Arch Gen Psychiatry -- On the benefits of antipsychotics in schizophrenia

[Guest guest]

http://archpsyc.ama-assn.org/cgi/eletters/68/2/128#14060

On the benefits of antipsychotics in schizophrenia

February 22, 2011



Hutton,

MA (Hons) ClinPsyD

Greater Manchester West Mental Health NHS Foundation Trust

Send reply to journal:

Re: On the benefits of antipsychotics in schizophrenia

E-mail Hutton

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 (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

“unconvincingâ€. 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

credibilityâ€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 sen 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.

References

(1) Ho, B., sen, 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) , 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. & , M. (2010). Risperidone versus

placebo for schizophrenia. Cochrane Database of Systematic Reviews 1.

(http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD006918/pdf_fs.ht\

ml). 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.ht\

ml). Accessed 4th April 2010

(5) Leucht, S., Arbter, D., Engel, R. R., Kissling, W. & , 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, 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.htm\

l). 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.

(18) Lieberman. J. A., Stroup, S., McEvoy, J. P., Swartz, M. S., Rosenheck, R.

A., Perkins, D. O., Keefe, R. S. E., , S. M., , C. E., Lebowitz, B.

D., Severe, J., Hsiao, J. K. (2005). Clinical Antipsychotic Trials of

Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic

drugs in patients with chronic schizophrenia. New England Journal of Medicine,

353, 1209-1223.

(19) Villeneuve, K., Potvin, S., Lesage, A., & , L. (2010). Meta-analysis

of rates of drop-out from psychosocial treatment among persons with

schizophrenia spectrum disorder. Schizophrenia Research, 121, 266-270.

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.

Sent via BlackBerry by AT & T

[Guest guest]

http://archpsyc.ama-assn.org/cgi/eletters/68/2/128#14060

On the benefits of antipsychotics in schizophrenia

February 22, 2011



Hutton,

MA (Hons) ClinPsyD

Greater Manchester West Mental Health NHS Foundation Trust

Send reply to journal:

Re: On the benefits of antipsychotics in schizophrenia

E-mail Hutton

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 (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

“unconvincingâ€. 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

credibilityâ€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 sen 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.

References

(1) Ho, B., sen, 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) , 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. & , M. (2010). Risperidone versus

placebo for schizophrenia. Cochrane Database of Systematic Reviews 1.

(http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD006918/pdf_fs.ht\

ml). 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.ht\

ml). Accessed 4th April 2010

(5) Leucht, S., Arbter, D., Engel, R. R., Kissling, W. & , 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, 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.htm\

l). 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.

(18) Lieberman. J. A., Stroup, S., McEvoy, J. P., Swartz, M. S., Rosenheck, R.

A., Perkins, D. O., Keefe, R. S. E., , S. M., , C. E., Lebowitz, B.

D., Severe, J., Hsiao, J. K. (2005). Clinical Antipsychotic Trials of

Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic

drugs in patients with chronic schizophrenia. New England Journal of Medicine,

353, 1209-1223.

(19) Villeneuve, K., Potvin, S., Lesage, A., & , L. (2010). Meta-analysis

of rates of drop-out from psychosocial treatment among persons with

schizophrenia spectrum disorder. Schizophrenia Research, 121, 266-270.

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.

Sent via BlackBerry by AT & T

[Guest guest]

http://archpsyc.ama-assn.org/cgi/eletters/68/2/128#14060

On the benefits of antipsychotics in schizophrenia

February 22, 2011



Hutton,

MA (Hons) ClinPsyD

Greater Manchester West Mental Health NHS Foundation Trust

Send reply to journal:

Re: On the benefits of antipsychotics in schizophrenia

E-mail Hutton

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 (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

“unconvincingâ€. 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

credibilityâ€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 sen 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.

References

(1) Ho, B., sen, 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) , 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. & , M. (2010). Risperidone versus

placebo for schizophrenia. Cochrane Database of Systematic Reviews 1.

(http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD006918/pdf_fs.ht\

ml). 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.ht\

ml). Accessed 4th April 2010

(5) Leucht, S., Arbter, D., Engel, R. R., Kissling, W. & , 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, 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.htm\

l). 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.

(18) Lieberman. J. A., Stroup, S., McEvoy, J. P., Swartz, M. S., Rosenheck, R.

A., Perkins, D. O., Keefe, R. S. E., , S. M., , C. E., Lebowitz, B.

D., Severe, J., Hsiao, J. K. (2005). Clinical Antipsychotic Trials of

Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic

drugs in patients with chronic schizophrenia. New England Journal of Medicine,

353, 1209-1223.

(19) Villeneuve, K., Potvin, S., Lesage, A., & , L. (2010). Meta-analysis

of rates of drop-out from psychosocial treatment among persons with

schizophrenia spectrum disorder. Schizophrenia Research, 121, 266-270.

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.

Sent via BlackBerry by AT & T

[Guest guest]

http://archpsyc.ama-assn.org/cgi/eletters/68/2/128#14060

On the benefits of antipsychotics in schizophrenia

February 22, 2011



Hutton,

MA (Hons) ClinPsyD

Greater Manchester West Mental Health NHS Foundation Trust

Send reply to journal:

Re: On the benefits of antipsychotics in schizophrenia

E-mail Hutton

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 (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

“unconvincingâ€. 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

credibilityâ€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 sen 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.

References

(1) Ho, B., sen, 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) , 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. & , M. (2010). Risperidone versus

placebo for schizophrenia. Cochrane Database of Systematic Reviews 1.

(http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD006918/pdf_fs.ht\

ml). 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.ht\

ml). Accessed 4th April 2010

(5) Leucht, S., Arbter, D., Engel, R. R., Kissling, W. & , 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, 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.htm\

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(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.

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(16) Vinogradov, S., Fisher, M., Warm, H., Holland, C., Kirshner, M. A., &

Pollock, B. G. (2009). The cognitive cost of anticholinergic burden: Decreased

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(17) Ray, W. A., Chung, C. P., Murray, K. T., Hall, K. & Stein, M. (2009).

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England Journal of Medicine 360, 225-235.

(18) Lieberman. J. A., Stroup, S., McEvoy, J. P., Swartz, M. S., Rosenheck, R.

A., Perkins, D. O., Keefe, R. S. E., , S. M., , C. E., Lebowitz, B.

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(19) Villeneuve, K., Potvin, S., Lesage, A., & , L. (2010). Meta-analysis

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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.

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