Antipsychotic medication and longitudinal changes in brain

volume in schizophrenia

- meta-analysis and results from the Northern Finland 1966 Birth Cohort Study

Jouko Miettunenjouko.miettunen@oulu.fi

Department of Psychiatry, University of Oulu, Finland

Conflicts of interest:None

Relatively little is known on factors associating with

longitudinal changes in brain morphometry in

schizophrenia after the illness onset.

Our aim was to systematically review longitudinal MRI

studies with at least two-year scan-interval on the

relation between the dose or type of antipsychotic

medication and brain morphometric changes in

schizophrenia and related psychoses.

SYSTEMATIC REVIEW AND META-ANALYSIS

decreases in grey matter and global brain volume and increments in cerebrospinal fluid (CSF) or ventricular volume during drug treatment

contradictory findings when comparing typical and atypical medications

basal ganglia volume increment after treatment with especially typical antipsychotics

have included also short follow-ups!

Previous reviews

Moncrieff & Leo (Psychol Med 2010); Navari & Dazzan (Psychol Med 2009); Smieskova et al. (Curr Pharm Des 2009); Shepherd et al. (Neurosci Biobehav Rev 2012); Fusar-Poli et al. (Neurosci Biobehav Rev 2013)

Studies were systematically collected using the

databases of PubMed, Scopus, Web of Knowledge,

and PsycINFO (1223 hits).

We calculated correlations between antipsychotic

dose and brain volume changes.

2-year scan-interval was required

Results reported only as “non-significant” were

also included (correlation = zero)

meta-analysis

brain regions (12)

total brain, cerebrum, frontal lobe, temporal lobe,

parietal lobe, occipital lobe, cerebellum, limbic

area, basal ganglia, pituitary gland, paracentral

lobule, and CSF and ventricles.

brain tissue types (4)

grey matter (GM), white matter (WM), CSF, and

volumes

meta-analysis

Sample (13 samples) follow-up

brain areas

Iowa Longitudinal Study, USA (FE: n=23-211) 2-7 years several areasWestmoreland Corson et al. 1999; Ho et al. 2003; McCormick et al. 2005; Ho et al. 2007; Ho et al. 2011Utrecht Schizophrenia Project, Netherlands (PT: n=90-105)

4.8 years several areas

van Haren et al. 2007, 2008, 2011; Collin et al. 2012    Prospective Longitudinal Study of Schizophrenia and the Mental Health Clinical Research Center, Iowa, USA (PT: n=14)

2.5 years caudate nucleus L/R

Heitmiller et al. 2004    Boston, MA, USA (PT: n=23) 2.9 years septum pellucidum, cavum septi

pellucidumDavidson et al. 2012    Chicago, IL, USA (PT: n=20) 2 years several areasCobia et al. 2012    Philadelphia, PA, USA (FE: n=20, PT: n=20) 2.6 years whole brain, CSF, frontal lobe,

temporal lobeGur et al. 1998    Melbourne, Australia (FE: n=23, PT: n=11) 2 years whole brain, long and short insular

cortex L/RTakahashi et al. 2009    Chiba, Japan (0.2 Tesla) (PT: n=15) 10 years lateral ventriclesSaijo et al. 2001    Toyama, Japan (FE: n=18-20) 2.7 years several areasTakahashi et al. 2010, 2011a, 2011b, 2013    Toyama, Japan (PT: n=17) 2.2 years pituitary glandTakahashi et al. 2012    Sibling-pair sample, Utrecht, Netherlands (PT: n=10)

5 years several areas

Brans et al. 2008    FE = first episode, PT = previously treated

Most (83%) of the reported correlations were statistically non-significant.

In the studies with significant findings, use of antipsychotics more often associated with decrease than increase of brain volumes, even in the very few studies taking into account illness severity.

meta-analysis

  studies random effect meta-analysis  n correlation (95%

CI)z test sign.

GM        - cerebrum 3 -0.02 (-0.30 - 0.27) 0.12 0.901WM        - cerebrum 3 0.04 (-0.07 - 0.16) 0.72 0.471CSF        - CSF and ventricles

4 0.00 (-0.11 - 0.11) 0.00 0.998

volume        - total 3 0.00 (-0.15 - 0.15) 0.00 >0.999- frontal lobe 5 -0.12 (-0.41 - 0.16) 0.86 0.389- temporal lobe

9 -0.02 (-0.14 - 0.10) 0.34 0.731

- cerebellum 3 0.03 (-0.08 - 0.14) 0.47 0.639         

meta-analysis by tissue type and brain area combinations

Cerebrum *** atypical dose associated with less progressive decrease of GM (Brans et al. 2008)* clozapine dose associated with reduction and typical and clozapine dose associated with reduction of GM (Ho et al. 2011)

Frontal lobe *** total dose associated with reduction in first episode patients (Gur et al. 1998)** clozapine associated with reduction of GM (Ho et al. 2011) and with increase of right superior and right and left medial frontal cortex (van Haren et al. 2011), non-clozapine atypical dose associated with increase of right medial frontal cortex (van Haren et al. 2011), and typical dose associated with reduction of left precentral cortex (van Haren et al. 2011)* total, typical and nonclozapine atypical dose associated with reduction of GM (Ho et al. 2011), olanzapine and clozapine increased volume in a cluster in superior frontal gyrys (van Haren et al. 2007)

Temporal lobe *** total dose associated with reduction in first episode patients (Gur et al. 1998), total and atypical dose associated with less reduction of right and left caudal superior temporal gyrys, total dose with less reduction of left planum temporale (Takahashi et al. 2010) and of whole fusiform gyrus (Takahashi et al. 2011b)** clozapine associated with decrease of GM (Ho et al. 2011)* total dose associated with decrease of GM (Ho et al. 2011)

Parietal lobe * total, clozapine and nonclozapine atypical dose associated with GM reduction and nonclozapine atypical dose with WM increment (Ho et al. 2011)

CSF and ventricles ^ clozapine correlated with reduction of sulcal CSF (Ho et al. 2011)Limbic system *** typical dose associated with increase and atypical and risperidone with decrease of anterior

cingulate cortex (McCormick et al. 2005)** clozapine associated with increase in right cingulate cortex (van Haren et al. 2011) * clozapine associated with decrease of thalamus (Ho et al. 2011)

Basal ganglia *** typical dose increased and atypical dose decreased globus pallidus (Westmoreland Corson et al. 1999), clozapine increased putamen (Ho et al. 2011)** typical dose increased putamen (Westmoreland Corson et al. 1999), total dose increased putamen (Ho et al. 2011)* clozapine decreased and nonclozapine atypical increased caudate volume, typical dose and nonclozapine atypical dose increased putamen (Ho et al. 2011), typical dose increased volume in selected voxels in caudate (van Haren et al. 2007)

***=large (r ≤ 0.5), **=moderate (0.3 ≤ r < 0.5), *=small (r > 0.1), ^=smaller than 0.1 correlation

Statistically significant findings

In performed meta-analyses of specific brain areas no significant associations were found.

We did not find any clear differences between typical and atypical exposure and brain volume change.

Studies focusing on first episode patients were more likely to find an effect than studies on previously treated patients.

In the studies with significant findings in grey matter, high antipsychotic dose was more frequently associated with decrease (27% of correlations) than with increase (10%).

meta-analysis

All members of the general population-based Northern Finland Birth Cohort 1966 with any psychotic disorder were invited for a MRI brain scan at the age of 34 years.

A follow-up was conducted on average 9 years later.

Brain scans at both time points were obtained from 33 subjects with schizophrenia.

Northern Finland 1966 Birth Cohort

scan-interval antipsychotic cumulative dose associated with total brain volume loss, even when adjusted with symptoms (beta =-0.43, p=0.018).

Veijola J, et al. ManuscriptSOFAS = Social and Occupational Functioning Assessment Scale, PANSS = Positive and Negative Syndrome Scale

Antipsychotic medication may contribute to changes in brain structure in some areas of the brain.

The current available data is inconclusive and therefore more good quality long-term follow-up studies are needed focusing on the possible association between antipsychotic medication and brain structures.

Covariates ?severity of illness, substance abuse, smoking, duration

of illnessCombine data sets ?

conclusions

Sanna Huhtaniska, BMed; Juha Veijola, prof.; Matti Isohanni, prof.; Erika Jääskeläinen, MScD; Jouko Miettunen, PhDDepartment of Psychiatry, Institute of Clinical Medicine, University of Oulu, Oulu, Finland & Department of Psychiatry, Oulu University Hospital, Oulu, FinlandNoora Hirvonen, MAInformation Studies, Faculty of Humanities, University of Oulu, Oulu, FinlandJukka Remes, MScDepartment of Diagnostic Radiology, Oulu University Hospital, Oulu, FinlandGraham K Murray, MScDDepartment of Psychiatry, University of Cambridge, Cambridge, UK

Email: jouko.miettunen@oulu.fi