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Questioning the ‘neuroprotective’ hypothesis: does drug treatment prevent brain damage in early psychosis or schizophrenia?

  • Joanna Moncrieff (a1)
Summary
Summary

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.

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References
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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.
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Questioning the ‘neuroprotective’ hypothesis: does drug treatment prevent brain damage in early psychosis or schizophrenia?

  • Joanna Moncrieff (a1)
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Neuroprotection, Resveratrol and Schizophrenia

Feargus F. O'Croinin, Psychiatrist
30 March 2011

The editorial by Moncrieff (1) is a refreshing reappraisal of the neuroprotective hypothesis as it relates to medication and early psychosisand schizophrenia. Clearly there is a need for better agents for neuroprotection in early psychosis and schizophrenia.

One compound that has received little attention in psychiatry is the polyphenol, resveratrol, present in grapes and wine. Numerous studies haveshown it has neuroprotective effects and anti-neurodegenerative activitiesas well as showing promise in Huntington's, Parkinson's and Alzheimer's diseases. Anti-cancer, anti-inflammatory, blood-sugar-lowering as well as cardioprotective effects have been reported in animal studies with resveratrol, suggesting that this is an agent of promise also for psychiatry. It has a favourable side-effect profile and is generally welltolerated.(2)

There is an urgent need for effective neuroprotective strategies in psychiatry. Giving antipsychotics the mantle of being neuroprotective encourages the maintenance of the status quo and lessens the urgency for discovery of effective neuroprotective compounds.

(1) Moncrieff J, Questioning the 'neuroprotective' hypothesis: does drug treatment prevent brain damage in early psychosis or schizophrenia? Br J Psych (2011): 198, 85-87

(2) Vang O, Das DK, Resveratrol and Health: Ann.N.Y. Acad. Sci. (2011): 1215, 1-170
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Neuroprotective Hypothesis

GEORGE M SIMPSON, Professor of Research Psychiatry
30 March 2011

We were interested in Dr. Moncrieff’s thoughtful,troublesome but important editorial Questioning theNeuroprotective hypothesis (1). One part of thisdeals with duration of untreated psychosis andoutcome and the flaws in some of these studies. Wewould like to remind readers of May’s early studypublished in the 60s before anti psychotics had beengiven their name(2). He compared first hospitaladmissions suffering from Schizophrenia who wererandomly assigned to five different treatments for asix month inpatient period. (An attempt was made tomatch for a prognosis). Treatmentincluded ‘ataractics’ mainly trifluoperazine alone orcombined with psychotherapy compared to psychotherapyalone, milieu therapy or ECT. At the end of sixmonths drugs alone or combined with psychotherapy didbetter than psychotherapy alone or milieu therapy asdid ECT. This was trending to be maintained 2-5 yearslater. This study can be criticized in many ways (apreliminary report was published in this journal inthe May 1965 issue) (3), or it can be seen as apioneering effort which clearly showed theineffectiveness of the orthodoxy of the day-psychodynamic oriented psychotherapy and also showedthat delayed active treatment (a minimum of sixmonths) appeared to influence outcome two years later.

However Schizophrenia does not appear to be a singleentity. Not all patients have enlarged ventricles andso it is possible that medication could beneuroprotective for some but not for others.Be that as it may the animal data and the recentarticle by Beng Choo Ho(4) and colleagues demonstratethat there is a dose dependent group change in brainvolume produced by all anti psychotics includingClozapine. There was no untreated group and so thequestion is still not completely answered.Nevertheless there is need for care in the use ofanti psychotics. Their use to promote sleep, inanxiety and even mood disorders needs to bequestioned. The same can be said for antipsychoticpolypharmacy and the tendency for higher thanoriginally recommended dosages to be prescribed, e.gthe original studies to market quetiapine used 200mgper day, now dosages of 400,600,800mg or even higherare not uncommon.

A comparison of lithium and an atypicalantipsychotic in Bipolar disorder with appropriateimaging would be most helpful at this time.

References1. Moncrieff, Joanna. Questioningthe neuroprotective hypothesis: does drug treatmentprevent brain damage in early psychosis orschizophrenia. The British Journal of Psychiatry(2011) 198, 85-87. doi:10.1192/bjp.bp.110.087952. Ho, Beng-Choon. Long term AntipsychoticTreatment and Brain Volumes, a longitudinal study offirst episode Schizophrenia. Arch GenPsychiatry/Vol.68 (No.2) February 2011.www.archgenpsychiatry.com3. May, P.R.A. Treatment of Schizophrenia, Acomparative study of five treatment methods. ScienceHouse, 1968. USA.4. May, P.R.A and Tuma, A.H: Treatment ofschizophrenia. British J of Psychiatry.3:503-510, June 1965
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Oxidative cell stress in the debate on neuroprotection

Peter Lepping, Consultant Psychiatrist, Visiting Professor, AMD
08 March 2011

I read Dr Moncrieff's editorial with much interest and ceratinly agree in principle with her conclusion that antipsychotics are not currently provento be neuroprotective (1). I was surprised though that she did not mentionthe influence of oxidative cell stress in the debate. In an improtant review Ng and colleagues' evidence points to oxidative stress as an important factor in the biologic aspects of aetiology and mortality in patientswith schizophrenia (2). This has in part driven claims of olanzapine and other second generation antipsychotics to be neuroprotective based on small studies that showed a reduction of cell stress markers in patients taking those medications and many in vitro studies (3). We have shown in abig systematic review that there are currently no convincing human studiesto show any presistent evidence that antipsychotics are neuroprotective byreducing oxidative cell stress in humans suffering from schizophrenia (4).This fully supports Dr Moncrieff's argument that caution should be appliedbefore claims of neuroprotection are being taken for granted.



References:1. Moncrieff J.Questioning the 'neuroprotective' hypothesis: does drug treatment prevent brain damage in early psychosis or schizophrenia? Br J Psychiatry. 2011 Feb;198:85-7.2. Ng F, Berk M, Dean O, et al. Oxidative stress in psychiatric disorders:evidence base and therapeutic implications. Int J Neuropsychopharmacol.2008;11(6):851–876. 3.Zhang XY, Tan YL, Cao LY, et al. Antioxidant enzymes and lipid peroxidation in different forms of schizophrenia treated with typical and atypical antipsychotics. Schizophr Res. 2006;81(2–3):291–300.4. Lepping P, Delieu J, Mellor R, Williams JH, Hudson PR, Hunter-Lavin C. Antipsychotic medication and oxidative cell stress: a systematic review. JClin Psychiatry. 2010 Jun 29. [Epub ahead of print]
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The Language of Science

Saad F Ghalib, consultant in old age psychiatry
08 March 2011

It seems that the tendency of research in psychiatry to jump into conclusions based on incomplete evidence,has become the rule rather than the exception.

Hardly,a day goes by without some new evidence supporting the beneficial effects of antipsychotics and antidepressants.However,research papaers(few and far between)that attest to the contrary(neuroleptic induced dysphoria,neuroleptic induced deficit syndrom)scarcely come to theattention of psychiatrists.In my practice,a sizeable number of patients treated with antidepressants have reported feelings of emotional dullness.Therefore,one is left with no option but to consider,that in a significant minority of patients,the possibility of antidepressants' induced altered state of mind/brain,thereby masking the underlying condition,which can easily be mistaken for improvement.

It is increasingly the case that psychiatric research grounds explanatory power on strengthening probability as if P-values somehow imply material causation.Often,the pharmaceutical industry is very quick to license or extend the life of their products even when evidence is flimsy.Why care?after all the FDA requires only two positive trials to license a medicine,and until very recently they were not obliged to publish negative trials.

I certainly agree with Moncrieff et al,that extra care should be taken when making an interpretation of research data.In real life,this is not the case though.If a number of depressed patients improve on Carbamazepine,we conclude that the medicine has antidepressant properties.We do not question the nature of the processes that underlie what we call depression.

I am fully aware that to speak of patients' symptoms as having some meaning is synonymous with heresy(Freuds' genius gone to waste).However,with the plethora of diagnostic labels,and apart from beingrecipes for dispensing psychotropics,as yet,no serious attempt has been made to question their relevance from patients' perspective.

The diagnostic system has made it,without a doubt,far much easier forpsychiatrists to discuss patients using the same language.However,this does not mean that we rae on the same wave length with our patients' experiences,thoughts and emotions.May be we should pay more attention to the language(the logic)of symptoms.This,in my opinion is true empathy.Thismay well have the potential for an ontological understanding of psychiatric disorders.Hence,more amenable to scientific scrutiny.

Declaration of interest:None
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Reaching Cells

Dr Peter John Gordon, Old Age Psychiatrist
09 February 2011

Reply to the Editorial: Questioning the ‘neuroprotective’ hypothesis:does drug treatment prevent brain damage in early psychosis or schizophrenia? By Joanna Moncrieff.

As an old age psychiatrist, you may not be surprised to know that neuroprotection is a matter that I willingly reconsider in light of advancing science. However I currently share Dr Moncrieff’s reading of theevidence: that it is premature to advocate that antipsychotic medications are neuroprotective.1 If this is indeed so, science must prove it, beforeit becomes rationale for intervention.

Like Dr Moncrieff, I do not argue against the appropriate use of antipsychotic medications, for so used they are our best treatment of suchsuffering. However, like aspirin 2, breast-feeding and rather many more recent examples under media focus, might medical science be adding to confusion by offering wisdom before supporting evidence is established? Weshould consider here that in March 2004, the Committee for Safety of Medicine advocated that risperidone and olanzapine, should not be used to treat psychotic symptoms in older patients with dementia as review had found that they caused a three-fold increase in the risk of stroke. 3

Dr Moncrieff is also surely correct to raise the far from invisible spectre of tardive dyskinesia. As for Lithium, well it may be neurotrophic4, and it is certainly a most effective mood stabiliser, but we must not forget that it is also potently nephrotic. As an old-age psychiatrist, I am very familiar with having to stop Lithium due to its effects on the kidney. It is anecdotal I know, but I have had many patients treated with lithium since early adulthood who have gone on to develop dementia.

Perhaps others reading this Editorial will have turned their thoughtsto antidepressants and the evidence that they are potentially neuroprotective ? 5 It was back in 2004 that Professor Reid of Aberdeen University published his paper New Cells, New Connections 6, revealing the relationship between stress and neurogenesis in the hippocampus. Perhaps I am alone, but I am bemused why such thoughtful research has not been made more of? Not least in that it offers a potential explanation of how one’s ‘early social landscape’ (formative relations and stresses) might account for later recurrent depression. Reid’s research here seems highly intuitive and pulls the swingometer back to the middle from the extremity of today’s neurodeterminism.

Having said all this, I am myself cynical that antidepressants are neuroprotective, even though some studies are now suggesting they can decrease both Alzheimer pathology and reverse memory impairment. 7 As many of such studies are based on rats administered paroxetine, perhaps weshould wait a little before offering antidepressants as ‘Parr’s life pills. ’8 Though at least I should be okay, as my hippocampus must be bursting with new neurons and considering such I can be confident that allI say here has the backing of brain like Einstein.

I shall not finish on that cynical note, just a cautionary one. Let our cells not over-reach in scientific conclusion until both good research, and time, reveal the whole story. Neuroprotection may be a truth, but surely science must prove such, before prescribing such an ‘optimiser.’ 9

1. Moncrieff, J; Questioning the ‘neuroprotective’ hypothesis: does drug treatment prevent brain damage in early psychosis or schizophrenia? The British Journal of Psychiatry (2011) 198: 85-87.

2. Barnett, H; Burrill, P; Iheanacho, I: Change Page: Don’t use aspirin for primary prevention of cardiovascular disease BMJ 340 (Published 21 April 2010)

3. Duff, G; Committe onSafety of Medicines; Atypical Antipsychotics and Stroke; 9th March 2004

4. Zhu, Z; Wang, Q; Han, B; William, C: Neuroprotective effect and cognitive outcome of chronic lithium on traumatic brain injury in mice; Brain Research Bulletin, Volume 83, Issue 5, 30 October 2010, Pages 272-277

5. Lloyd, A; Ferrier,N.I; Barber,R; Gholkar,A; Young,A.H; O’Brien,J: Hippocampal volume change in depression: late- and early-onset illness compared. The British Journal of Psychiatry, Jun 2004; 184: 488 - 495.

6. Reid, I.C; Stewart, C.A: Brain Plasticity and Antidepressant Treatments: New Cells, New Connections. Neurotoxicity Research, 2004, VOL.6(6). pp. 483-491

7. Bales, K.R; Paroxetine administration decreases AD-like pathology and reverses memory impairments in a transgenic model of Alzheimer disease. Experimental neurology 2007 (2007) 1-3

8. A corner of history: Preventive Medicine, Volume 1, Issue 4, December 1972, Pages 565-570

9. Brain Profiling Group: Damian, M; Kreis, M; Krumm, B; Hentschel, FOptimized neuropsychological procedures at different stages of dementia diagnostics. Journal of the Neurological Sciences , 229-230 , 95-101. (2005).
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