Recently, researchers in China (Ran et al) 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 so treated .
Consistent with the Leucht et al 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.” This research 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, Feb. 10, 2016].
This finding 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 AP 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-naïve patients with schizophrenia showed significant gray matter volume deficits in frontal, cingulate, temporal, and other brain regions. .
Furthermore, Lesh et al  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 AP use is being considered.
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 AP use in patients with schizophrenia.
Without a doubt, both the literature and clinical experience point to considerable risk in discontinuing AP 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 APs in certain settings and populations. Indeed, these medications are almost certainly over-used–without substantial evidence for their efficacy–in patients with ordinary anxiety disorders or insomnia; for adolescent “acting out”; and for “agitation” in geriatric or nursing home populations .
Finally, discussion of long-term AP use must be placed in the larger perspective of general medical care, in which physicians are constantly struggling with the perennial “risk vs. 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 .
This finding is very reassuring. But in the end, the devastating suffering and incapacity of chronic schizophrenia is reason enough to warrant the judicious long-term use of antipsychotic medication.