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The British Journal of Psychiatry
(2011) 198: 85-87. doi: 10.1192/bjp.bp.110.085795
© 2011 The Royal College of
Psychiatrists

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Editorials

Questioning the ‘neuroprotective’ hypothesis: does drug treatment prevent
brain damage in early psychosis or
schizophrenia?
Joanna Moncrieff, MRBS, MSc, MD,
MRCPsych

Department of Mental Health Sciences, University College
London, 67–73 Riding House Street, London W1W 7EJ, UK. Email: j.moncrieff{at}ucl.ac.uk

Declaration of interest

J.M. is the co-chair person of the Critical
Psychiatry Network.

ABSTRACT

TOP
ABSTRACT
INTRODUCTION
Brain imaging research
Neuropathological findings
Duration of untreated psychosis
Evidence on neuroprotection
Conclusions
REFERENCES

The idea
that psychotic disorders are characterised by progressive
neurodegeneration that can be reversed by drug treatment is
used to justify early treatment of increasing numbers of mostly
young people. I argue that there is little evidence to support
the view that old- or new-generation antipsychotics are
‘neuroprotective’, and some evidence that the drugs themselves may be
responsible for the decline in brain matter observed in some
studies.

INTRODUCTION

TOP
ABSTRACT
INTRODUCTION
Brain imaging research
Neuropathological findings
Duration of untreated psychosis
Evidence on neuroprotection
Conclusions
REFERENCES

Joanna Moncrieff (pictured) is a senior lecturer at
University College London and a consultant psychiatrist at the
North East London Foundation Trust.

Almost 7 million prescriptions for antipsychotic drugs were issued
outside hospital in England in 2008, an increase of 48% since
1998.1 Data
from the USA also indicate dramatically increased rates of
prescription of antipsychotics to young people over recent
years.2 Ideas
about the benefits of early drug treatment in psychosis, along with
other factors such as the marketing of bipolar disorder,3 are
likely to have contributed to the increasing prescription of these
drugs.

The importance of starting drug treatment early, and of continuing
treatment in people who would like to stop, is often justified
by the prevalent belief that schizophrenia or psychosis involves
a progressive loss of brain tissue that can be arrested or
reduced by treatment with antipsychotic drugs.4
Accordingly, the drugs are sometimes referred to as having
‘neuroprotecive’ properties. This belief is founded on a variety of
evidence, all of which is debatable and open to other
interpretations.

Brain imaging research

TOP
ABSTRACT
INTRODUCTION
Brain imaging research
Neuropathological findings
Duration of untreated psychosis
Evidence on neuroprotection
Conclusions
REFERENCES

The main
area believed to support the ‘neuroprotection’ hypothesis is brain
imaging research illustrating that people with schizophrenia or
psychosis show a progressive reduction in brain volume and an
enlargement of ventricles and cerebral spinal fluid. All such
studies, however, involve people who have taken long-term
antipsychotic medication. A large study showing greater decline in
brain volume in patients with first-episode psychosis taking
haloperidol compared with olanzapine has been interpreted as
indicating the neuroprotective effects of olanzapine.5 The
authors acknowledged, however, that the study might also be
interpreted as demonstrating differential drug-induced changes.
Supporting the latter interpretation, a study of macaque monkeys
treated with therapeutic doses of olanzapine and haloperidol
for 18 months found an 8% reduction in mean fresh brain weight
in monkeys treated with haloperidol and 11% in those on olanzapine
compared with non-drug-treated controls.6

The great majority of studies of individuals who are drug-naive or
have received only minimal treatment, do not show the global deficit
in brain volume commonly associated with patients who have received
drug treatment, including, most importantly, the only three studies
involving people with long-term conditions who had not been exposed
to drug treatment.7 Results
from two studies of people considered to be at high risk of
psychosis are also believed to demonstrate progressive brain tissue
loss prior to and in the early stages of psychotic illness. Many
of the Australian cohort, however, were taking antipsychotic
medication during some of the follow-up period.8 In the
Edinburgh study, high-risk individuals who progressed to psychosis
showed greater temporal lobe reduction than those who did not
progress, but did not differ from controls.9
Overall, therefore, imaging studies provide little evidence of
progressive brain tissue loss in non-drug-treated patients with
schizophrenia. Moreover, the effects of drug treatment have not been
excluded as a cause of the tissue loss seen in some studies of
drug-treated patients.7

Neuropathological findings

TOP
ABSTRACT
INTRODUCTION
Brain imaging research
Neuropathological findings
Duration of untreated psychosis
Evidence on neuroprotection
Conclusions
REFERENCES

Post-mortem
studies have generally not found the large-scale neuronal loss and
gliosis characteristic of neurodegenerative disorders in the brains
of people with schizophrenia, although there is some evidence of
local reduction of neuronal sub-populations and local loss of
dendritic spines and length.10
Again, however, all studies have involved people on long-term
medication. Some studies with drug-naive patients have found reduced
serum levels of brain derived neurotrophic factor (BDNF),11 but
this finding is not specific to schizophrenia, and BDNF has also been
found to be involved in mood disorders and the stress response.
Although schizophrenia has been suggested to involve increased or
abnormal apoptosis, several studies confirm that markers of
apoptosis in neurodegenerative disorders such as Alzheimer’s
disease are not raised in post-mortem tissue from patients with
chronic schizophrenia, and the role of apoptosis earlier on in the
condition remains speculative.12

Duration of untreated psychosis

TOP
ABSTRACT
INTRODUCTION
Brain imaging research
Neuropathological findings
Duration
of untreated psychosis
Evidence on neuroprotection
Conclusions
REFERENCES

Another
frequently cited, indirect strand of evidence for the hypothesis that
schizophrenia arises from progressive brain pathology that can be
arrested by drug treatment is the association found in some studies
(although not all) between the duration of untreated psychosis and
outcome. However, it has long been recognised that conditions with a
long and insidious early course are frequently more severe than those
with a sudden onset. Duration of untreated psychosis is strongly
related to mode of onset13 and
other characteristics of the psychosis itself,14
which makes it likely that it is simply a proxy measure of a
more severe underlying condition. Research on duration of
untreated psychosis and outcome has not adequately controlled for
mode of onset and other potential confounding factors.15

Trials of early intervention have shown some positive results, but
have not analysed the role of medication over and above other aspects
of the intervention, and long-term results are disappointing
(reviewed in Bosanac et al).15 Two
trials of drug treatment for young people at high risk of psychosis
suggested that the rate of conversion to psychosis was reduced,
although not by a statistically significant degree in the larger
of the two trials.16 A
larger naturalistic study has so far found that drug treatment has
not reduced the onset of psychosis.17

Evidence on neuroprotection

TOP
ABSTRACT
INTRODUCTION
Brain imaging research
Neuropathological findings
Duration of untreated psychosis
Evidence
on neuroprotection
Conclusions
REFERENCES

At a
neuropathological level, ideas about drug treatment being
neuroprotective developed because of evidence that some psychiatric
drugs, notably lithium, increase activity in some pathways
associated with neurotrophism and neurogenesis.18 The
functional implications of these findings are unclear, however. One
study, for example, found that although lithium reduced levels
of kainate-induced excitotoxic motor neuron cell death,
surviving cells were not undamaged.19 In
any case, evidence of antipsychotics has not consistently
demonstrated these sorts of effects.18
The view that new atypical antipsychotics have a particular
neuroprotective effect may derive from an animal study of olanzapine
and clozapine that detected upregulation of the neuroprotective
Bcl-2 (B-cell lymphoma 2) protein.20
However, Bcl-2 is also upregulated in neurodegenerative disorders
such as Alzheimer’s disease, where it is regarded as evidence of a
compensatory mechanism. Other studies have not replicated this
finding, but one study found increased activity of the
pro-apoptotic protease capase-3 in animals treated with old and new
antipsychotics.21

Effects of antipsychotics, particularly atypicals, on cognitive
function is also cited as evidence of their neuroprotective
effects, but whether or not any antipsychotics improve cognition
independently of symptoms remains uncertain. The suggested
superior effects of atypical antipsychotics have also been
questioned by the findings of the Clinical Antipsychotic Trials
of Intervention Effectiveness (CATIE) study, in which the greatest
long-term improvements in cognitive function were seen in the
perphenazine group.22

In contrast to ideas about neuroprotective effects, there is
suggestive evidence that antipsychotics reduce brain tissue
volume, as described above,7 and
they are known to cause the pathological brain syndrome known as
tardive dyskinesia. Research suggests that as well as involuntary
movements, tardive dyskinesia is associated with general cognitive
decline, suggesting that antipsychotics can induce generalised brain
dysfunction.23

Conclusions

TOP
ABSTRACT
INTRODUCTION
Brain imaging research
Neuropathological findings
Duration of untreated psychosis
Evidence on neuroprotection
Conclusions
REFERENCES

Antipsychotics
are undoubtedly useful in suppressing the symptoms of psychotic
conditions, but the evidence presented here suggests there is little
basis to the belief that they reverse an underlying neurodegenerative
process in people with schizophrenia or psychosis. Neuropathological
studies do not support the idea that antipsychotic drugs, including
the new or atypical antipsychotics, have neuroprotective effects.
Some research suggests they may even contribute to the decline in
brain volume seen in people with these diagnoses, and they are known
to induce neurological damage in the form of tardive dyskinesia in
some long-term users. The idea that antipsychotic drugs are
neuroprotective should not therefore be used as a justification for
prescribing or continuing to prescribe them, if other considerations
do not also support their use. Psychiatrists should be particularly
cautious about the use of antipsychotics in the early or prodromal
stages of psychosis, where, as others have pointed out, there is
the potential to do much harm.15

REFERENCES

TOP
ABSTRACT
INTRODUCTION
Brain imaging research
Neuropathological findings
Duration of untreated psychosis
Evidence on neuroprotection
Conclusions
REFERENCES

1

Information Centre for Health and Social Care. Prescription Cost
Analysis 2008. NHS Information Centre, 2009.2

Olfson M, Blanco C, Liu L, Moreno C, Laje G. National trends in the
outpatient treatment of children and adolescents with antipsychotic drugs.
Arch Gen Psychiatry 2006; 63: 679 –85.[Abstract/Free Full Text]3

Healy D. The latest mania: selling bipolar disorder. PLoS Med 2006;
3: e185.[CrossRef][Medline][Search
for full text]4

Lieberman JA. Is schizophrenia a neurodegenerative disorder? A clinical
and neurobiological perspective. Biol Psychiatry 1999; 46: 729
–39.[CrossRef][Medline][Search
for full text]5

Lieberman JA, Tollefson GD, Charles C, Zipursky R, Sharma T, Kahn RS, et
al. Antipsychotic drug effects on brain morphology in first-episode psychosis.
Arch Gen Psychiatry 2005; 62: 361 –70.[Abstract/Free Full Text]6

Dorph-Petersen KA, Pierri JN, Perel JM, Sun Z, Sampson AR, Lewis DA. The
influence of chronic exposure to antipsychotic medications on brain size
before and after tissue fixation: a comparison of haloperidol and olanzapine
in macaque monkeys. Neuropsychopharmacology 2005; 30: 1649 –61.[CrossRef][Medline][Search
for full text]7

Moncrieff J, Leo J. A systematic review of the effects of antipsychotic
drugs on brain volume. Psychol Med 2010; 40: 1409 –22.[CrossRef][Medline][Search
for full text]8

Takahashi T, Wood SJ, Yung AR, Soulsby B, McGorry PD, Suzuki M, et al.
Progressive gray matter reduction of the superior temporal gyrus during
transition to psychosis. Arch Gen Psychiatry 2009; 66: 366 –76.[Abstract/Free Full Text]9

Lawrie SM, Whalley HC, Abukmeil SS, Kestelman JN, Miller P, Best JJK, et
al. Temporal lobe volume changes in people at high risk of schizophrenia with
psychotic symptoms. Br J Psychiatry 2002; 181: 138 –43.[Abstract/Free Full Text]10

Jarskog LF, Miyamoto S, Lieberman JA. Schizophrenia: new pathological
insights and therapies. Annu Rev Med 2007; 58: 49 –61.[CrossRef][Medline][Search
for full text]11

Chen DC, Wang J, Wang B, Yang SC, Zhang CX, Zheng YL, et al. Decreased
levels of serum brain-derived neurotrophic factor in drug-naive first-episode
schizophrenia: relationship to clinical phenotypes. Psychopharmacology
(Berl) 2009; 207: 375 –80.[CrossRef][Search
for full text]12

Jarskog LF, Glantz LA, Gilmore JH, Lieberman JA. Apoptotic mechanisms in
the pathophysiology of schizophrenia. Prog Neuropsychopharmacol Biol
Psychiatry 2005; 29: 846 –58.[CrossRef][Medline][Search
for full text]13

Morgan C, Abdul-Al R, Lappin JM, Jones P, Fearon P, Leese M, et al.
Clinical and social determinants of duration of untreated psychosis in the
ÆSOP first-episode psychosis study. Br J Psychiatry 2006; 189:
446 –52.[Abstract/Free Full Text]14

Owens DC, Johnstone EC, Miller P, Macmillan JF, Crow TJ. Duration of
untreated illness and outcome in schizophrenia: test of predictions in
relation to relapse risk. Br J Psychiatry 2010; 196: 296 –301.[Abstract/Free Full Text]15

Bosanac P, Patton GC, Castle DJ. Early intervention in psychotic
disorders: faith before facts? Psychol Med 2010; 40: 353 –8.[CrossRef][Medline][Search
for full text]16

McGlashan TH, Zipursky RB, Perkins D, Addington J, Miller T, Woods SW, et
al. Randomized, double-blind trial of olanzapine versus placebo in patients
prodromally symptomatic for psychosis. Am J Psychiatry 2006;
163: 790 –9.[Abstract/Free Full Text]17

Walker EF, Cornblatt BA, Addington J, Cadenhead KS, Cannon TD, McGlashan
TH, et al. The relation of antipsychotic and antidepressant medication with
baseline symptoms and symptom progression: a naturalistic study of the North
American Prodrome Longitudinal Sample. Schizophr Res 2009; 115:
50 –7.[CrossRef][Medline][Search
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Hunsberger J, Austin DR, Henter ID, Chen G. The neurotrophic and
neuroprotective effects of psychotropic agents. Dialogues Clin Neurosci
2009; 11: 333 –48.[Medline][Search
for full text]19

Caldero J, Brunet N, Tarabal O, Piedrafita L, Hereu M, Ayala V, et al.
Lithium prevents excitotoxic cell death of motoneurons in organotypic slice
cultures of spinal cord. Neuroscience 2010; 165: 1353 –69.[CrossRef][Medline][Search
for full text]20

Bai O, Zhang H, Li XM. Antipsychotic drugs clozapine and olanzapine
upregulate bcl-2 mRNA and protein in rat frontal cortex and hippocampus.
Brain Res 2004; 1010: 81 –6.[CrossRef][Medline][Search
for full text]21

Jarskog LF, Glantz LA, Gilmore JH, Lieberman JA. Apoptotic mechanisms in
the pathophysiology of schizophrenia. Prog Neuropsychopharmacol Biol
Psychiatry 2005; 29: 846 –58.[CrossRef][Medline][Search
for full text]22

Keefe RS, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, et al.
Neurocognitive effects of antipsychotic medications in patients with chronic
schizophrenia in the CATIE Trial. Arch Gen Psychiatry 2007; 64:
633 –47.[Abstract/Free Full Text]23

Waddington JL, O’Callaghan E, Larkin C, Kinsella A. Cognitive dysfunction
in schizophrenia: organic vulnerability factor or state marker for tardive
dyskinesia? Brain Cogn 1993; 23: 56 –70.[CrossRef][Medline][Search
for full text]

Received for publication August
11, 2010. Accepted for publication September 15, 2010.

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© 2011 The Royal
College of Psychiatrists.

Online ISSN: 1472-1465

Print ISSN: 0007-1250