Elsevier

Biological Psychiatry

Volume 54, Issue 6, 15 September 2003, Pages 587-598
Biological Psychiatry

Original article
Selective deficit of hippocampal N-acetylaspartate in antipsychotic-naive patients with schizophrenia

https://doi.org/10.1016/S0006-3223(03)00185-9Get rights and content

Abstract

Background

Studies using proton magnetic resonance spectroscopy in schizophrenia have demonstrated abnormality of N-acetylaspartate but are confounded by the effects of phase of illness and medication. There is mounting evidence that antipsychotic medication influences N-acetylaspartate.

Methods

A group of first-episode patients who had received no, or minimal, antipsychotic medication was examined at baseline and after 3 months treatment. Normal comparison subjects were examined at the same interval. Ratios of N-acetylaspartate, creatine plus phosphocreatine, and choline-containing compounds in the left prefrontal cortex, hippocampus, and basal ganglia were measured.

Results

The mean duration of symptoms for all patients was 31.6 (SD 26.1) weeks. A significant reduction of hippocampal N-acetylaspartate/creatine plus phosphocreatine was found in the antipsychotic-naive group relative to those previously treated and to controls at baseline (F = 7.3, p < .002). No group differences were found at follow-up.

Conclusions

Hippocampal N-acetylaspartate/creatine plus phosphocreatine appears to be selectively affected early in the course of illness. The finding of neurochemical differences between treatment naive and previously treated patients confirms the relevance of medication status in proton magnetic resonance spectroscopy studies. Further investigation of the influence of medication at this stage of illness is warranted.

Introduction

Evidence of hippocampal dysfunction in schizophrenia is provided by proton magnetic resonance spectroscopy (1H-MRS), which may be a more sensitive tool for the detection of neuronal pathology compared with other imaging modalities (Deicken et al 1999). N-acetylaspartate (NAA) to creatine plus phosphocreatine (Cr+Pr) ratio (NAA/Cr+PCr) in the temporal lobe is significantly reduced compared with controls in most studies Nasrallah et al 1994, Fukuzako et al 1995, Maier et al 1995, Renshaw et al 1995, Bertolino et al 1996, Yurgelun-Todd et al 1996, Cecil et al 1999, Deicken et al 1999. However, some studies show no difference Buckley et al 1994, Heimberg et al 1998, Bartha et al 1999 or an insignificant trend (Kegeles et al 1998). Despite the advantages of 1H-MRS as a noninvasive imaging tool, important questions remain unresolved regarding phase of illness and the effect of medication status on 1H-MRS findings. Until recently, it was regarded as unlikely that antipsychotic medication has an effect on NAA measures based on in vivo investigations Bertolino et al 1996, Bertolino et al 1998a, Deicken et al 2000 and postmortem results (Tsai et al 1995); however, the potential for medication effects has been highlighted by the finding that temporal lobe NAA/Cr+PCr ratio is higher in patients on combination psychotropic regimes (neuroleptics plus benzodiazepines or tricyclic antidepressants) compared with those on neuroleptics alone (Buckley et al 1994). Furthermore, the level of glutamine (which is intimately related to the synthesis of NAA via the transamination of glutamate) has been shown to be influenced by antipsychotic medication in drug naive first-episode patients examined with 1H-MRS before and after treatment (Stanley et al 1996). In addition, using a within-subject design, patients have demonstrated significantly higher N-acetylaspartate measures while on antipsychotics compared to a medication-free phase (Bertolino et al 2001). Furthermore, antidepressants may affect the choline (Cho) peak in some brain regions (Renshaw et al 1997), and electroconvulsive therapy has been shown to normalize a reduced hippocampal choline signal in depressive patients (Ende et al 2000).

Despite a number of inconsistencies, few studies have specifically addressed the issue of medication status Choe et al 1996, Stanley et al 1996, Heimberg et al 1998, and it remains an important potential confound. With regard to phase of illness, only a minority of investigations of NAA measures have considered first-episode patients Pettegrew et al 1991, Buckley et al 1994, Renshaw et al 1995, Stanley et al 1996, Cecil et al 1999, Bartha et al 1999. Of the others, looking at patients with relatively long duration of illness, almost all were medicated. No associations have been found between NAA measures and dose or duration of antipsychotic medication Stanley et al 1996, Deicken et al 1997, though atypical antipsychotics may behave differently (Heimberg et al 1998). No report of 1H-MRS has described the potential effect of medication on metabolite differences over time in the hippocampus of first-episode schizophrenia patients.

It was hypothesized that metabolic abnormalities would be present in patients with short duration of psychosis and that these abnormalities would be influenced by antipsychotic treatment. We examined three brain areas in the left hemisphere, prefrontal cortex, hippocampus, and basal ganglia in a sample of drug naive and minimally treated patients experiencing a first episode of psychosis compared with controls.

Section snippets

Subjects

Thirty-seven patients (26 men and 11 women) experiencing their first episode of psychosis and 25 controls (17 men and 8 women) between 16 and 40 years of age were recruited from United Kingdom catchment areas as described previously (Fannon et al 2000). Patients were recruited as inpatients or outpatients on referral from clinical services. Of the 37 patients recruited, 33 (22 men, 11 women) and 18 normal comparison subjects (13 men, 5 women) underwent 1H-MRS at study entry. Twenty patients (15

Demographic variables

Table 1 shows comparative demographic variables for the patients experiencing their first psychotic episode and the comparison subjects. There were no differences between the groups for height, age, parental socioeconomic status, handedness, gender, or ethnicity (all F < 1.6, p > .2; χ2 < 5, p > .5). The patients experiencing their first psychotic episode had significantly fewer years of education than did the comparison subjects (F = 10.3, df = 2, 46, p < .001).

Clinical variables

The mean age at onset of

Discussion

This study demonstrated a significant deficit of NAA/Cr+PCr ratio in medication naive patients experiencing their first episode of psychosis relative to those who had been previously treated and to normal controls. This finding was specific to the hippocampus and was not present in the prefrontal cortex or basal ganglia. After 3 months of antipsychotic treatment, no significant differences were found between the groups or within individual patients with respect to NAA/Cr+PCr ratios. The volume

Acknowledgements

Support for this research was provided by Grosvenor House Group Estates and PsychMed Ltd.

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