The n-3 polyunsaturated fatty acid/dopamine hypothesis of schizophrenia.

The dopamine hypothesis of schizophrenia has been the most influential since the 1970s. Normally, the prefrontal dopamine system suppressively controls the limbic dopamine system. Since the activities of prefrontal dopaminergic neurons are reduced in schizophrenia, the suppressive effect of the prefrontal area on the limbic system is reduced, and activities of the limbic dopamine system are enhanced. Reduced activities of the prefrontal dopamine system contribute to negative symptoms and cognitive disorders, and increased activities of the limbic dopamine system induce positive symptoms. While the dopamine hypothesis explains the relationship between dopamine kinetics and psychiatric symptoms in schizophrenia, it is not a direct explanation of its etiology. The cause of the abnormal activities of dopaminergic neurons in schizophrenia and its resultant symptoms are unknown. Since the late 1980s, it has been revealed that the n-3 fatty acid concentration is reduced in the plasma and erythrocyte membranes of schizophrenic patients and that the administration of n-3 fatty acids may be effective for the treatment of schizophrenia. Whether or not n-3 fatty acid deficiency plays a direct role in schizophrenia etiology, and the mechanisms underlying their therapeutic effect have yet to be clarified. Recently, the dopamine hypothesis and n-3 fatty acid hypothesis have been suggested to represent different aspects of the same pathology of schizophrenia. In schizophrenia, the brain concentrations of certain n-3 fatty acids are decreased. In rodents, n-3 fatty acid deficiency has been shown to cause decreases in dopamine concentration, number of vesicles and D2 receptors at prefrontal presynaptic terminals. The following minireview provides a summary of findings from n-3 fatty acid deficient animal models and their relevance to schizophrenia pathology is discussed.

[The n-3 fatty acid/dopamine hypothesis in schizophrenia].

The dopamine hypothesis of schizophrenia has been most influential since the 1970s. Normally, the prefrontal dopamine system suppressively controls the limbic dopamine system. Since the activities of prefrontal dopaminergic neurons are reduced in schizophrenia, the suppressive effect of the prefrontal area on the limbic system is reduced, and activities of the limbic dopamine system are enhanced. Reduced activities of the prefrontal dopamine system cause negative symptoms and cognitive disorders, and the increased activity of the limbic dopamine system induces positive symptoms. While the dopamine hypothesis explains the relationship between intracranial dopamine kinetics and psychiatric symptoms in schizophrenia, it is not a direct explanation of its etiology. The cause of the activities of dopaminergic neurons in schizophrenia and the resultant symptoms are unknown. n-3 Fatty acids are not synthesized in the human body and are called "essential fatty acids". Since the late 1980s, it has been revealed that the n-3 fatty acid concentration is reduced in the plasma and erythrocyte membranes of schizophrenic patients, and that the administration of n-3 fatty acids is effective for the treatment of schizophrenia. However, how n-3 fatty acid deficiency induces psychiatric symptoms remains unclear, and the mechanism of the therapeutic effect of n-3 fatty acids has not been clarified. Recently, the dopamine hypothesis and n-3 fatty acid hypothesis have been suggested to represent different aspects of the same pathology of schizophrenia. In schizophrenia, the inactivation of phospholipase A2 causes an excessive depletion of essential fatty acids from the Sn2 position of cell membrane phospholipids, and the brain concentrations of essential fatty acids decrease. This causes decreases in dopamine vesicles, dopamine concentration, and D2-receptors at prefrontal presynaptic terminals. The reduced activity of dopaminergic neurons in the prefrontal area induce negative symptoms and cognitive disorders. Furthermore, as the suppression of activities in the limbic dopamine system by the prefrontal area is reduced, the dopamine concentration and D2-receptors increase in the striate body. As a result, the hyperactivity of the limbic dopamine system induces positive symptoms. The administration of antipsychotics and n-3 fatty acids act on different points in this etiological cascade.

Magnetic resonance imaging study of the ventricle-brain ratio in parents of schizophrenia subjects.

Structural abnormalities found in probands with schizophrenia have been reported to occur to some degree in their unaffected relatives. However, there has yet to be a study that has focused on brain changes of parents of schizophrenics who are not the presumed obligate carriers. Using MRI, the authors studied the ventricle-brain ratio (VBR) of 9 pairs of parents of schizophrenics and 18 age- and sex-matched healthy controls. VBRs of the unaffected parents of schizophrenics were significantly larger than those of the controls. Our results suggest that large VBRs aggregate in the parents of schizophrenics and may serve as an indicator of vulnerability to the disorder.

Genomewide high-density SNP linkage analysis of 236 Japanese families supports the existence of schizophrenia susceptibility loci on chromosomes 1p, 14q, and 20p.

The Japanese Schizophrenia Sib-Pair Linkage Group (JSSLG) is a multisite collaborative study group that was organized to create a national resource for affected sib pair (ASP) studies of schizophrenia in Japan. We used a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the Illumina BeadArray linkage mapping panel (version 4) comprising 5,861 SNPs, to perform a genomewide linkage analysis of JSSLG samples comprising 236 Japanese families with 268 nonindependent ASPs with schizophrenia. All subjects were Japanese. Among these families, 122 families comprised the same subjects analyzed with short tandem repeat markers. All the probands and their siblings, with the exception of seven siblings with schizoaffective disorder, had schizophrenia. After excluding SNPs with high linkage disequilibrium, we found significant evidence of linkage of schizophrenia to chromosome 1p21.2-1p13.2 (LOD=3.39) and suggestive evidence of linkage to 14q11.2 (LOD=2.87), 14q11.2-q13.2 (LOD=2.33), and 20p12.1-p11.2 (LOD=2.33). Although linkage to these regions has received little attention, these regions are included in or partially overlap the 10 regions reported by Lewis et al. that passed the two aggregate criteria of a meta-analysis. Results of the present study--which, to our knowledge, is the first genomewide analysis of schizophrenia in ASPs of a single Asian ethnicity that is comparable to the analyses done of ASPs of European descent--indicate the existence of schizophrenia susceptibility loci that are common to different ethnic groups but that likely have different ethnicity-specific effects.

Obstetric complications in siblings of Japanese schizophrenics: data from the Maternal and Child Health Handbook.

Although the precise etiology of schizophrenia remains unknown, the development of schizophrenia has been associated with a history of obstetric complication (OC). Furthermore, some studies show structural and functional brain abnormalities in the unaffected siblings of schizophrenics. In this study the perinatal histories of 18 unaffected siblings of schizophrenics and 15 unrelated healthy controls, as detailed in their mothers' Maternal and Child Health Handbook records, were retrospectively analyzed. Records were scored for obstetric complication by the method developed by [Parnas, J., Schulsinger, F., Teasdale, T.W., Shulsinger, H., Feldman, P.M., Mednick, S.A., 1982. Perinatal complications and clinical outcome within the schizophrenia spectrum. Br. J. Psychiatry 140, 416-420]. The authors found the sibling group had greater pregnancy and birth complication (PBC) frequency, severity and total scores than the control population.

[Omega-3 fatty acids in mood disorders].

The etiology and treatment of mood disorders has not yet been elucidated. Omega (omega)-3 fatty acids are essential fatty acids, which cannot be synthesized in the human body. Eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) are representative omega-3 fatty acids which are found in fish (eg., mackerel, herring, Chinook salmon) and vegetables (eg., flax, walnut, canola). The peripheral level of EPA and DHA decrease in patients with major depression, and EPA is useful for its treatment. Further research is required on omega-3 fatty acids in patients with mood disorders.

[Effect of factors on plasma haloperidol concentration/dose ratio].

It has been known that the serum concentration of antipsychotics is varied according to individual case. There are several factors that may affect the plasma levels of antipsychotics; e.g., antipsychotic dose, body weight, interaction with other drugs, enzyme activity in the human liver, age and smoking. The enzyme cytochrome P450 2D6 (CYP2D6) is an important factor affecting the plasma levels of antipsychotics, because CYP2D6 is involved in the metabolism of these drugs. In this paper, we review the effect of several factors on plasma haloperidol concentration.

Effects of smoking and cytochrome P450 2D6*10 allele on the plasma haloperidol concentration/dose ratio.

OBJECTIVE: This study was carried out to evaluate the influence of CYP2D6 polymorphism and smoking on the plasma clearance of haloperidol (HAL) levels, accounting for the antipsychotic dose, body weight, and coadministration of other drugs. METHODS: Subjects were 110 Japanese patients (66 male, 44 female) diagnosed with schizophrenia, dementia, or mood disorder and treated orally with HAL. Venous blood was obtained from each patient to determine the HAL concentration/dose (C/D) ratio (plasma concentration of HAL divided by the daily dose of HAL per body weight) and for CYP2D6 genotyping. RESULTS: There was no significant difference in the HAL C/D ratio between nonsmokers and smokers. In patients with a non-2D6*10 homozygous genotype, smokers had a significantly lower HAL C/D ratio than nonsmokers, whereas smokers with a 2D6*10 homozygous genotype had a significantly higher HAL C/D ratio than those with a non-2D6*10 homozygous genotype. CONCLUSION: Our results suggest that the effect of smoking on the HAL C/D ratio depends on the CYP2D6*10 genotype.

Effects of age and the CYP2D6*10 allele on the plasma haloperidol concentration/dose ratio.

The authors studied the effect of aging and the CYP2D6*10 polymorphism on the plasma haloperidol (HAL) concentration after chronic administration of HAL. Subjects were 110 Japanese patients (66 male) treated orally with HAL. Venous blood was obtained from each patient for determination of the HAL concentration/dose (C/D) ratio (the plasma concentration of HAL divided by the daily dose of HAL per kilogram body weight) and for CYP2D6 genotyping. Overall, there was a significant linear correlation between the HAL C/D ratio and age. In subgroup analyses, the correlation was significant for patients with non-2D6*10 homozygous genotypes, but not for those with the 2D6*10 homozygous genotype. Overall, the HAL C/D ratio was significantly higher in older subjects (at least 50 years old) than younger ones (less than 50 years old). The ratio was significantly higher in older than in younger subjects for patients with non-2D6*10 homozygous genotypes, but not for those with the 2D6*10 homozygous genotype. Our results indicate that the effect of age on the HAL C/D ratio depends upon the CYP2D6*10 genotype. Because there are racial differences in the CYP2D6 genotype, further studies should investigate age effects on the HAL C/D ratio in different patient populations.

CYP2D6*10 alleles do not determine plasma fluvoxamine concentration/dose ratio in Japanese subjects.

OBJECTIVE: The purpose of the present study was to investigate whether plasma fluvoxamine (FV) concentration is associated with CYP2D6*10 allele polymorphisms. METHODS: Subjects were 46 Japanese patients (21 males) carrying neither *3, *4 nor *5 alleles and treated orally using FV. Venous blood was obtained from each patient for determination of FV concentration/dose (C/D) ratio (plasma concentration of FV divided by daily dose of FV per body weight) and CYP2D6 genotyping. RESULTS: No significant differences in FV C/D ratio were found between subjects with no (n=13), one (n=18) or two (n=15) *10 alleles. CONCLUSION: Our results indicate that CYP2D6*10 genotypes do not exert significant effects on FV C/D ratio. As CYP2D6 genotypes differ with ethnic background, further studies should be conducted in different populations.