribed experienced psychotic activity, at 4 or more of 6 follow-up assessments over 20 years. Longitudinally, patients with schizophrenia to whom antipsychotics had not been prescribed showed significantly less psychotic activity than those prescribed antipsychotics (P < .05). This led Harrow and others to suggest a “recovery paradox,” in which antipsychotics help in the short term but lose effectiveness in the long term.

More precisely, the study authors concluded that “. . . antipsychotic medications do not eliminate or reduce the frequency of psychosis in schizophrenia, or reduce the severity of post-acute psychosis, although it is difficult to reach unambiguous conclusions about the efficacy of treatment in purely naturalistic or observational research.”⁵ (Italics added.)

This last italicized point, however, is crucial. As Dr Pierre has pointed out, patients in the Harrow study-like those in the Wunderink study-were not randomized. Patients themselves were allowed to decide whether or not to continue medication. This means that those with milder symptoms may have “self-selected” to discontinue medication, whereas those with more severe illness-who would be expected to have a poorer outcome-elected to stay on medication.

So the Harrow studies did not prove that long-term antipsychotic treatment per se worsened outcome. It is more likely, as Dr Pierre notes, that the type or severity of patients’ symptoms determined whether they and their doctors decided to continue medication. Thus, in analyzing the Harrow studies, some critics of antipsychotic treatment may have misperceived the “arrow of causality.”

Another recent study cited by critics of long-term antipsychotic use was a 2015 review by Sohler and colleagues.⁶ The authors examined data from 18 English-language, published reports, based on studies conducted between 1947 and 2010. The authors compared outcomes in patients who received antipsychotic medication during a follow-up period of at least 2 years with outcomes in patients who did not receive antipsychotics. The study tested the hypothesis that “. . . people with schizophrenia who are exposed to long-term treatment with antipsychotic medications have worse outcomes than people with schizophrenia who are not exposed to these medications.”⁶

Owing to “ubiquitous study design flaws” in the data examined, the authors concluded that the published data were “inadequate to test this hypothesis.” And, by extension, “. . . these data were also inadequate to conclusively evaluate whether long-term antipsychotic medication treatment results in better outcomes on average.” This is certainly a disappointing finding for clinicians who prescribe long-term antipsychotic treatment; however, the study in no way demonstrated that long-term antipsychotic treatment worsens outcomes for patients with schizophrenia who receive such treatment. The authors explicitly state, “Our study did not support the hypothesis that long-term treatment with antipsychotic medication causes harm.”⁶

Indeed, data from other sources suggest that long-term antipsychotic treatment clearly improves outcome in schizophrenia. For example, Prof Stefan Leucht and colleagues⁷ examined relapse rates in persons with schizophrenia or schizophrenia-like psychoses, either maintained on antipsychotic medication or given a placebo. The researchers looked at 65 randomized, controlled trials involving 6493 participants, covering studies from 1959 to 2011. They concluded that “. . . the efficacy of antipsychotic drugs for maintenance treatment in schizophrenia was clear. Antipsychotic drugs were significantly more effective than placebo in preventing relapse at 7 to 12 months.”⁷

On average, about 27% relapsed while taking medication versus 64% taking placebo. Moreover, only 10% of patients in the treatment group were readmitted to the hospital, compared with 25% of those who were given placebo. Quality of life was also better in participants who stayed on medication. Of course, the authors noted, “This [benefit] must be weighed against the side effects of antipsychotic drugs,”⁷ which can include sedation, weight gain, and movement disorders.

“Both the literature and clinical experience point to considerable risk in discontinuing antipsychotic treatment, for many chronically psychotic patients.”             

Recently, researchers in China carried out a 14-year prospective study of outcome in persons with schizophrenia (N = 510) who had never been treated with antipsychotic medication; their outcomes were compared with those of persons who had been treated.⁸ Consistent with the findings of Leucht and colleagues, the results of the Chinese study showed that partial and complete remission rates in treated patients were significantly higher than those in the never-treated group (57.3% vs 29.8%).⁸ Moreover, the authors concluded that “. . . never-treated/remaining untreated patients may have a poorer long-term outcome (for example higher rates of death and homelessness) than treated patients.” This was not a randomized study, of course; nevertheless, it provides no support for the claim that long-term antipsychotic treatment worsens outcome in schizophrenia.

Withdrawal, relapse, and brain changes

Critics sometimes charge that apparent relapse among persons with schizophrenia does not represent a bona fide recurrence of the original illness. Rather, they claim, it is simply a “withdrawal effect” that occurs when antipsychotic medication is rapidly discontinued, owing to a flare-up of “super-sensitized” dopaminergic neurons. Yet when we look at the time course of psychotic relapse, it usually occurs several months after discontinuation of the antipsychotic (Joseph M. Pierre, MD, personal communication, February 10, 2016).

This is not consistent with what we know about most drug withdrawal syndromes, which usually occur days to a few weeks after a drug is suddenly stopped. Thus, the “withdrawal psychosis/super-sensitivity psychosis” notion remains, at best, a highly speculative hypothesis, in so far as psychotic relapse is concerned.

Some studies also raise the possibility that antipsychotic medication can cause structural changes in certain brain regions, leading some critics to sound the alarm about “brain damage” from these drugs. Indeed, some MRI data indicate an association between antipsychotic use and reductions in cortical gray matter in patients with schizophrenia,^9,10 compared with non-medicated patients and normal controls. Allowing for the uncertainties of MRI interpretation, these findings are surely concerning. However, their clinical significance is not yet clear.

Thus, schizophrenia itself is linked with numerous brain abnormalities, such as progressive loss of brain cells, even in persons never exposed to antipsychotic medication. For example, in one study, antipsychotic-naive patients with schizophrenia showed significant gray matter volume deficits in frontal, cingulate, temporal, and other brain regions.⁹

Furthermore, Lesh and colleagues¹⁰ found that while short-term treatment with antipsychotics was associated with prefrontal cortical thinning, treatment was also associated with better scores on a continuous performance task (AX-CPT). The authors concluded that the results warranted caution “. . . in interpreting neuroanatomical changes as being related to a potentially adverse effect on brain function.”

In my view, we need more research to sort out this complex issue, while always weighing carefully the neurological risks of antipsychotic treatment (including movement disorders) against their very real benefits. A careful informed consent discussion with patients and/or their guardians is certainly warranted whenever long-term antipsychotic use is being considered.

Conclusions

Recent studies of long-term antipsychotic treatment are not unanimous or unequivocal in their findings; however, in my view, the preponderance of evidence points to the net benefits of long-term antipsychotic use in patients with schizophrenia. Without a doubt, both the literature and clinical experience point to considerable risk in discontinuing antipsychotic treatment, for many chronically psychotic patients.^1,2

That said, critics of psychiatry are right in calling attention to the misuse or over-use of antipsychotics in certain settings and populations. Indeed, these medications are almost certainly over-used-without substantial evidence for their efficacy-in patients who have ordinary anxiety disorders or insomnia; for adolescent “acting out”; and for “agitation” in geriatric or nursing home populations.¹¹

Finally, discussion of long-term antipsychotic use must be placed in the larger perspective of general medical care, in which physicians are constantly struggling with the perennial “risk versus benefit” equation. Many life-saving treatments in other medical specialties-from cancer chemotherapy to cardiac surgery-are associated with significant risks. But we must also consider the risks of absent or inadequate treatment, and the inherent morbidity and mortality of the illness itself.

In this regard, a recent study of overall mortality in schizophrenia found that compared with no exposure, both moderate and high antipsychotic exposures were associated with substantially lower overall mortality.¹² This is a very reassuring finding. But in the end, the devastating suffering and incapacity of chronic schizophrenia are reason enough to warrant the judicious long-term use of antipsychotic medication.

Acknowledgments-This piece emerged in the course of discussions with Drs Allen Frances, E. Fuller Torrey, Bernard Carroll, and Joseph Pierre, for whose assistance and contributions to the field I am most appreciative. This essay, however, represents my own synthesis of the data.

For further reading:

Pies RW. The bogus “epidemic” of mental illness in the US. Psychiatric Times. June 18, 2015 http://www.psychiatrictimes.com/blogs/bogus-epidemic-mental-illness-us. Accessed February 22, 2016.

Torrey EF. Anatomy of a non-epidemic-a review by Dr Torrey. Treatment Advocacy Center. http://www.treatmentadvocacycenter.org/component/content/article/2085-anatomy-of-a-non-epidemic-a-review-by-dr-torrey. Accessed February 22, 2016.  

This article was originally posted on 2/22/2016 and has since been updated.

Disclosures:

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References:

1. Frances A. Do antipsychotics help or harm psychotic symptoms? Psychol Today. February 1, 2016. https://www.psychologytoday.com/blog/saving-normal/201602/do-antipsychotics-help-or-harm-psychotic-symptoms. Accessed February 22, 2016.

2. Pierre J. Do antipsychotics worsen schizophrenia in the long-run? Psychol Today. August 8, 2014. https://www.psychologytoday.com/blog/psych-unseen/201408/do-antipsychotics-worsen-schizophrenia-in-the-long-run. Accessed February 22, 2016.

3. Wunderink L, Nieboer RM, Wiersma D, et al. Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy: long-term follow-up of a 2-year randomized clinical trial. JAMA Psychiatry. 2013;70:913-920.

4. Mayoral-van Son J, Ortiz-Garcia de la Foz V, Martinez-Garcia O, et al. Clinical outcome after antipsychotic treatment discontinuation in functionally recovered first-episode nonaffective psychosis individuals: a 3-year naturalistic follow-up study. J Clin Psychiatry. 2015 Dec 8. [Epub ahead of print].

5. Harrow M, Jobe TH, Faull RN. Does treatment of schizophrenia with antipsychotic medications eliminate or reduce psychosis? A 20-year multi-follow-up study. Psychol Med. 2014;44:3007-3016.

6. Sohler N, Adams BG, Barnes DM, et al. Weighing the evidence for harm from long-term treatment with antipsychotic medications: a systematic review. Am J Orthopsychiatry. 2015 Dec 14. [Epub ahead of print].

7. Leucht S, Tardy M, Komossa K, et al. Maintenance treatment with antipsychotic drugs for schizophrenia. Cochrane Database Syst Rev. 2012;5:CD008016.

8. Ran MS, Weng X, Chan CL, et al. Different outcomes of never-treated and treated patients with schizophrenia: 14-year follow-up study in rural China. Br J Psychiatry. 2015;207:495-500.

9. Venkatasubramanian G. Neuroanatomical correlates of psychopathology in antipsychotic-naïve schizophrenia. Indian J Psychiatry. 2010;52:28-36.

10. Lesh TA, Tanase C, Geib BR, et al. A multimodal analysis of antipsychotic effects on brain structure and function in first-episode schizophrenia. JAMA Psychiatry. 2015;72:226-234.

11. Gellad WF, Aspinall SL, Handler SM, et al. Use of antipsychotics among older residents in VA nursing homes. Med Care. 2012;50:954-960.

12. Tiihonen J, Mittendorfer-Rutz E, Torniainen M, et al. Mortality and cumulative exposure to antipsychotics, antidepressants, and benzodiazepines in patients with schizophrenia: an observational follow-up study. Am J Psychiatry. 2015 Dec 7. [Epub ahead of print]. http://ajp.psychiatryonline.org/doi/abs/10.1176/appi.ajp.2015.15050618. Accessed February 22, 2016.