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Objective: Many chronic inpatients with schizophrenia demonstrate enduring psychiatric symptoms and various side effects of antipsychotic drugs. Several biological markers such as prolactin, thyroid hormones and brain-derived neurotrophic factor (BDNF) are reportedly associated with psychiatric symptoms and/or antipsychotic side effects in patients with schizophrenia but to date findings are inconsistent. The objective of the present study was to comprehensively investigate the association of psychiatric and extrapyramidal symptoms with hormones and BDNF in chronic schizophrenia., Methods: In this study, 93 chronic inpatients with schizophrenia were comprehensively investigated in order to examine the association of psychiatric and extrapyramidal symptoms with prolactin, thyroid hormones (free triiodothyronine (T₃), free thyroxine (T₄), thyroid stimulating hormone), cortisol and BDNF. Symptoms were assessed via the Positive and Negative Syndrome Scale (PANSS), Mini-Mental State Examination (MMSE), and drug-induced extrapyramidal symptoms scale (DIEPSS)., Results: Multiple regression analyses revealed that antipsychotic dose was the only variable that predicted significant variance in PANSS positive subscale scores, that BDNF and free T₃ predicted significant variance in MMSE scores, and that prolactin and free T₃ predicted significant variance in DIEPSS scores., Conclusion: These findings suggest that BDNF, free T₃, and prolactin may be associated with cognitive function and/or extrapyramidal symptoms in patients with chronic schizophrenia. Notably, free T₃ may be possibly associated with better cognitive function and less extrapyramidal symptoms, although our cross-sectional study could not reveal a causal relationship., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Loss of antipsychotic efficacy (tachyphylaxis), possibly linked to an increase in D₂ receptor number and sensitivity, is a significant impediment to treatment in chronic schizophrenia patients. Animal studies, however, suggest that aripiprazole may be free from tachyphylaxis. The aim of the present study was to investigate this hypothesis. In this preliminary study, aripiprazole-treated patients were retrospectively investigated for the presence or absence of tachyphylaxis. Clinical Global Impression-Improvement (CGI-I) scores did not significantly change and there was no significant association of CGI scores with fixed dose duration. This suggests that aripiprazole may be free from tachyphylaxis., (© 2012 The Authors. Psychiatry and Clinical Neurosciences © 2012 Japanese Society of Psychiatry and Neurology.)

Introduction: Conventional antipsychotic medications are associated with elevated prolactin levels, resulting in hyperprolactinemia and a number of unwanted side effects. Several atypical antipsychotics, on the other hand, are less likely to evoke hyperprolactinemia. The aim of this study was to investigate the prevalence of hyperprolactinemia induced by conventional antipsychotic drugs, examine changes in serum prolactin levels and psychiatric symptoms after switching to quetiapine, and identify the relevant characteristics of patients who may be suitable to switch to quetiapine., Method: Sixty-nine of 74 consecutive female patients who had received conventional antipsychotic drugs were initially included in the study. Of these, 49 (71 %) patients suffered from hyperprolactinemia, of which a further 25 were subsequently switched to quetiapine. Psychiatric symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS), and serum prolactin levels were measured just before and at 4 and 8 weeks after switching., Results: Eight of the 25 (32 %) "switch" patients dropped out due to psychotic exacerbation during the 8 weeks. In the remaining 17 (68 %) patients, serum prolactin levels were significantly decreased without any significant change in PANSS scores after switching. The 17 patients who completed the switch had previously demonstrated significantly lower positive symptom scores compared to the 8 dropout patients., Conclusion: The present findings suggest that 71 % of female patients receiving conventional antipsychotic drugs may suffer from hyperprolactinemia and that approximately two-thirds of patients can be switched to quetiapine, resulting in an improvement in hyperprolactinemia. The main characteristic of the switched patients may be fewer positive symptoms.

Studies of schizophrenia show lack of agreement about the relationship of symptomatological and cognitive factors to insight. In this study, positive and negative symptomatology and cognitive function were assessed by the Positive and Negative Syndrome Scale (PANSS), the Wisconsin Card Sorting Test (WCST), and the Wechsler Adult Intelligence Scale Revised (WAIS-R) in male chronic schizophrenic patients in relation to level of insight measured with the Japanese version of the Schedule for the Assessment of Insight (SAI-J). Negative symptoms were significantly and negatively associated with overall insight, particularly with treatment compliance and recognition of mental illness. The present findings suggest that aspects of insight such as treatment compliance and recognition of mental illness are negatively associated with negative symptoms., (Copyright 2004 Elsevier Ireland Ltd.)

The purpose of the present study was to determine the characteristics of repeatedly secluded female inpatients. Fifty female inpatients in a typical mental hospital were retrospectively investigated from the viewpoint of their recent history of seclusion, age, psychiatric symptoms rated by the Positive and Negative Syndrome Scale, doses of antipsychotics, and serum prolactin levels. The patients were divided into three groups (none, once, twice or more) by the frequency of seclusion in the most recent year. The three groups were significantly different in terms of positive symptoms, general psychopathological symptoms and serum prolactin levels. Unexpectedly, the seclusion frequency was negatively associated with serum prolactin levels. The present findings suggest that repeatedly secluded female inpatients suffered from relatively low prolactin levels as well as more positive and psychopathological symptoms. Further prospective studies are warranted to confirm these findings and to investigate whether low prolactin levels are useful in predicting the risk of frequent seclusion in female inpatients.

Lithium addition to neuroleptic treatment brought about some improvement in 6 schizophrenic inpatients. In 3 of them, however, enhancement of daily activity did not parallel improvement in psychiatric symptoms. This suggests that lithium addition may enhance daily activity independently of psychiatric symptoms, and that lithium effects should also be assessed from the viewpoint of daily activity.

Serotonergic neurotransmission may be involved in the etiology of schizophrenia. We systematically searched for human tryptophan hydroxylase (TPH) coding polymorphisms, and detected a novel pentanucleotide repeat deletion polymorphism (GTTTT)4/5 in TPH intron 1b. We also confirmed A779C intron 7. Neither polymorphism showed a significant association with schizophrenia (182 patients with schizophrenia, 148 controls). A significant association, however, between A779C genotypes and the total Manchester Scale (MS) scores was found in male patients (P = 0.045). Subsequently, a significant association was also found between A779C genotypes and the MS negative symptoms scores in male patients (P = 0.030). These results suggest that the TPH gene may play a role in the negative symptoms in male patients with schizophrenia.

We examined the relationships among the clinical efficacies of risperidone, plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, and changes in plasma free MHPG (pMHPG) in 14 schizophrenic patients. Clinical improvement in negative symptoms of schizophrenia treated with risperidone has been associated with increased pMHPG and, in the present study, there were positive correlations between plasma 9-hydroxyrisperidone concentrations and increased pMHPG levels. These results suggest that risperidone might improve negative symptoms in schizophrenia by influencing noradrenergic neurons.

Possible involvement of sigma receptors in the pathogenesis of schizophrenia has been suggested. In this study we searched systematically for polymorphisms in the 5'-franking region of the sigma(1) receptor. Genetic variation in this region could reduce the expression of the gene, and this suggestion is compatible with findings of reduced sigma binding sites in several cortical regions of schizophrenia. We confirmed G-241T and G-240T polymorphisms; these two consecutive polymorphisms were resolved to be in complete linkage disequilibrium with each other by single-strand conformation polymorphism (SSCP) analysis. We also identified the A61C (Gln2Pro) polymorphism, which was in almost complete linkage disequilibrium with G-241T/G-240T. There was no significant difference in the distribution of alleles or overall genotypes of the polymorphisms between schizophrenic patients (n = 129) and controls (n = 140). We found slight increased homozygosity for T-241/T-240 and C61 in patients compared with controls using multiple comparison (p = 0. 045). However, the significance did not remain when a Bonferroni correction was made (p = 0.135). These results do not support that the sigma(1) receptor gene plays a major role in the pathogenesis of schizophrenia. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:118-122, 2000., (Copyright 2000 Wiley-Liss, Inc.)

Recently, the authors suggested that the lithium dose prediction equation created by Zetin and associates cannot always accurately predict a required lithium dose and that the inclusion of renal function data may improve the accuracy of the equation. The charts of 70 patients were reviewed to obtain data regarding factors thought to affect serum lithium concentrations, including renal function, and an equation to estimate the dose intended to achieve an expected concentration was derived by stepwise multiple linear regression. The equation was also applied to 30 other patients to evaluate its accuracy. The authors obtained the following equation: daily lithium carbonate dose (in milligrams) = 100.5 + 752.7 x (expected lithium concentration in millimoles per liter) - 3.6 x (age in years) + 7.2 x (weight in kilograms) - 13.7 x (blood urea nitrogen [BUN] in milligrams per deciliter). When the equation was applied to 30 patients, the mean +/- SD of deviations from the expected concentration was 0.15 +/- 0.30 mmol/L, and 19 patients (63%) had deviations of less than 0.20 mmol/L. On the other hand, when the equation set forth by Zetin and associates was applied to the same patients, the mean +/- SD of deviations from the expected concentration was 0.52 +/- 0.42 mmol/L, and only 6 patients (20%) had deviations of less than 0.20 mmol/L. Although it is necessary to measure BUN levels before starting lithium, this equation may be simpler and more accurate than that offered by Zetin and associates.

We studied the relationship between schizophrenia and the DdeI polymorphism in the 5' untranslated region (5'UTR) of the dopamine D1 receptor (DRD1) gene. This polymorphism is an A (A1 allele) to G (A2 allele) transition in the 5' UTR of exon 2 at bp -48 (A-48G). One hundred forty-eight schizophrenics and 148 control subjects were investigated. No significant differences in genotypic counts and allele frequencies between schizophrenics and controls were found. Although a significant difference between the patients classified as disorganized type and the controls was discovered both in genotypic counts and allele frequencies, neither association proved significant when a Bonferroni correction was used. Moreover, there were no differences in scores of main symptoms of schizophrenia based on the Manchester Scale between patients with A1/A1 genotype and those with A1/A2 genotype. These findings suggest that this gene may not be involved in the pathogenesis of schizophrenia.

Serotonergic (5-hydroxytryptamine; 5-HT) transmission may play an important role in the treatment and/or pathogenesis of schizophrenia. Previous studies reported that several atypical antipsychotic agents have high affinities for the 5-HT6 receptor. The 5-HT6 receptor gene polymorphism might contribute to the genetic background of this disorder. One hundred and fifty unrelated patients with schizophrenia and 150 unrelated healthy controls were genotyped for a biallelic polymorphism (267C/T) at the 5-HT6 receptor gene. No significant positive association between the 5-HT6 receptor genotype and schizophrenia was observed. Our results suggests that the 267C/T polymorphism of the 5-HT6 receptor gene may not be involved in the susceptibility to schizophrenia.

There is little information regarding the effects of risperidone addition to neuroleptic treatment in chronic schizophrenia. As a preliminary study, 10 neuroleptic-treated schizophrenic inpatients received risperidone (high 5HT2A/D2 ratio, i.e. the ratio between 5HT2A and D2 receptor occupancy) and mosapramine (low 5HT2A/D2 ratio) in a randomized, single-blind, crossover, add-on study consisting of 8 weeks of treatment each with risperidone and mosapramine. Although both additions resulted in significant, albeit modest, improvement, there was no significant difference in the scores on the Positive and Negative Syndrome Scale for Schizophrenia between risperidone and mosapramine addition. These results suggest that risperidone and mosapramine bring about comparable effects in add-on design. Thus, risperidone with a high 5HT2A/D2 ratio does not seem to be better than mosapramine with a low 5HT2A/D2 ratio when combined with conventional neuroleptics. Further studies including a large number of patients and a double-blind design are needed.

Clinical observations indicate that a proportion of patients with schizophrenia experience cognitive impairment, which suggests that a neurodegenerative basis might be involved in the etiology of schizophrenia. Apolipoprotein E (ApoE), which has been confirmed to be genetically associated with Alzheimer's disease, is thus highlighted as a candidate gene for schizophrenia. Recently, novel functional polymorphisms in the ApoE transcriptional regulatory region have been found. To investigate whether these polymorphisms are associated with the risk of schizophrenia, we genotyped 144 patients with schizophrenia and 134 controls for two polymorphisms (-491A/T and -219G/T). No significant positive associations between both polymorphisms and schizophrenia were observed. Our findings exclude the regulatory region of the ApoE gene as a locus that might confer increased susceptibility to schizophrenia.

Previous studies have shown that many neuroleptics are metabolized by debrisoquine 4-hydrolase (CYP2D6), which exhibits genetic polymorphisms. In Oriental populations, poor metabolizers (PMs) with a lack of CYP2D6 activity are rare, although the CYP2D6*10 allele, which is associated with decreased CYP2D6 activity, is commonly found. The authors examined the relationship between tardive dyskinesia (TD) and CYP2D6 polymorphisms, including the CYP2D6*10 allele. Subjects consisted of 100 Japanese schizophrenics. TD was evaluated using the Abnormal Involuntary Movement Scale (AIMS). Genotyping for the presence of the CYP2D6*3, CYP2D6*4 and CYP2D6*10 alleles was performed using allele-specific PCR amplification and endonuclease digestions. The frequency of the CYP2D6*10 allele was 0.52, and only one allele showed the PM genotype. There was a significant difference in the allelic distribution of CYP2D6*10 between subjects with and without TD. We also found significant genotypic and allelic associations with dichotomized total AIMS scores of 6 or more (moderate or severe abnormal movements) and with scores of less than 6 (mild or no movements). After these associations were adjusted for confounding variables (gender, age, duration of illness and neuroleptic dose) by regression analysis, the CYP2D6*10 genotype showed significant association with the total AIMS score, and a modest association with TD occurrence. These results indicate that the CYP2D6*10 genotype may play a role in the development of moderate or severe abnormal movements.

Serotonin (5-hydroxytryptamine, 5-HT) may play an important role in the pathogenesis of schizophrenia. Previous studies suggested that the efficacy of atypical neuroleptic drugs (e.g., risperidone and clozapine) on negative symptoms may be related to the 5-HT2a receptor. Although association studies between MspI polymorphism (T102C) and the 5-HT2a receptor gene and schizophrenia have been reported, their results are still controversial. The aim of this study was to examine the association between T102C polymorphism of the 5-HT2a receptor gene and schizophrenia as well as the association between the polymorphism and negative symptoms in a Japanese population (106 patients with schizophrenia and 109 healthy controls). No significant positive associations were observed. Our results suggest that the 5-HT2a receptor gene is not involved in the pathogenesis of schizophrenia or negative symptoms.

Catechol-O-methyltransferase (COMT) is an enzyme which inactivates catecholamine neurotransmitters by methylation, and is considered a candidate for involvement in schizophrenia. A functional COMT gene polymorphism influencing the enzyme activities, the high activity (val-108) and the low activity allele (met-108), was recently confirmed. We investigated a genetic association between schizophrenia and the COMT gene polymorphism in 150 Japanese schizophrenics and controls. We detected the low activity met-108 allele more frequently in schizophrenics than in the controls, and found that subjects sharing the met-108 allele (val/met and met/met) are significantly more common in the patients than in the controls. The results suggest that the low activity met-108 allele may be involved in susceptibility for schizophrenia.

We studied the effect of lithium addition to neuroleptic treatment in chronic schizophrenia, for which contradictory results have been produced in previous studies. Twenty-one chronic schizophrenic inpatients received lithium in a study with randomized, double-blind, placebo-controlled, cross-over design consisting of 8 weeks each of treatment with lithium capsules and identical placebo capsules. The total Brief Psychiatric Rating Scale (BPRS) scores at week 8 of the lithium treatment were improved significantly compared with those at week 8 of the placebo treatment. Of the BPRS subscales, however, only anxiety-depression improved, whereas none of the subscales for anergia, thought disturbance, activation and hostile-suspiciousness improved. There was no significant difference between the total Scale for the Assessment of Negative Symptoms (SANS) scores at any time during lithium and placebo treatment. These results suggest that the addition of lithium to neuroleptic treatment improves anxiety-depression in chronic schizophrenia.

The effect of lithium on thyroid function was studied in 18 neuroleptic-treated male chronic schizophrenic in-patients. Lithium carbonate was administered for 8 weeks at a dosage giving a mean serum level of 0.79 mmol/l. Blood was obtained just before and after 8 weeks of lithium administration to determine the serum free thyroxine (free T4) levels, free triiodothyronine (free T3) levels and thyrotropin (TSH) levels. Overall, free T4 and TSH levels significantly increased whereas free T3 levels did not change. Two (11%) patients had abnormally increased free T4 levels and abnormally decreased free T3 levels after 8 weeks of lithium administration. These findings suggest that lithium may inhibit the peripheral conversion of free T4 to free T3 in some susceptible patients.

Background: Recently, one prospective study confirmed the safety and accuracy of a lithium-dose prediction equation created by Zetin et al., but no definitive conclusion on the reliability of the equation has been established as yet., Method: The authors applied the Zetin et al. equation to 18 chronic male schizophrenic inpatients. Predicted doses to reach the serum lithium concentration of 0.4 mmol/L were calculated and prescribed in the form of lithium capsules. At Weeks 1 and 3 after treatment initiation, morning blood samples were collected about 12 hours after the last lithium dose for the measurement of serum lithium concentrations., Results: None of the 18 patients achieved the desired concentration (0.4 mmol/L) exactly. The mean +/- SD of serum lithium concentrations at Week 1 was 1.01 +/- 0.29 mmol/L (range, 0.2-1.5) and at Week 3 was 0.94 +/- 0.35 mmol/L (range, 0.2-1.8). Lithium concentrations were lower than 0.4 mmol/L in only 1 patient and were higher than 0.4 mmol/L in the other 17 patients. The deviations from the unexpected value were significantly correlated with the renal function (blood urea nitrogen and serum creatinine levels) but not with the neuroleptic doses administered to the patients. Moreover, our patients were relatively older and weighed relatively less than the patients described in the previous prospective study., Conclusion: The Zetin et al. equation cannot always accurately predict a required lithium dose. Renal function data, even when they range within normal values, may be useful to improve the accuracy of the equation, particularly in patients who are older or weigh less than the norm.