In recent years, controversy has persisted over the maintenance treatment of antipsychotics.
On the one hand, most psychiatrists who have treated severely impaired patients have no doubts about the effectiveness and necessity of long-term antipsychotic treatment in order to avoid relapse of symptoms;
On the other hand, a number of recent studies seem to have impacted on these views, and some psychiatric commentators have clung to these studies, arguing against long-term antipsychotic use and even claiming that in the long run, antipsychotics worsen the mental status and clinical presentation of schizophrenic patients.
This article is not a sprawling review of decades of antipsychotic treatment literature; rather, it is a review of some recent studies and controversial interpretations in the literature. I argue that interpreting these complex studies requires an in-depth understanding of medical study design: both psychopharmacological factors and numerous confounding factors can have an impact on treatment outcomes.
Unfortunately, some psychiatric critics lacking medical training continue to blindly determine that psychiatrists prescribe long-term antipsychotics to the detriment of their patients.
Primary psychosis: better cure rates with discontinuation of medication?
With regard to long-term antipsychotic treatment, we should be specific to the problem, not generalize. There are fewer gold standards, randomized studies, and placebo-controlled studies than we might think, and there are always multiple interpretations of the available findings.
Nonetheless, my main argument – and I believe most randomized, long-term schizophrenia studies will support the argument that antipsychotic treatment is useful in preventing relapse of the disease. Some data suggest that the maintenance antipsychotic group exhibits better “quality of life” than the discontinuation group; there is no convincing evidence that maintenance treatment leads to worsening of schizophrenia or related disorders, or worse clinical outcomes, than discontinuation.
Lex Wunderink’s study
Recent data from Dr. Lex Wunderink suggest that long-term AP treatment may do more harm than good. In fact, Wunderink and colleagues compared relapse rates in the dose reduction/discontinuation (DR) and maintenance therapy (MT) groups during a 7-year follow-up of first-episode psychosis patients (FEP). After 6 months of symptom remission, patients were randomly assigned to the DR and MT groups for 18 months of treatment. At the end of the trial, a follow-up treatment plan was arranged by the clinician.
The primary outcome of the trial was the recovery rate, with recovery defined as meeting criteria for symptom and functional remission. As predicted by many psychiatrists, patients in the reduced-dose/discontinuation (DR) group had a significantly higher relapse rate than the maintenance therapy (MT) group after 18 months of subgroup treatment. However, at 7-year follow-up, unexpected results yielded a significantly higher cure rate in the DR group than in the MT group (40.4% vs. 17.6%). This finding seems to suggest that long-term AP maintenance treatment may be detrimental to patients with first-episode schizophrenia.
But as schizophrenia expert Joseph M. Pierre, MD, points out, this conclusion is not rigorous.
First, most patients in the DR group in the trial were still receiving AP despite being on a low dose;
Second, as Dr. Pierre explains, “…although the initial treatment group assignment was randomized, the dose adjustment in the second group after the trial depended on the psychiatrist’s ad hoc judgment based on clinical response.”
In other words, this was not a truly randomized study. Rather than saying that the AP treatment worsened the illness, it is more likely that: when patients see their doctors lowering the dose, they feel that it is because the previous treatment worked; conversely, when patients see their doctors maintaining the high dose, they feel that it is because the previous treatment was ineffective.
As Dr. Pierre said, “…this study did not set up a control group to compare the difference between maintenance and discontinuation, as had been set up for the high-dose group versus the low-dose group.” At best, Dr. Wunderink’s findings may suggest that “less is more” for patients with first-episode psychosis; in other words, lowering the AP dose is more likely to lead to higher recovery rates and improved social functioning for patients than maintaining a high dose. The study did not confirm a clear causal relationship between long-term AP maintenance and poorer cure rates.
Truth: High risk of discontinuation
In addition, in a recent open-label, non-randomized, prospective study of discontinuation of AP medication in patients with first-episode psychosis, Spanish researchers found that discontinuation was significantly associated with psychotic relapse. patients with relapse had more severe symptoms and lower functional status after 3 years. relapse rates reached 67.4% (31/46) in the discontinuation group and 31.8% (7/22) in the maintenance group at 3-year follow-up. /22).
After the occurrence of relapse, resumption of medication may consolidate the efficacy to reduce the recurrence rate. Undoubtedly, the lack of a randomized design, the relatively small sample size, and the fact that the analysts were not blinded to medication status constitute major limitations of this study – but the findings still do not support the contention that maintenance AP treatment worsens the final outcome of a single psychotic episode.
First-episode schizophrenia: better to use medication than not?
It is important to note that only a fraction of patients with first-episode psychosis are schizophrenic at first, and usually schizophrenia has a long course and presents chronically. And there are many fairly transient psychotic disorders that never recur, making long-term AP treatment unnecessary. So what does the recent literature tell us about the relationship between AP treatment and relapse rates in patients with schizophrenia?
Martin Harrow’s study
Opponents of long-term AP medication often cite studies by Dr. Martin Harrow and colleagues. Over a period of 20 years, Harrow and colleagues followed 139 patients with schizophrenia on antipsychotic medication, and surprisingly, Harrow found that patients who discontinued their medication were less ill and had significantly higher cure rates compared to those on maintenance medication.
Specifically, more than 70% of patients with schizophrenia on ongoing AP prescription therapy still had psychotic symptoms at least four out of six assessments at the subsequent follow-up of more than 20 years.
Longitudinally, patients with schizophrenia who were not on antipsychotics had significantly less psychotic activity compared to those on medication (p<0.05). This has led Harrow and others to propose a "recovery paradox" in which antipsychotics are effective in the short term, but lose their effectiveness in the long term.
More specifically, the study authors concluded, “…antipsychotic treatment did not eliminate or reduce the frequency of psychotic episodes in patients with schizophrenia, nor did it reduce the severity of subsequent episodes, although it is difficult to draw definitive conclusions about the effects of treatment in purely naturalistic or observational studies.”
The last sentence is crucial. As Pierre has pointed out: the patients in the Harrow study – like the patients in the Wunderink study – were non-randomized. The patients themselves could all decide whether they wanted to continue medication. This means that patients with milder symptoms may “self-select” to stop taking their medication, while those with more severe symptoms may be perceived to have worse outcomes – and choose to continue taking their medication.
So Harrow’s study did not demonstrate that long-term AP therapy inherently worsens clinical outcomes. As Dr. Pierre points out, it is more likely that the type and severity of the patient’s symptoms determined whether they and their physicians chose to continue the medication. Thus, in analyzing Harrow’s study, some AP treatment opponents may have misunderstood the cause-and-effect relationship.
Sohler’s study
Another literature cited by long-term AP treatment opponents is a 2015 review from Sohler and colleagues. The authors analyzed data for reports published in 18 English-speaking countries between 1947 and 2010. The authors compared the outcomes of patients treated with AP with those not treated with AP at a minimum 2-year follow-up. This study was designed to test the hypothesis that “…patients with schizophrenia who are chronically exposed to AP therapy have worse outcomes than patients with schizophrenia who are not exposed to AP therapy.”
Due to “unavoidable study design flaws” in the data analysis, the authors conclude that the published data “do not adequately test this hypothesis.” And add, “…these data also do not adequately validate that long-term AP treatment achieves better-than-average outcomes.” This is certainly a disappointing finding for clinicians with AP prescribing authority, however, this study at least does not prove that long-term AP treatment is detrimental to the prognosis of patients with schizophrenia. The authors clearly state, “Our study does not support the hypothesis that long-term AP treatment causes impairment.”
The truth: Medication is much better than no medication
In fact, data from other sources suggest that long-term AP treatment significantly improves outcomes in schizophrenia. For example, Professor Stefan Leucht and colleagues did the following experiment, which examined relapse rates in patients with schizophrenia or schizoid psychosis given antipsychotic medication or placebo, respectively. The researchers looked at 65 randomized controlled trials (RCTs) involving 6,493 participants from 1959 to 2011. They concluded, “…the efficacy of antipsychotics in the maintenance treatment of schizophrenia is clear.
Antipsychotics were significantly more effective than placebo in preventing relapse at 7-12 months.” On average, 27% of patients on medication relapsed, compared to 64% in the placebo group. Also, only 10 percent of patients in the treatment group were readmitted to the hospital compared to 25 percent in the placebo group. There was also a higher quality of life for participants who continued to use the medication. Of course, the authors noted, “This ‘benefit’ must be weighed against the side effects of antipsychotics, including sedation, weight gain and movement disorders.”
More recently, researchers in China conducted a 14-year prospective study comparing outcomes among 510 patients with schizophrenia who were never treated with antipsychotics to those who were treated with medication. Consistent with Leucht’s results, the Chinese researchers found that patients in the treated group had significantly higher rates of partial or complete remission than the untreated group – 57.3% vs. 29.8%. In addition, the authors concluded, “…patients in the untreated group may have worse long-term outcomes (e.g., high mortality and homelessness) compared with patients in the treated group.” Of course, this was not a randomized study either, but again, it does not support the idea that long-term AP treatment detracts from the prognosis of schizophrenia.
Drugs cause relapse + scourge the brain?
Critics sometimes point out that an apparent relapse in a person with schizophrenia does not represent a true relapse of the primary illness. Instead, they claim that it is a simple “withdrawal response” due to a hypersensitivity of dopaminergic neurons when antipsychotics are suddenly stopped. But when we look back at the timing of relapse in psychosis, we find that relapse usually occurs several months after discontinuation.
This is inconsistent with most of the drug discontinuation symptoms we know of, which usually occur within a few weeks of abrupt discontinuation. Therefore, the “discontinuation response/hypersensitivity reaction” still seems to be only a theoretical hypothesis for psychiatric relapse.
At the same time, some studies have discussed the possibility that antipsychotics can cause structural changes in certain brain regions, leading critics to warn about the “brain damage” caused by these drugs. In fact, some MRI data show an association between AP treatment and reduced cortical gray matter in schizophrenia patients compared to non-medicated and normal controls. These results are still valid considering the uncertainty of MRI interpretation. However, their clinical significance is unclear.
This is because, even if never treated with AP, schizophrenia itself is associated with many brain abnormalities, such as a progressive reduction in brain cells. For example, in one study, significant reductions in gray matter volume in the frontal lobe, cingulate gyrus, temporal lobe, and other brain regions were demonstrated in patients with schizophrenia who were not treated with antipsychotics.
In addition, Lesh and colleagues found that although short-term antipsychotic treatment was associated with prefrontal cortical thinning, treatment also improved patients’ scores on the continuous operational test (AX-CPT). The authors conclude that the findings need to be treated with caution, “…for the interpretation of neuroanatomical alterations that are associated with potential adverse effects on brain function.”
In my opinion, more research is needed to address this complex issue, and the neurological risks of medications (including movement disorders) should be fully considered along with the benefits of the medication when applying antipsychotic treatment. Whenever long-term treatment with AP is being considered, detailed discussions with patients and/or their guardians regarding informed consent are essential.
Summary
The results of recent studies on long-term antipsychotic treatment are inconsistent or inconclusive; however, individuals believe that the preponderance of evidence suggests that long-term treatment with AP is beneficial for patients with schizophrenia. There is no doubt that both the literature and clinical experience point to the risk of discontinuing AP therapy for many patients with chronic schizophrenia.
That said, psychiatric commentators are right to call attention to the misuse and abuse of APs, within certain settings and populations. Indeed, these medications are almost certainly being overused – without proven effectiveness – in people with generalized anxiety and insomnia, in impulsive behavior in adolescents, in agitation in the elderly, and in people in nursing homes.
Finally, the discussion of long-term AP use must take place at a higher level of medical care, where physicians have to figure out and maintain the “risk-benefit” balance over time. Many of the well-known medical treatments are accompanied by clear risks – from cancer chemotherapy to heart surgery. But we must also consider the non-existent or inadequate risks of treatment, as well as the recurrence and mortality rates inherent in the disease itself.
In this regard, a recent study of overall mortality in patients with schizophrenia showed lower overall mortality in the moderate and high dose AP treatment groups compared to the unexposed AP treatment group. This is a very stimulating finding. However: the devastating suffering and the long-term distress of chronic schizophrenia for patients is enough to make long-term antipsychotic treatment a wise choice.