Donald H. Linszen

Significantly reduced docosahexaenoic and docosapentaenoic acid concentrations in erythrocyte membranes from schizophrenic patients compared with a carefully matched control group

BACKGROUNDnFatty acid research in schizophrenia has demonstrated an altered cell membrane phospholipid metabolism. Erythrocyte membrane phospholipid composition closest reflects that of neuronal membranes.nnnMETHODSn(Poly)(un)saturated fatty acid concentrations were measured in the erythrocyte membranes of 19, consecutively admitted, medicated young schizophrenic patients and then compared with matched control subjects. Psychiatric symptomatology was rated with the Positive and Negative Symptom Scale and Montgomery-Asberg Depression Rating Scale. Because diet, hormones, and cannabis influence fatty acid metabolism, we included these factors in our study.nnnRESULTSnThe most distinctive findings concerned the omega-3 series: C22:5 omega-3, C22:6 omega-3 (docosahexaenoic acid), and the sum of omega-3 fatty acids were significantly decreased. Interestingly, C20:4 omega-6 (arachidonic acid) was not lowered. In the omega-9 series, higher levels of C22:1 omega-9 and lower levels its elongation product, C24:1 omega-9 (nervonic acid), were found. Interestingly, the other arm of the desaturation-elongation sequence of C18:1 omega-9, C20:3 omega-9, was lower in patients. The total omega-9 fatty acid levels were also lower in patients.nnnCONCLUSIONSnSignificant differences in erythrocyte fatty acid composition were found. The differences were not due to diet or hormonal status and could not be explained by the medication or cannabis use. No consistent pattern emerged from the different fatty acid abnormalities and the clinical symptom scores.

Component structure of the expanded Brief Psychiatric Rating Scale (BPRS-E).

The component structure of the expanded Brief Psychiatric Rating Scale (BPRS-E) was analyzed in a sample (n=150) of consecutively admitted general psychiatric inpatients and compared with a group (n=97) of adolescent patients with schizophrenia spectrum diagnoses. A stable five-component solution, of which four were interpretable, was found across groups. The component scales of the 24-item version of the BPRS had good internal consistency, allowed better coverage of schizophrenia and affective symptoms than the 18-item version but did not distinguish the schizophrenia diagnostic subgroups. The implications of the findings are discussed.

Assessment of endogenous dopamine release by methylphenidate challenge using iodine-123 iodobenzamide single-photon emission tomography

This double-blind, placebo-controlled study assessed pharmacologically induced endogenous dopamine (DA) release in healthy male volunteers (n=12). Changes in endogenous DA release after injection of the psychostimulant drug methylphenidate were evaluated by single-photon emission tomography (SPET) and constant infusion of iodine-123 iodobenzamide ([123I]IBZM), a D2 receptor radioligand that is sensitive to endogenous DA release. Methylphenidate induced displacement of striatal [123I]IBZM binding, resulting in a significantly decrease in the specific to non-specific [123I]IBZM uptake ratio (average: 8.6%) in comparison with placebo (average: −1.9%). Moreover, injection of methylphenidate induced significant behavioural responses on the following items: excitement, anxiety, tension, and mannerisms and posturing. The results of this study demonstrate the feasibility of using constant infusion of [123I]IBZM and SPET imaging to measure endogenous DA release after methylphenidate challenge and to investigate neurochemical aspects of behaviour.

Genetic variation in COMT and PRODH is associated with brain anatomy in patients with schizophrenia

Haploinsufficiency of 22q11 genes including catechol‐O‐methyltransferase (COMT) and proline dehydrogenase (PRODH) may result in structural and functional brain abnormalities and increased vulnerability to schizophrenia as observed in patients with microdeletions of 22q11. Thus, COMT and PRODH could be modifier genes for schizophrenia. We examined association of polymorphisms in COMT and PRODH with brain anatomy in young patients with schizophrenia and schizoaffective disorder. We acquired structural magnetic resonance imaging data from 51 male patients and genotyped two single nucleotide polymorphisms (SNPs) in the COMT gene and three in the PRODH gene. Statistical Parametric Mapping software and optimized voxel‐based morphometry were used to determine regional gray matter (GM) and white matter (WM) density differences, and total GM and WM volume differences between genotype groups. Two nonsynonymous SNPs in the PRODH gene were associated with bilateral frontal WM density reductions and an SNP in the P2 promoter region of COMT (rs2097603) was associated with GM increase in the right superior temporal gyrus. Furthermore, we found evidence for COMT and PRODH epistasis: in patients with a COMT Val allele (rs4680) and with one or two mutated PRODH alleles, we observed increased WM density in the left inferior frontal lobe. Our results suggest that genetic variation in COMT and PRODH has significant effects on brain regions known to be affected in schizophrenia. Further research is needed to investigate the role of 22q11 genes on brain structure and function and their role in vulnerability for schizophrenia.

Dopamine D2 receptor occupancy by olanzapine or risperidone in young patients with schizophrenia

A crucial characteristic of antipsychotic medication is the occupancy of the dopamine (DA) D2 receptor. We assessed striatal DA D2 receptor occupancy by olanzapine and risperidone in 36 young patients [31 males, 5 females; mean age 21.1 years (16-28)] with first episode schizophrenia, using [123I]iodobenzamide (IBZM) SPECT. The occupancy of DA D2 receptors was not significantly different between olanzapine and risperidone. However, in subgroups of most prescribed doses, DA D2 occupancy was higher in the risperidone 4-mg group (79%) compared to the olanzapine 15-mg group (62%). [123I]IBZM binding ratios decreased with olanzapine dose (r = -0.551; P < 0.01), indicating higher DA D2 receptor occupancy with higher olanzapine dose. Akathisia and positive symptoms were correlated with [123I]IBZM binding ratio (r = -0.442; P < 0.01; and r = -0.360; P < 0.05, respectively). Prolactin (PRL) levels were elevated in the risperidone, but not in the olanzapine group, at comparable D2 receptor occupancy levels. In the olanzapine group, PRL levels were correlated with [123I]IBZM binding ratio (r = -0.551; P < 0.01). In conclusion, both olanzapine and risperidone induce a high striatal D2 receptor occupancy, dependent on dose and group formation. The lower incidence of prolactin elevation with olanzapine, compared to risperidone, may not be attributed to a lower D2 receptor occupancy.

Higher occupancy of muscarinic receptors by olanzapine than risperidone in patients with schizophrenia

Abstract. Rationale: In vitro data have shown anticholinergic properties of the atypical antipsychotic drug olanzapine. Substantial occupancy of muscarinic receptors may be an explanation for the low incidence of extrapyramidal side effects induced by olanzapine. Objectives: To obtain an in vivo measurement of muscarinic receptor occupancy by olanzapine compared with risperidone in patients with schizophrenia stabilised on medication. Methods: Five patients with schizophrenia treated with olanzapine and five patients treated with risperidone were studied. Muscarinic receptor occupancy in the striatum and cortex was studied in vivo with SPECT using [123I]-IDEX as a radioligand. SPECT data were compared with those of six healthy subjects. Results: Patients stabilised on olanzapine showed significantly lower mean (±SD) striatal and cortical (1.50±0.21 and 1.51±0.22, respectively) muscarinic receptor binding ratios of [123I]-IDEX (reflecting higher levels of muscarinic receptor occupancy) than controls (3.91±0.61 and 3.65±0.70, respectively). Furthermore, [123I]-IDEX binding ratios in patients treated with risperidone were slightly lower than controls, reaching significance only in the striatum (2.99±0.27 versus 3.91±0.61, for risperidone and controls). Conclusions: The substantial occupancy of muscarinic receptors in the striatum and cortex by olanzapine may be an explanation for the low incidence and severity of extrapyramidal side effects of this antipsychotic drug. Furthermore, it may also explain the anticholinergic side effects of olanzapine.

Symptom response and side-effects of olanzapine and risperidone in young adults with recent onset schizophrenia

The symptom response and side-effects of olanzapine and risperidone were compared in patients with recent onset schizophrenia. Actively symptomatic patients (n=44) randomly received olanzapine 15u2009mg (median dose) or risperidone 4u2009mg (median dose). Symptom response and side-effects were measured during a 6–10-week treatment study. No major differences were observed between the two treatment groups. Symptoms improved significantly on the Positive and Negative Syndrome Scale total score, positive subscale and general psychopathology subscale for both treatment groups. Using five symptom dimensions, both drugs were effective in treating positive symptoms and agitation/excitement symptoms, and neither olanzapine or risperidone influenced disorganization and depression symptoms. Results on the negative symptoms subscale and symptom dimension were inconclusive. No major differences were found in the frequency of the reported side-effects akathisia, parkinsonism and weight gain. These data indicate that the differences between olanzapine and risperidone in symptom response are small. In spite of the relatively low power of the study, we could exclude the presence of substantially different treatment effects between olanzapine and risperidone.

Age at onset of non-affective psychosis in relation to cannabis use, other drug use and gender

BACKGROUNDnCannabis use is associated with an earlier age at onset of psychotic illness. The aim of the present study was to examine whether this association is confounded by gender or other substance use in a large cohort of patients with a non-affective psychotic disorder.nnnMETHODnIn 785 patients with a non-affective psychotic disorder, regression analysis was used to investigate the independent effects of gender, cannabis use and other drug use on age at onset of first psychosis.nnnRESULTSnAge at onset was 1.8 years earlier in cannabis users compared to non-users, controlling for gender and other possible confounders. Use of other drugs did not have an additional effect on age at onset when cannabis use was taken into account. In 63.5% of cannabis-using patients, age at most intense cannabis use preceded the age at onset of first psychosis. In males, the mean age at onset was 1.3 years lower than in females, controlling for cannabis use and other confounders.nnnCONCLUSIONSnCannabis use and gender are independently associated with an earlier onset of psychotic illness. Our findings also suggest that cannabis use may precipitate psychosis. More research is needed to clarify the neurobiological factors that make people vulnerable to this precipitating effect of cannabis.

Polyunsaturated fatty acids and brain white matter anisotropy in recent-onset schizophrenia: a preliminary study

Brain white matter myelin abnormalities and cell membrane fatty acid abnormalities have been implicated in schizophrenia and other psychiatric disorders. We investigated in young adults with a psychotic disorder (n=12) whether (poly)unsaturated fatty acid concentrations in erythrocyte membranes are related to an MRI measure of brain white matter, which depends on the degree of myelination. A significant correlation was found between total (poly)unsaturated fatty acid concentration and fractional anisotropy of a fronto-temporal white matter tract (r=0.503, P=0.048). Unsaturated fatty acids may be necessary for the myelinating activity of oligodendrocytes or for myelin maintenance. These results warrant further investigation.

Personality and schizophrenic relapse

The predictive value of personality traits and disorders for the short-term course of schizophrenia was assessed in a cohort of 93 adolescent patients. Personality disorders, particularly antisocial personality disorder, were found to be predictive of the course of schizophrenia. Axis II comorbidity as defined in the Diagnostic and statistical manual of mental disorders influences the course of schizophrenia and therefore more attention should be paid to this pathology in the prevention of relapse in schizophrenia.