The effect of atypical antipsychotics on brain N-acetylaspartate levels in antipsychotic-naïve first-episode patients with schizophrenia: a preliminary study

Figures & data

Table 1 Review of previous studies

Author	Antipsychotics	Duration	Methods	Main results
Steen et al (2006)^Citation8	Drug naïve		Systematic review and meta-analysis	Whole brain and hippocampal volume were reduced
Fannon et al (2003)^Citation9	Haloperidol, olanzapine, risperidone	3 months	First-episode, ^1H MRS, NAA/Cr, antipsychotics at baseline and after 3 months	A significant reduction in hippocampal NAA/Cr
Bustillo et al (2008)^Citation10	Haloperidol, quetiapine	2 years	^1H MRS, frontal and occipital lobes, caudate nucleus, and cerebellum	Typical or atypical antipsychotics did not result in NAA changes
Lieberman et al (2005)^Citation11	Haloperidol, olanzapine	104 weeks	^1H MRS assessments performed at weeks 0, 12, 24, 52, and 104	Haloperidol had significant decreases in gray matter volume; olanzapine did not
Lindquist et al (2000)^Citation12	Haloperidol, clozapine, olanzapine	1 week	In vivo ^1H MRS, 4.7 T (animals)	No significant changes in NAA/Cr
Bustillo et al (2004)^Citation13	Haloperidol, clozapine	6 weeks	Three groups treated with antipsychotics or vehicle/6 weeks. NAA were determined by HPLC (animals)	No differences in NAA in cortex, striatum, and thalamus compared to animals treated with vehicle
Harte et al (2005)^Citation14	Haloperidol decanoate	24 weeks	Measured NAA in brain tissue taken from 43 males	NAA increased in the striatum
McLoughlin et al (2009)^Citation15	Haloperidol, clozapine, olanzapine, risperidone, aripiprazole		Metabolites were determined using ^1H MRS	Antipsychotics, with the exception of olanzapine, consistently increased NAA levels in at least one brain area
Bustillo et al (2006)^Citation16	Haloperidol decanoate	6 months	^1H MRS at 11.7 T in ex vivo, medial frontal and cingulate cortex, striatum, nucleus accumbens, dorsal and ventral hippocampus, amygdala, and temporal cortex (animals)	Did not result in changes in NAA, glutamate, glutamine, and other metabolites in the proton spectrum
Lindquist et al (2011)^Citation17	Haloperidol, clozapine	6 months	^1H MRS, 6 months, NAA, Cr, and Cho (animals)	Only the Cho/Cr ratio showed a significant time-by-treatment effect
Bertolino et al (2001)^Citation18	Clozapine, risperidone, haloperidol, fluphenazine, trifluoperazine, olanzapine, thiothixene, mesoridazine		^1H MRS studied twice, DLPFC	Patients on antipsychotics had significantly higher NAA measures in the DLPFC
Bustillo et al (2010)^Citation19	Quetiapine, risperidone, haloperidol, clozapine	12 months	^1H MRS of the AC, frontal white matter, and thalamus at 4 T. NAA, Glu, Gln, and Gln/Glu	NAA reductions and correlated elevations of Gln/Glu in the AC are present early in schizophrenia
Braus et al (2002)^Citation20	Traditional neuroleptics and atypical antipsychotics		NAA was closely correlated with perseveration errors seen on the WCST	Atypical antipsychotics modify the function of anterior cingulate neurons (improve cognitive function)
Bustillo et al (2001)^Citation21	Haloperidol, clozapine		Treated patients and normal controls, ^1H MRS of the caudate nuclei and the left frontal lobe	Exposure to haloperidol led to frontal NAA reductions previously reported in schizophrenia
Szulc et al (2007)^Citation22	Perphenazine, perazine, haloperidol, clozapine, olanzapine, risperidone		^1H MRS, voxels of 2×2×2 cm, left frontal, left temporal lobe, and left thalamus	Decrease in NAA due to typical medication may be caused by the progression of the disease, previous drug history, or by drugs
Yeo et al (2000)^Citation23			^1H MRS, right frontal white matter, visual two-back test assessed working memory	Cr and NAA positively correlated with working memory skills
Valenzuela et al (2000)^Citation24			NAA, frontal subcortical white matter, and the occipitoparietal gray matter correlated with performance in different cognitive domains	Neurometabolic fitness of the frontal subcortical–cortical axonal fibers may be important in mediating fluid intellectual processing
Bertolino et al (2003)^Citation25			Subjects underwent ^1H MRS and were given the N-back working memory test	Reductions of NAA in the hippocampal area and DLPFC, positive correlation between NAA in the DLPFC and performance during the two-back working memory condition
Bertolino et al (2000)^Citation26			^1H MRS, NAA, and PET during performance of the WCST	NAA in the DLPFC strongly correlated with activation of the distributed working memory network
Tanaka et al (2006)^Citation27			^1H MRS, left frontal lobe in 14 patients with schizophrenia and in 13 healthy comparison subjects	Decreased NAA in the left frontal lobe of patients was correlated with negative symptoms and cognitive dysfunction
Bracken et al (2013)^Citation28			^1H MRS reporting measurements of NAA in schizophrenia with focus of methodology	Lower NAA more likely to have used longer echo times (TEs), while studies with shorter TEs reported no change
Reid et al (2013)^Citation29			^1H MRS to quantify levels of NAA, Glu, Glx, and Cho in the left substantia nigra	No differences in levels of NAA/Cr, Glx/Cr, or Cho/Cr between the groups. Significant correlation between Glx/Cr and overall cognitive performance
Szulc et al (2013)^Citation30			Reviewed 27 studies, 16 before/after treatment and 11 cross-sectional about antipsychotics in schizophrenia and NAA alterations	Antipsychotics may act by increasing NAA levels in selected brain areas (frontal lobe and thalamus), especially during the short-time observation
Szulc et al (2012)^Citation31			PANSS, CGI, WCST, TMT, verbal fluency test, and ^1H MRS were performed. Regions: left frontal, temporal, thalamus. Metabolites: NAA, Cho, myo-inositol, Glx	Correlation between WCST, negative symptoms score, education level, and myo-inositol ratio in the frontal lobe; role of the thalamus “transmission station” for psychopathology development (especially negative) in schizophrenia

Abbreviations: ¹H MRS, proton magnetic resonance spectroscopy; AC, anterior cingulate; CGI, Clinical Global Impression Scale; Cho, choline; Cr, creatine; DLPFC, dorsolateral prefrontal cortex; Gln, glutamine; Glu, glutamate; Glx, glutamine plus glutamate; HPLC, high-performance liquid chromatography; NAA, N-acetylaspartate; PANSS, Positive and Negative Syndrome Scale; PET, positron emission tomography; TMT, Trail Making Test; WCST, Wisconsin Card Sorting Test; T, Tesla; N-back, N-back working memory test.

Figure 1 A typical ¹H spectrum and the spectroscopic volume of interest: left dorsolateral prefrontal cortical region.

Note: Image from an outpatient of Polyclinic Neuron, Croatian Institute for Brain Research (Zagreb, Croatia).

Table 2 Sociodemographic characteristics of the two investigated groups

	More than one antipsychotic N=15					One antipsychotic N=10					P-value
	Mean	SD	Percentiles			Mean	SD	Percentiles
			25th	50th (median)	75th			25th	50th (median)	75th
Age, years	25.00	3.25	22.00	25.00	28.00	26.10	3.00	23.00	26.00	29.0	0.402
Education, years	11.93	0.70	12.00	12.00	12.00	12.80	1.87	11.75	12.00	14.50	0.330
Duration of disease, months	23.73	14.71	11.00	21.00	38.00	24.90	7.50	18.75	24.00	27.50	0.560
Male sex: n (%)*	12 (80%)					8 (80%)					0.610

Note:

* P<0.05.

Abbreviations: SD, standard deviation; N, number of patients.

Table 3 Differences in measured values found across the group taking more than one antipsychotic drug (N=15) – Wilcoxon test

	Minimum	Maximum	25th percentile	Median	75th percentile
PANSS positive 0*	12.00	28.00	13.00	17.00	19.00
PANSS positive 12*	8.00	15.00	10.00	11.00	13.00
PANSS negative 0	12.00	31.00	20.00	21.00	26.00
PANSS negative 12	16.00	27.00	17.00	21.00	22.00
PANSS general 0*	28.00	55.00	30.00	33.00	37.00
PANSS general 12*	23.00	34.00	28.00	31.00	33.00
PANSS total 0*	59.00	114.00	65.00	72.00	81.00
PANSS total 12*	49.00	75.00	57.00	62.00	69.00
CGI-S 0*	3.00	5.00	3.00	4.00	5.00
CGI-S 12*	1.00	4.00	2.00	2.00	3.00
TOL DX 0	15.00	65.00	30.00	34.00	53.00
TOL DX 12	4.00	84.00	27.00	35.00	55.00
LN 0*	9.00	15.00	11.00	12.00	13.00
LN 12*	13.00	22.00	18.00	19.00	22.00
TMT-A 0	28.00	111.00	41.00	64.00	76.00
TMT-A 12	34.00	85.00	45.00	51.00	61.00
PSP 0*	45.00	80.00	55.00	60.00	70.00
PSP 12*	63.00	84.00	68.00	73.00	76.00
NAA/Cr 0*	1.280	2.690	1.570	1.850	2.010
NAA/Cr 12*	1.240	2.710	1.370	1.700	1.770

Note:

* P<0.05.

Abbreviations: CGI-S, Clinical Global Impression of Severity; Cr, creatinine; LN, Letter–Number Span Test; NAA, N-acetylaspartate; PANSS, Positive and Negative Syndrome Scale; PSP, Personal and Social Performance Scale; TMT-A, Trail Making Test A; TOL DX, Tower of London – Drexel University.

Table 4 Differences in measured values found across the group sticking to the same antipsychotic drug throughout the study course (N=10) – Wilcoxon test

	Minimum	Maximum	25th percentile	Median	75th percentile
PANSS positive 0*	13.00	21.00	15.25	16.50	18.25
PANSS positive 12*	7.00	17.00	8.50	10.00	13.00
PANSS negative 0*	17.00	29.00	20.00	23.50	25.50
PANSS negative 12*	16.00	27.00	17.00	21.00	22.25
PANSS general 0	27.00	44.00	29.00	33.50	40.50
PANSS general 12	24.00	42.00	28.75	30.50	33.50
PANSS total 0*	60.00	85.00	64.00	77.00	83.00
PANSS total 12*	53.00	80.00	54.00	62.00	67.00
CGI-S 0*	3.00	5.00	3.00	4.00	5.00
CGI-S 12*	1.00	4.00	2.00	3.00	3.00
TOL DX 0	23.00	55.00	30.00	41.50	49.00
TOL DX 12	7.00	78.00	15.00	24.50	58.00
LN 0*	4.00	17.00	8.00	10.00	12.00
LN 12*	15.00	21.00	17.00	18.50	19.00
TMT-A 0	38.00	109.00	44.00	66.00	83.00
TMT-A 12	37.00	81.00	43.00	51.00	72.00
PSP 0*	45.00	65.00	51.00	54.00	65.00
PSP 12*	57.00	78.00	64.00	70.50	75.00
NAA/Cr 0*	1.360	2.100	1.620	1.685	1.820
NAA/Cr 12*	1.640	2.590	1.880	1.925	2.180

Note:

* P<0.05.

Abbreviations: CGI-S, Clinical Global Impression of Severity; Cr, creatinine; LN, Letter–Number Span Test; NAA, N-acetylaspartate; PANSS, Positive and Negative Syndrome Scale; PSP, Personal and Social Performance Scale; TMT-A, Trail Making Test A; TOL DX, Tower of London – Drexel University.

Table 5 Spearman’s correlation coefficients (rho) between functional outcome and NAA/Cr level at the beginning of the study and after 12 months

		More than one antipsychotic N=15		One antipsychotic N=10
		0 NAA/Cr	12 NAA/Cr	0 NAA/Cr	12 NAA/Cr
PANSS positive 0	rho	0.032	0.327	−0.414	−0.549
	P-value	0.908	0.234	0.235	0.100
PANSS negative 0	rho	0.081	0.263	−0.079	−0.341
	P-value	0.774	0.343	0.828	0.334
PANSS general 0	rho	−0.110	−0.017	0.188	−0.316
	P-value	0.696	0.952	0.602	0.374
PANSS total 0	rho	0.105	0.288	0.079	−0.394
	P-value	0.708	0.298	0.829	0.260
HAM-D 0	rho	0.229	0.015	0.748	0.056
	P-value	0.412	0.958	0.013	0.878
SAS 0	rho	0.193	0.025	0.108	0.362
	P-value	0.491	0.929	0.766	0.304
CGI-S 0	rho	−0.040	0.104	−0.360	−0.809
	P-value	0.888	0.713	0.307	0.005
TOL DX 0	rho	−0.509	−0.195	0.207	0.286
	P-value	0.053	0.485	0.567	0.424
LN 0	rho	−0.112	−0.068	−0.171	0.250
	P-value	0.692	0.810	0.637	0.486
TMT-A 0	rho	−0.179	0.159	−0.418	−0.673
	P-value	0.524	0.571	0.229	0.033
PSP 0	rho	−0.169	−0.337	0.148	0.412
	P-value	0.547	0.219	0.684	0.236
PANSS positive 12	rho	−0.522	−0.422	0.233	−0.098
	P-value	0.046	0.118	0.517	0.787
PANSS negative 12	rho	−0.250	−0.180	0.068	−0.006
	P-value	0.368	0.520	0.853	0.987
PANSS general 12	rho	−0.392	−0.146	0.091	0.006
	P-value	0.148	0.602	0.802	0.987
PANSS total 12	rho	−0.411	−0.202	0.245	−0.043
	P-value	0.128	0.470	0.496	0.907
HAM-D 12	rho	0.113	0.598	0.443	0.117
	P-value	0.687	0.019	0.200	0.748
SAS 12	rho	−0.148	−0.062	−0.007	0.052
	P-value	0.600	0.825	0.984	0.886
CGI-S 12	rho	0.200	0.108	0.658	−0.111
	P-value	0.474	0.702	0.039	0.761
CGI-I 12	rho	0.080	0.068	0.623	−0.159
	P-value	0.776	0.810	0.054	0.661
TOL DX 12	rho	−0.586	−0.265	0.248	0.188
	P-value	0.022	0.341	0.489	0.603
LN 12	rho	0.385	0.617	0.228	0.426
	P-value	0.156	0.014	0.526	0.220
TMT-A 12	rho	−0.497	−0.023	−0.012	−0.480
	P-value	0.059	0.934	0.973	0.160
PSP 12	rho	0.136	0.020	−0.134	0.146
	P-value	0.628	0.944	0.713	0.688

Abbreviations: CGI-I, Clinical Global Impression of Improvement; CGI-S, Clinical Global Impression of Severity; Cr, creatinine; HAM-D, Hamilton Depression Rating Scale; LN, Letter–Number Span Test; NAA, N-acetylaspartate; PANSS, Positive and Negative Syndrome Scale; PSP, Personal and Social Performance Scale; SAS, Simpson–Angus Scale; TOL DX, Tower of London – Drexel University; TMT-A, Trail Making Test A.

Figure 2 Comparison of NAA/Cr levels between two groups that had more than one antipsychotic, or had one antipsychotic.

Notes: (A) Both groups showed improvement in total PANSS score. (B) In the drug-changing group, the NAA/Cr ratio decreased; however, in the group sticking to the same antipsychotic drug, the NAA/Cr ratio increased after 12 months.
Abbreviations: Cr, creatinine; NAA, N-acetylaspartate; PANSS, Positive and Negative Syndrome Scale.

SteenRGMullCMcClureRHamerRMLiebermanJABrain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studiesBr J Psychiatry200618851051816738340

 PubMed Web of Science ®Google Scholar

FannonDSimmonsATennakoonLSelective deficit of hippocampal N-acetylaspartate in antipsychotic-naïve patients with schizophreniaBiol Psychiatry200354658759813129653

 PubMed Web of Science ®Google Scholar

BustilloJRRowlandLMJungRProton magnetic resonance spectroscopy during initial treatment with antipsychotic medication in schizophreniaNeuropsychopharmacology200833102456246618094668

 PubMed Web of Science ®Google Scholar

LiebermanJATollefsonGDCharlesCAntipsychotic drug effects on brain morphology in first-episode psychosisArch Gen Psychiatry200562436137015809403

 PubMed Web of Science ®Google Scholar

LindquistDMHawkRMKarsonCNKomoroskiRAEffects of antipsychotic drugs on metabolite ratios in rat brain in vivoMagn Reson Med200043335535810725877

 PubMed Web of Science ®Google Scholar

BustilloJWolffCMyers-y-GutierrezATreatment of rats with antipsychotic drugs: lack of an effect on brain N-acetyl aspartate levelsSchizophr Res2004661313914693350

 PubMed Web of Science ®Google Scholar

HarteMKBachusSBReynoldsGPIncreased N-acetylaspartate in rat striatum following long-term administration of haloperidolSchizophr Res2005752–330330815885521

 PubMed Web of Science ®Google Scholar

McLoughlinGAMaDTsangTMAnalyzing the effects of psychotropic drugs on metabolite profiles in rat brain using 1H NMR spectroscopyJ Proteome Res2009841943195219714815

 PubMed Web of Science ®Google Scholar

BustilloJBarrowRPazRLong-term treatment of rats with haloperidol: lack of an effect on brain N-acetyl aspartate levelsNeuropsychopharmacology200631475175616132064

 PubMed Web of Science ®Google Scholar

LindquistDMDunnRSCecilKMLong term antipsychotic treatment does not alter metabolite concentrations in rat striatum: an in vivo magnetic resonance spectroscopy studySchizophr Res20111281–3839021429713

 PubMed Web of Science ®Google Scholar

BertolinoACallicottJHMattayVSThe effect of treatment with antipsychotic drugs on brain N-acetylaspartate measures in patients with schizophreniaBiol Psychiatry2001491394611163778

 PubMed Web of Science ®Google Scholar

BustilloJRRowlandLMMullinsP1H-MRS at 4 Tesla in minimally treated early schizophreniaMol Psychiatry201015662963619918243

 PubMed Web of Science ®Google Scholar

BrausDFEndeGWeber-FahrWDemirakcaTTostHHennFAFunctioning and neuronal viability of the anterior cingulate neurons following antipsychotic treatment: MR-spectroscopic imaging in chronic schizophreniaEur Neuropsychopharmacol200212214515211872332

 PubMed Web of Science ®Google Scholar

BustilloJRLaurielloJRowlandLMEffects of chronic haloperidol and clozapine treatments on frontal and caudate neurochemistry in schizophreniaPsychiatry Res2001107313514911566430

 PubMed Web of Science ®Google Scholar

SzulcAGalinskaBTarasowEN-acetylaspartate (NAA) levels in selected areas of the brain in patients with chronic schizophrenia treated with typical and atypical neuroleptics: a proton magnetic resonance spectroscopy (1H MRS) studyMed Sci Monit200713Suppl 1172217507880

 PubMedGoogle Scholar

YeoRAHillDCampbellRVigilJBrooksWMDevelopmental instability and working memory ability in children: a magnetic resonance spectroscopy investigationDev Neuropsychol200017214315910955200

 PubMed Web of Science ®Google Scholar

ValenzuelaMJSachdevPSWenWShnierRBrodatyHGilliesDDual voxel proton magnetic resonance spectroscopy in the healthy elderly: subcortical-frontal axonal N-acetylaspartate levels are correlated with fluid cognitive abilities independent of structural brain changesNeuroimage200012674775611112406

 PubMed Web of Science ®Google Scholar

BertolinoASciotaDBrudaglioFWorking memory deficits and levels of N-acetylaspartate in patients with schizophreniform disorderAm J Psychiatry2003160348348912611829

 PubMed Web of Science ®Google Scholar

BertolinoAEspositoGCallicottJHSpecific relationship between prefrontal neuronal N-acetylaspartate and activation of the working memory cortical network in schizophreniaAm J Psychiatry20001571263310618009

 PubMed Web of Science ®Google Scholar

TanakaYObataTSassaTQuantitative magnetic resonance spectroscopy of schizophrenia: relationship between decreased N-acetylaspartate and frontal lobe dysfunctionPsychiatry Clin Neurosci200660336537216732755

 PubMed Web of Science ®Google Scholar

BrackenBKRouseEDRenshawPFOlsonDPT2 relaxation effects on apparent N-acetylaspartate concentration in proton magnetic resonance studies of schizophreniaPsychiatry Res2013213214215323769421

 PubMed Web of Science ®Google Scholar

ReidMAKraguljacNVAvsarKBWhiteDMden HollanderJALahtiACProton magnetic resonance spectroscopy of the substantia nigra in schizophreniaSchizophr Res20131472–334835423706412

 PubMed Web of Science ®Google Scholar

SzulcAGalińska-SkokBWaszkiewiczNBibulowiczDKonarzewskaBTarasówEProton magnetic resonance spectroscopy changes after antipsychotic treatmentCurr Med Chem201320341442723157634

 PubMed Web of Science ®Google Scholar

SzulcAGalińska-SkokBTarasówEClinical and cognitive correlates of the proton magnetic resonance spectroscopy measures in chronic schizophreniaMed Sci Monit2012186CR390CR39822648255

 PubMed Web of Science ®Google Scholar