Setting the Record Straight on Antipsychotics

COMMENTARY

My first experience with antipsychotic medication was in the early 1960s, shortly after they were introduced. As is usual with new treatments, benefits were appreciated before harms were realized. Delusions and hallucinations improved, but patients developed many very unpleasant side effects-a strange fixed stare, muscle rigidity, uncontrollable movements, agitation, sedation, and lots of others.

I and others hoped that “expectant treatment” with antipsychotics could provide patients with benefits, while minimizing harms. The idea was to reduce the lifetime burden of side effects by limiting meds to episodes of relapse. Medication would gradually be tapered once the patient was stabilized, to be restarted promptly only if, and when, symptoms later returned.

I led one of the research teams doing controlled studies of expectant treatment. About one-third of patients taken off meds did fine, but two thirds had relapses, sometimes terrible ones-while the group kept on antipsychotics had only half their rate of relapse. I learned the painful lesson that, for people with severe and chronic mental illness, going off meds is a risky gamble, one that is usually not worth taking. This was confirmed by hundreds of clinical experiences working in emergency rooms and hospitals. By far the most common cause of psychotic relapse is going off antipsychotic medicine.

In the 1990s, a new generation of antipsychotics was introduced that initially showed great promise. The new medications were no more effective than the old. But they were much better tolerated because they usually didn’t cause the muscle rigidity or agitated restlessness that had made patients feel so uncomfortable and look so strange.

The honeymoon didn’t last long. Too often, the new meds caused massive weight gain, increasing the risks of diabetes, cardiovascular disease, and shortened life expectancy. And because their side-effect profile was less overt, the new antipsychotics lent themselves to careless over-prescription for phony indications: ordinary anxiety or insomnia; conduct problems in poor kids or those in foster homes; and “agitation” in elderly residents of understaffed nursing homes. Antipsychotics were also prescribed for unnecessarily long periods-sometimes many years-for people who had experienced only a brief, first-time psychotic episode. I and many others have fought vigorously against these dangerous misuses of antipsychotic medication.

The weight gain and consequent risk of diabetes should, by themselves, provide sufficient warning against the reckless over-prescription of antipsychotics and sufficient encouragement to limit their use only for clearly defined and narrow indications.

But in recent years, critics of psychiatry have added an additional, counterintuitive argument against antipsychotics-that they actually cause or worsen psychotic symptoms and should not be used on a long-term basis.

Not surprisingly, this bold claim has quickly gained currency among those who have had a bad experience with antipsychotic medication. For them, it was indeed more harmful than helpful and they generalize from their own personal experience to assume antipsychotics are equally harmful for everyone else. This generalizing, and the proselytizing that often comes with it, has dangers for others who go on to have a very different lived experience. Influenced by popular books and blogs, people who truly need antipsychotic medications discontinue them-sometimes with disastrous consequences.

Patients with chronic psychotic symptoms usually do quite well on medications and quite badly off them. The decision to stay on or go off antipsychotics has tremendous significance in a person’s life-and is sometimes a matter of life and death.

I have asked Dr Ronald Pies, Professor of Psychiatry at SUNY Upstate Medical University and Tufts University, to set the record straight on what the literature does and does not say about long-term use of antipsychotics.

Dr Pies writes:

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.

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 Wunderink¹ suggest that for some people experiencing 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.

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 quite brief bouts of psychosis that never return, making long-term antipsychotic treatment unnecessary.

But when we look at relapse rates in patients with schizophrenia, we see a different picture. Prof. Stefan Leucht and colleagues² examined relapse rates in persons with schizophrenia or schizophrenia-like psychoses, comparing those maintained on antipsychotic medication vs those given a placebo. Leucht reviewed 65 randomized controlled trials (RCTs) involving 6493 participants, covering studies from 1959 to 2011.

The authors 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.”

About 27% relapsed while taking medication, versus 64% taking placebo. Quality of life was also better in participants staying on medication.

Of course, the authors noted that “This [benefit] must be weighed against the side effects of antipsychotic drugs,” which include sedation, weight gain, and movement disorders.

Recently, researchers in China³ carried out a 14-year prospective study of outcome in people with schizophrenia (N=510) who had never been treated with antipsychotic medication, and compared outcome with those who were treated. Consistent with the Leucht’s findings, the Chinese investigators found that partial and complete remission rates in treated patients were significantly higher than that in the never-treated group-57.3% vs. 29.8%. 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.”

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” causing a flare-up of “super-sensitized” brain cells. Yet when we look at the time course of psychotic relapse, it usually occurs several months after discontinuation of the antipsychotic. 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 stopped. Thus, the “withdrawal psychosis” or “supersensitivity psychosis” notions remain, at best, highly speculative.

Some studies also raise the possibility that antipsychotic medication can cause structural changes in certain brain regions, leading some to raise the alarm about “brain damage” from these drugs. Yet schizophrenia itself is linked with numerous brain abnormalities, including progressive loss of brain cells, even in persons never exposed to antipsychotic medication. We need more research to sort out this issue, while always weighing the neurological risks of treatment, including movement disorders, against the very real benefits.

Critics of long-term antipsychotic use often cite studies done by Dr Martin Harrow and colleagues.⁴ Harrow looked at 139 patients with schizophrenia who were either on or off antipsychotic medications, over a 20-year study period. Harrow found that those not on antipsychotics had a lower severity of psychosis and significantly greater rates of recovery compared to those taking antipsychotics. This led Harrow to suggest a “recovery paradox” in which antipsychotics help in the short-term, but lose effectiveness in the long-term.

However, as UCLA schizophrenia expert Dr Joseph M. Pierre⁵ has pointed out, patients in the Harrow studies were not randomized. Patients themselves were allowed to decide whether or not to continue medication. This means that those with milder symptoms likely 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 far more likely that the severity of patients’ symptoms determined whether or not they and their doctors decided to continue medication. In interpreting the Harrow studies, non-medical critics of antipsychotic treatment have misperceived direction of the arrow of causality.

Thanks so much, Dr Pies, for this illuminating review.

Beyond the scientific literature, there are also 2 huge, naturalistic experiments illustrating that psychosis was, and is, an enormous problem, without invoking antipsychotics as its cause.

As Dr E. Fuller Torrey⁶ has pointed out, in 1955, there were about 600,000 people living in state mental hospitals. Not all of these had severe and chronic psychotic symptoms, but hospital records indicate that the majority did. Chronic psychosis before the 1950s can’t possibly have been caused by antipsychotics, because the medication did not then exist. This is an uncontrolled, but compelling refutation of the cart-before-the-horse assumption that meds cause the symptoms.

The lifetime course of chronic psychosis in the pre-medication era also helps explain the misinterpretation that medications are unnecessary to treat chronic psychosis, or even make it worse. Twenty to thirty percent of patients recovered more or less completely before medication was available-exactly as happens now. These “spontaneous recoverers” are often the people most opposed to medication and are used to justify claims that meds are actually harmful in chronic psychosis.

But we mustn’t forget the remaining 70% to 80% who did poorly without meds. Their chronic, psychotic symptoms could not have been caused by antipsychotics, because they had never taken them. In those days, such people were warehoused in state hospitals; now they often wind up in jail or homeless.

The second “natural experiment” began in the 1950s when hundreds of thousands of the severely ill were discharged from hospital, often without access to medication. The result: we now have about 250,000 homeless people and about 350,000 of the mentally ill in jail or prisons for nuisance crimes-avoidable, had their psychiatric symptoms been treated. The quality of life for the majority of people with untreated severe mental illness is abysmal.⁷

As Dr Torrey points out, “. . . on any given day in the United States, half of all individuals with schizophrenia, or about 1 million people, are not being treated. This is a huge natural experiment. . . Many of these individuals are found in public shelters, sleeping under bridges, in jails, and in prisons.”⁶

There is no “one size fits all” approach to psychiatric care. Medications are not all good or all bad. Misapplied to people who don’t really need them, they are bad. Prescribed properly to people who do, they are good. Meds that are harmful for someone who doesn’t need them are essential for someone who does.

The misleading idea that antipsychotic medications cause or worsen psychosis legitimizes the incorrect view that long-term medication is bad for everyone. A minority of people with chronic, severely impairing psychotic symptoms may eventually do fine off meds, but the majority will have relapses that are always disruptive and often dangerous.

Even factoring in all the side effects, going off antipsychotic medication is usually a bad bet for the severe and chronically ill. The consequences of relapse can be unpredictable and sometimes horrible. Patients, families, and prescribers need to understand both the real benefits and the very real risks of antipsychotic medications. The mistaken idea that antipsychotics cause psychosis is an unnecessary and dangerous distraction from what is already a tough enough risk/benefit calculation.

Disclosures:

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References:

1. 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. http://www.ncbi.nlm.nih.gov/pubmed/23824214.
2. Leucht S, Tardy M, Komossa K, et al. Maintenance treatment with antipsychotic drugs for schizophrenia. Cochrane Database Syst Rev. 2012 May 16;5:CD008016. http://www.ncbi.nlm.nih.gov/pubmed/22592725.
3. 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. http://www.ncbi.nlm.nih.gov/pubmed/26382951.
4. 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. http://www.ncbi.nlm.nih.gov/pubmed/25066792.
5. 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 17, 2016.
6. 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 17, 2016.
7. Frances A. World’s best-and worst-places to be mentally ill. Psychiatric Times. December 29, 2015. http://www.psychiatrictimes.com/blogs/couch-crisis/worlds-best-and-worst-places-be-mentally-ill. Accessed February 17, 2016.