In the September issue of the German journal Der Nervenarzt appears a “pros and cons” debate on the topic: “Can long-term treatment with antipsychotics lead to structural brain damage?”. The “pro” position is represented by Volkmar Aderhold and colleagues, I have written the “contra” position (Gründer, Der Nervenarzt 2013; 84: 1120-1122).
For reasons of copyright I can only make my own work available here. But if one reads both papers together, one will notice that the two positions are not very far apart. I have tried to present the data – within the available scarce page limit – as objectively as possible.
The publication can be downloaded here.
For my international readership I have translated the article into English. This is also done with kind permission of Springer-Verlag. Here is the translation:
When in spring 2011 Ho et al. from the group of Nancy Andreasen reported in the prestigious Archives of General Psychiatry that at least part of the structural brain changes, which can be observed in patients with schizophrenia longitudinally, are associated with the use of antipsychotics, this sparked considerable media echo in the lay press. Under the headline “brain shrinkage by psycho pills?” the German weekly journal Der Spiegel concluded in its edition of 21/01/2013 that “agents for schizophrenia […] could even aggravate the disease which they seek to heal”. Nancy Andreasen’s group at the University of Iowa had studied 211 patients with a schizophrenic disorder longitudinally between 1991 and 2009 with magnetic resonance tomography. On average, the patients were studied 3 times (maximum: 5) over a period of up to 14 years (mean 7.2 years). The authors found that with the duration of the observation period the brain volume of the patients decreased and the ventricle size increased. The accumulated applied antipsychotic dose correlated to the loss of gray matter and the increase in volume of the putamen. The total dose of antipsychotic drugs administered was only moderately (negatively) correlated with the severity of disease (Spearman r = -0.21). The volume changes still correlated with the cumulative antipsychotic dose when corrected for duration and severity of the disease and the extent of substance abuse.
It has been known for many decades that patients with schizophrenia have reduced brain – especially prefrontal cortical and hippocampal – and increased ventricular volumes. Studies in first-episode patients who were never previously treated with a psychotropic drug, prove beyond doubt that these structural changes are associated with the disease itself, and that they are certainly not attributable to any form of treatment.
However, the first reports on structural brain changes associated with the administration of antipsychotics were published already in the 1990s. Chakos et al. in 1994 demonstrated an increase in the volume of the caudate nucleus in patients with schizophrenia, which they attributed to the antipsychotic treatment. The supposition that antipsychotics lead to plastic changes in this structure seems likely, since their binding in the basal ganglia is particularly high. Later, the same group reported that this increase in volume was reversed after switch to clozapine. Particularly revealing – because very easy to control – were studies in rhesus monkeys, which David Lewis and colleagues performed at the University of Pittsburgh. They treated the animals for 17 to 27 with either haloperidol or olanzapine at doses that lead to plasma concentrations similar to those measured in patients with schizophrenia treated with these drugs. The drug treatment led to a reduction of weight and volume of the brain of the treated monkeys of 8-11%. The structural changes were the most pronounced in frontal and parietal cortices. In addition, in the parietal cortex of the monkeys the numbers of astrocytes were significantly reduced by approximately 20% and of oligodendrocytes non-significantly by approximately 12%. Haloperidol and olanzapine led to changes in the same direction. Moncrieff and Leo in their meta-analysis (published 2010) of 26 volumetric MRI studies of patients who had been treated with antipsychotics arrived to the cautious conclusion that “some evidence points towards the possibility that antipsychotic drugs reduce the volume of brain matter and increase ventricular or fluid volume”.
However, the situation is not so clear that one could draw clear clinical conclusions. The first publication from Rene Kahn’s group from the University of Utrecht initially also suggested that in patients with a schizophrenic disorder the brain matter loss measured longitudinally correlated with the cumulative dose of antipsychotic drugs administered during the observation period. However, in the 5-year follow-up of their patient population, these authors then found that those patients with the least loss of gray matter in the frontal cortex had received the highest cumulative doses of clozapine or olanzapine. Furthermore, Lieberman et al. in the only available randomized MRI study (which, however, was funded by Eli Lilly and haloperidol doses were too high) demonstrated differential effects of treatment with haloperidol and olanzapine. While treatment with haloperidol was associated with a significant reduction in gray matter, this was not observed in patients who had been treated with olanzapine. There are two possible explanations for this observation: haloperidol is neurotoxic, while olanzapine is not; or: in patients treated with haloperidol the natural course of the disease was observed, which was delayed in olanzapine-treated patients. For such neuroprotective effects of antipsychotics, especially the second generation, there is evidence from various animal models.
This also applies to the above-mentioned study by Ho et al. (2011). These authors found a correlation between brain volume reduction and accumulated antipsychotic dose even when they corrected for the severity of the disease. However, patients who had received the highest antipsychotic doses had already at baseline significantly smaller brain volumes than the patients who had been treated with low to moderate doses. It might be that the patients with the most pronounced neurodegenerative process (who therefore were probably the most severely affected by the illness) were treated with the highest antipsychotic doses. Then Ho and colleagues have described a pure association rather than a causal relationship . They consequently concede:
“Associations between smaller brain tissue volumes and more antipsychotic treatment may still be moderated via illness severity despite our inclusion of illness severity as a covariate and obtaining similar results from different measures of illness severity.”
Moreover, only 31 of the 211 patients examined in the study were antipsychotic-naive. Most patients had already experienced drug treatment at the time of inclusion into the study, on average for a period of 0.43 years.
Only a prospective randomized long-term study in first-episode, never-treated patients could definitely answer the question of the influence of antipsychotic treatment on brain structure of patients with schizophrenia. One-half of the patients had to undergo the usual long-term drug treatment, the other half had to be kept off medication for at least a period of a few weeks, better months. This raises significant ethical issues, as all international guidelines recommend a long-term antipsychotic maintenance therapy after the first episode of a schizophrenic disorder. Ho et al. also conclude:
“The current study could have been strengthened by having control groups, eg, schizophrenia patients assigned to deferred or no antipsychotic treatment or healthy volunteers treated with antipsychotics for comparable periods. However, ethical standards in human subject research prohibit such comparison groups.”
Given the inconclusive data, requests to completely refrain from antipsychotic treatment whenever possible, or claims that antipsychotics “aggravate the disease which they seek to heal” (from Der Spiegel 21.01.2013) are not appropriate. Dozens of studies conducted in the past 5 decades have shown that patients who do not undergo relapse prevention significantly more often suffer from psychotic relapses than patients who are treated prophylactically. This is also true for the so-called interval therapy (or intermittent therapy), in which antipsychotic drug treatment is stopped after the acute episode and restarted with recurrence of psychotic symptoms.
In addition, numerous studies suggest that early drug treatment of a schizophrenic disorder improves the long-term outcome compared to a delayed onset of treatment. This is completely supported by further analysis of the data that Andreasen et al. unfortunately published just recently, 2 years after their first sensational publication. Now they show that the loss of brain volume in patients with schizophrenia is associated not only with the dose of the administered antipsychotics, as originally described, but also with the duration of the observed psychotic relapses. In fact, they now report the statistically strongest relationship between brain matter loss in the frontal cortex and relapse duration rather than between volume reduction and antipsychotic dose! Each long lasting relapse thus has a neurotoxic effect on a region of the brain which is centrally involved in schizophrenic disorders.
So, what to conclude from the available data?
- The indication for antipsychotic treatment has to be set rigorously; it has to be re-evaluated over the course of treatment.
- The lowest effective dose has to be chosen.
- Studies with intelligent prospective and randomized designs should be pursued in which different treatment strategies with the objective of risk-benefit evaluation are compared in order to provide an individual treatment plan to each patient in the future.
- The pharmaceutical industry should target the development of neuroprotective and -regenerative drugs.
This post is also available in: German