Long-term Antipsychotic Treatment and Brain Volumes: A Longitudinal Study of First-Episode Schizophrenia | Psychiatry and Behavioral Health | JAMA Psychiatry | JAMA Network
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    3 Comments for this article
    Brain Volume Loss and Neuroleptics
    Lynn E. DeLisi, MD | VA Boston Healthcare System and Harvard Medical Schoolq
    I am writing to respond with some concerns about the recently published Ho et al study in the February 2011 issue of The Archives General Psychiatry.1 This manuscript concludes that antipsychotic medications have a "subtle, but measurable influence on brain tissue loss over time". This assertion is serious because of the implications it has for clinical practice whereby patients and their clinicians may conclude that it is no longer wise to stay on maintenance doses of antipsychotics, particularly after a first episode. It is also an unwise conclusion and misperception, given the confounds of the Ho et al. study, and based on other clear findings in the literature that support the notion that schizophrenia in a progressive brain disorder and that early treatment may be beneficial for attenuating this progression.2 The following are facts that these authors are overlooking: 1. Clear ventricular enlargement has been known to be present as evidenced by large pneumoencephalographic studies long before the widespread use of antipsychotic medication.3,4,5
    2. In an early longitudinal study showing brain volume loss in patients after a first episode of schizophrenia, we noted that those patients who had the most evidence of loss over as much as a 10-year follow-up tended to be non-compliant with medication.6,7,8
    3. Volume loss can already be detected at the first episode, even in treatment-naive patients.9
    4. Several more recent studies of people at genetic high-risk for schizophrenia and those in the prodromal stage10,11,12,13 prior to ever receiving neuroleptic medication, show clear structural brain changes, and longitudinal studies that have been completed indicate that some of these changes predict who develops a psychosis.14,15
    Thus, these four facts alone provide evidence for a cautionary note that should inform clinicians treating people who develop schizophrenia to still not hesitate to use neuroleptic medication and to continue medications long-term for the best possible clinical outcome. One also may wonder that if there were significant effects of neuroleptics on brain structural integrity, would not the FDA and pharmaceutical industry have noted this long ago and even more recently? The findings of Ho and colleagues are clearly not definitive and should not be taken in that context by clinicians.
    1. Ho BC, Andreasen NC, Ziebell S, Pierson R, Magnotta V. Long-term Antipsychotic Treatment and Brain Volumes: A Longitudinal Study of First- Episode Schizophrenia. Arch Gen Psychiatry. 2011; Feb;68(2):128-37.
    2. Borgwardt SJ, Dickey C, Hulshoff Pol H, Whitford TJ, DeLisi LE. Workshop on defining the significance of progressive brain change in schizophrenia: December 12, 2008 American College of Neuropsychopharmacology (ACNP) all-day satellite, Scottsdale, Arizona. The rapporteurs' report. Schizophrenia Research. 2009;112(1-3):32-45.PMID: 19477100.
    3. Jacobi W, Winkler H. Encephalographische studien an chronische schizophrenen. Arch Psychiatr Nervenkr. 1927; 81:299–332.
    4. Moore MD, Nathan AR, Elliot G, et al. Encephalographic studies in mental disease. Am J Psychiatry. 1935; 92:43–67.
    5. Huber G. Pneumoencephalographische und psychopathologische bilder bei endogen psychosen. Springer, Berlin, Germany: 1957.
    6. DeLisi LE, Grimson R, Sakuma M, Tew W, Kushner M, Hoff AL. Schizophrenia as a chronic active brain process: a study of progressive brain structural change subsequent to the onset of schizophrenia. Psychiatry Res: Neuroimaging. 1997; 74:129–140.
    7. DeLisi LE, Sakuma M, Maurizio A, Hoff AL. Cerebral ventricular change over the first 10 years after the onset of schizophrenia. Psychiatry Res; Neuroimaging. 2004; 130:57–70.
    8. DeLisi LE, Sakuma M, Kushner M. Association of brain structural change with the heterogeneous course of schizophrenia from early childhood through five years subsequent to a first hospitalization. Psychiatry Res: Neuroimaging. 1998;84:75–88.
    9. Jayakumar PN, Venkatasubramanian G, Gangadhar BN, Janakiramaiah N, Keshavan MS. Optimized voxel-based morphometry of gray matter volume in first-episode, antipsychotic-naïve schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2005; 29:587–591.
    10. Pantelis C, Yucel M, Wood SJ, Velakoulis D, Sun D, Berger G, Stuart GW, Yung A, Phillips L, McGorry PD. Structural brain imaging evidence for multiple pathological processes at different stages of brain development in schizophrenia. Schizophr Bull. 2005; 31:672–696.
    11. DeLisi LE, Szulc KU, Bertisch H, Majcher M, Brown K, Bappal A, Branch CA, Ardekani BA.. Early detection of schizophrenia by diffusion weighted imaging. Psychiatry Res: Neuroimaging. 2006;148:61–66.
    12. Hoptman MJ, Nierenberg J, Bertisch HC, Catalano D, Ardekani BA, Branch CA, Delisi LE. A DTI study of white matter microstructure in individuals at high genetic risk for schizophrenia. Schizophrenia Research. 2008;106(2-3):115-24. PMID: 18804959.
    13. Takahashi T, Wood SJ, Yung AR, Walterfang M, Phillips LJ, Soulsby B, Kawasaki Y, McGorry PD, Suzuki M, Velakoulis D, Pantelis C. Superior temporal gyrus volume in antipsychotic-naive people at risk of psychosis. Br J Psychiatry. 2010 Mar;196:206-11. Erratum in: Br J Psychiatry. 2010; 196:333. PMID: 20194543.
    14. McIntosh AM, Owens DC, Moorhead WJ, Whalley HC, Stanfield AC, Hall J, Johnstone EC, Lawrie SM.Longitudinal Volume Reductions in People at High Genetic Risk of Schizophrenia as They Develop Psychosis. Biol Psychiatry. 2010 Dec 16.PMID: 21168123.
    15. Sun D, Phillips L, Velakoulis D, Yung A, McGorry PD, Wood SJ, van Erp TG, Thompson PM, Toga AW, Pantelis C. Progressive brain structural changes mapped as psychosis develops in "at risk" individuals. Schizophrenia Research. 2009; 108(1-3): 85-92. PMID: 19138834.

    Conflict of Interest: None declared
    On the benefits of antipsychotics in schizophrenia
    Paul Hutton, MA (Hons) ClinPsyD | Greater Manchester West Mental Health NHS Foundation Trust
    In a long-awaited publication, Ho and colleagues (2011)1 report that antipsychotic use in schizophrenia is associated with a progressive reduction in cortical tissue. Both Ho et al and Lewis (2011)2 argue the risks must be weighed against the benefits. This raises several questions.
    First, what are the benefits? One Cochrane review published last year (to little fanfare) found the multi-billion dollar drug risperidone to be not much better than placebo,3 describing the evidence for its effectiveness as “unconvincing”. Another found little evidence to suggest antipsychotics were better than benzodiazepenes.4 A meta-analysis by Leucht and colleagues, published in 2009, found
    only a moderate superiority of atypicals over placebo,5 but 18 of the 38 included studies were missing over half their outcome data. In most cases this data was replaced by using the now discredited6 approach of carrying last observation forward; an approach likely to bias outcomes in favour of the active treatment when fewer people leave active treatment early (a well- observed finding in antipsychotic trials but not necessarily attributable to antipsychotic efficacy). A recent survey found consultant psychiatrists, carers and Cochrane researchers agreed that trials with over 25% missing data “lack credibility”7 - only 5 comparisons from 4 trials (none of which were long-tem) included in Leucht et al met this criterion, three of which showed no benefit of antipsychotics over placebo. An interesting meta-regression found the superiority of antipsychotics over placebo diminishes as the probability of being randomised to placebo decreases,8 a finding consistent with the hypothesis that expectancy and unblinding due to side-effects leads to inflated estimates of drug effectiveness.9 Similar results have been found for trials of antidepressants in depression,10 where a Cochrane review found effect sizes to be much lower in trials which use active placebos to hide the giveaway side-effects of these drugs.11
    Indeed, Harrow & Jobe (2007)12 found that people with a schizophrenia diagnosis who chose not to take antipsychotics had better long-term functioning than those who did. An editorial in this months British Journal of Psychiatry convincingly rebutts the claim that antipsychotics have neuroprotective properties,13 while a recent neuroimaging study found that haloperidol given to healthy volunteers produced the fastest (reversible) reduction in brain volume ever seen.14 Furthermore, a prescient meta-analysis found that brain changes normally attributed to schizophrenia may in fact be caused by antipsychotic use15 while Vinogradov et al., (2009)16 reported that greater anticholinergic burden (due to antipsychotics and other psychotropic medications) is associated with a poorer response to intensive computerised cognitive training. Given the above, is it now time for a systematic reappraisal of the benefits of these drugs?
    Second, who will be in charge of weighing the risks and benefits? Are psychiatrists going to routinely discuss the dose-related non-trivial risk of sudden cardiac death17 and progressive loss of cortical tissue associated with these drugs with service users who retain treatment decision-making capacity (i.e., the majority)? Even if tissue loss is evidence of benefit, are service users going to be encouraged to decide if they want to wager their cortical tissue on this being true? Given 74% of service users discontinue antipsychotic medication over 18 months,18 are their psychiatrists also going to inform them that around 5 will need treatment for 1 to have a clinically significant improvement above placebo, as claimed by Leucht et al?
    Finally, in her New York Times interview* , Professor Andreasen argued the findings implied there was a need for greater use of cognitive and social therapies (interventions which appear to be highly acceptable to most service users19). This recommendation is missing from Ho et al but are they willing to make it now?
    *http://www.nytimes.com/2008/09/16/health/research/16conv.html, accessed 13th February, 2011.
    (1) Ho, B., Andreasen, N. C., Ziebell, S., Pierson, R., & Magnotta, V. Long-term antipsychotic treatment and brain volume: A longitudinal study of first-episode schizophrenia. Archives of General Psychiatry, 68, 2, 128-137.
    (2) Lewis, D. A. (2011). Antipsychotics and brain volume: Do we have cause for concern? Archives of General Psychiatry, 68, 2, 126-127.
    (3) Rattehalli, R. D., Jayarami, M. B. & Smith, M. (2010). Risperidone versus placebo for schizophrenia. Cochrane Database of Systematic Reviews 1. (http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD006918/pdf_fs.html). Accessed 4th April 2010
    (4) Volz A, Khorsand V, Gillies D, Leucht S. Cochrane Database of Systematic Reviews 2007; 1. Benzodiazepines for schizophrenia. (http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD000967/pdf_fs.html). Accessed 4th April 2010
    (5) Leucht, S., Arbter, D., Engel, R. R., Kissling, W. & Davis, J. M. (2009a). How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Molecular Psychiatry 14, 429- 447.
    (6) Hamer RM, Simpson PM. Last observation carried forward versus mixed models in the analysis of psychiatric clinical trials (Editorial). American Journal of Psychiatry 2009; 16: 639-641.
    (7) Xia J, Adams C, Bhagat N, Bhagat V, Bhoopathi P, El-Sayeh H, Pinfold V, Takriti Y. Losing participants before the end of the trial erodes credibility of findings. Psychiatr Bull 2009; 33: 254-257
    (8) Mallinckrodt, C. H., Zhang, L., Prucka W. R., & Millen, B. A. (2010). Signal Detection and Placebo Response in Schizophrenia: Parallels with Depression. Psychopharmacology Review, 43, 1, 53-72.
    (9) Colagiuri B. (2010). Participant expectancies in double-blind randomized placebo-controlled trials: potential limitations to trial validity. Clin Trials, 7, 246-255.
    (10) Papakostas, G. I., & Fava, M. (2009). Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD. European Neuropsychopharmacology, 19, 34-40.
    (11) Moncrieff, J., Wessely, S., & Hardy, R. (2004). Active placebos versus antidepressants for depression. Cochrane Database of Systematic Reviews 2004; 1. (http://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD003012/pdf_fs.html). Accessed 13th February 2011.
    (12) Harrow, M., & Jobe, T. H. (2007). Factors involved in outcome and recovery in schizopohrenia patients not on antipsychotic medications: A 15-year follow-up study. Journal of Nervous and Mental Disease, 195, 5, 406-414.
    (13) Moncrieff, J. (2011). Questioning the ‘neuroprotective’ hypothesis: does drug treatment prevent brain damage in early psychosis or schizophrenia? (Editorial).British Journal of Psychiatry, 198, 85-87.
    (14) Tost, H., Braus, D. F., Hakimi, S., Ruf, M., Vollmert, C., Hohn, F., & Meyer-Lindenberg, A. (2010). Acute D2 receptor blockade induces rapid, reversible remodeling in human cortical-striatal circuits. Nature Neuroscience, 13, 920-922.
    (15) Moncrieff J, Leo J. (2010). A systematic review of the effects of antipsychotic drugs on brain volume. Psychological Medicine, 40, 1409 –22.
    (16) Vinogradov, S., Fisher, M., Warm, H., Holland, C., Kirshner, M. A., & Pollock, B. G. (2009). The cognitive cost of anticholinergic burden: Decreased response to cognitive training in schizophrenia. American Journal of Psychiatry, 166,1055-1062.
    (17) Ray, W. A., Chung, C. P., Murray, K. T., Hall, K. & Stein, M. (2009). Atypical anstipsychotics drugs and the risk of sudden cardiac death. The New England Journal of Medicine 360, 225-235.
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    Conflict of Interest: I am a research clinical psychologist within the UK National Health Service (NHS). I provide psychological treatments to people experiencing psychosis within the context of various research trials, all of which are NHS-funded. One of these trials involves the provision of cognitive behavioural therapy to people who are experiencing psychosis yet have refused or declined antipsychotic medication for a period of at least 6 months (http://www.controlled-trials.com/ISRCTN29607432). I have received no financial renumeration from pharmaceutical companies.
    Brain volume decline in first-episode schizophrenics
    John J. Mooney, MD | Beth Israel Deaconess Medical Center, Boston MA,
    Ho et al.1 have reported that longer-term treatments with antipsychotics were associated with smaller total cerebral volumes, as well as reductions in specific brain regions. Ho et al1 have suggested that antipsychotics have direct effects on brain tissue in causing such changes. However this report does not specify whether or not all subjects receiving antipsychotics had reductions in brain volume, even though the mean change for the drug-treated cohort was in the direction of shrinkage. Perhaps there is a subsample of individuals who did not experience gray and white matter decline, offset by another subsample who show large losses in brain volume. If so, then a subsequent comparison of those who show the loss of volume with those who did not would provide a clue as to vulnerability to shrinkage of brain volume.
    We also wish to draw attention to another potential contributing factor, namely overweight/obesity, which are risks of long-term antipsychotic use in many patients. Debette et al2 have observed that the accumulation of visceral fat is associated with lower brain volumes in healthy middle-aged adults (n=733), and Debette et al2 cite smaller studies also reporting similar reductions in global brain volumes in younger obese populations. Can Ho et al1 identify any role or influence of overweight/obesity in their reported outcomes of long-term antipsychotic treatments on brain volume?
    Carl Salzman MD, John J. Mooney MD
    1. Ho B-C, Andreasen NC, Ziebell S, Pierson R, Magnotta V. Long-term antipsychotic treatment and brain volumes. A longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry 2011; 68: 128-137.
    2. Debette S, Beiser A, Hoffman U, DeCarli C, O'Donnell CJ, Massaro JM, Au R, Himali JJ, Wolf PA, Fox CS, Seshadri S. Visceral fat is associated with lower brain volume in healthy middle-aged adults. Ann Neurol 2010; 68: 136-144.

    Conflict of Interest: None declared
    Original Article
    February 7, 2011

    Long-term Antipsychotic Treatment and Brain Volumes: A Longitudinal Study of First-Episode Schizophrenia

    Author Affiliations

    Author Affiliations: Departments of Psychiatry (Drs Ho and Andreasen and Messrs Ziebell and Pierson) and Radiology (Dr Magnotta), University of Iowa Carver College of Medicine, Iowa City.

    Arch Gen Psychiatry. 2011;68(2):128-137. doi:10.1001/archgenpsychiatry.2010.199

    Context  Progressive brain volume changes in schizophrenia are thought to be due principally to the disease. However, recent animal studies indicate that antipsychotics, the mainstay of treatment for schizophrenia patients, may also contribute to brain tissue volume decrement. Because antipsychotics are prescribed for long periods for schizophrenia patients and have increasingly widespread use in other psychiatric disorders, it is imperative to determine their long-term effects on the human brain.

    Objective  To evaluate relative contributions of 4 potential predictors (illness duration, antipsychotic treatment, illness severity, and substance abuse) of brain volume change.

    Design  Predictors of brain volume changes were assessed prospectively based on multiple informants.

    Setting  Data from the Iowa Longitudinal Study.

    Patients  Two hundred eleven patients with schizophrenia who underwent repeated neuroimaging beginning soon after illness onset, yielding a total of 674 high-resolution magnetic resonance scans. On average, each patient had 3 scans (≥2 and as many as 5) over 7.2 years (up to 14 years).

    Main Outcome Measure  Brain volumes.

    Results  During longitudinal follow-up, antipsychotic treatment reflected national prescribing practices in 1991 through 2009. Longer follow-up correlated with smaller brain tissue volumes and larger cerebrospinal fluid volumes. Greater intensity of antipsychotic treatment was associated with indicators of generalized and specific brain tissue reduction after controlling for effects of the other 3 predictors. More antipsychotic treatment was associated with smaller gray matter volumes. Progressive decrement in white matter volume was most evident among patients who received more antipsychotic treatment. Illness severity had relatively modest correlations with tissue volume reduction, and alcohol/illicit drug misuse had no significant associations when effects of the other variables were adjusted.

    Conclusions  Viewed together with data from animal studies, our study suggests that antipsychotics have a subtle but measurable influence on brain tissue loss over time, suggesting the importance of careful risk-benefit review of dosage and duration of treatment as well as their off-label use.