| 1 | J. Med. Chem. 2000 Dec 43: 4893-909 |
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| PMID | 11123999 |
| Title | Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists. |
| Abstract | (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (4, LY354740), a highly selective and orally active group II metabotropic glutamate receptor (mGluR) agonist, has increased interest in the study of group II mGluRs. Our interest focused on a conformationally constrained form of compound 4, because it appeared that the rigid form resulted in not only selectivity for group II mGluR but was orally active. Therefore, we introduced a fluorine atom to compound 4, based on the molecular size (close resemblance to hydrogen atom) and electronegativity (effects on the electron distribution in the molecule) of this atom and carbon-fluorine bond energy. Compound (+)-7 (MGS0008), the best compound among 3-fluoro derivatives 7-10, retained the agonist activity of compound 4 for mGluR2 and mGluR3 ((+)-7: EC(50) = 29.4 +/- 3.3 nM and 45.4 +/- 8.4 nM for mGluR2 and mGluR3, respectively; 4: EC(50) = 18.3 +/- 1.6 nM and 62.8 +/- 12 nM for mGluR2 and mGluR3, respectively) and increased the oral activity of compound 4 ((+)-7: ED(50) = 5.1 mg/kg and 0.26 mg/kg for phencyclidine (PCP)-induced hyperactivity and PCP-induced head-weaving behavior, respectively; 4: ED(50) = >100 mg/kg and 3.0 mg/kg for PCP-induced hyperactivity and PCP-induced head-weaving behavior, respectively). In addition, a compound [(3)H]-(+)-7 binding study using mGluR2 or 3 expressed in CHO cells was successful ((+)-7: K(i) = 47.7 +/- 17 nM and 65.9 +/- 7.1 nM for mGluR2 and mGluR3, respectively; 4: K(i) = 23.4 +/- 7.1 nM and 53.5 +/- 13 nM for mGluR2 and mGluR3, respectively). On the basis of a successful result of compound 7, we focused on the introduction of a fluorine atom on the C6 position of compound 4. (1R,2S,5R, 6R)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid ((-)-11) exhibited a high degree of agonist activity for group II mGluRs equal to that of compound 4 or 7 ((-)-11: K(i) = 16.6 +/- 5.6 and 80.9 +/- 31 nM for mGluR2 and mGluR3, respectively). Our interest shifted to modification on CH(2) at C4 position of compound 11, since replacement of the CH(2) group with either an oxygen atom or sulfur atom yielded compound 5 or 6, resulting in increased agonist activity. We selected a carbonyl group instead of CH(2) at the C4 position of compound 11. The carbonyl group might slightly change the relative conformation of three functional groups, the amino group and two carboxylic acids, which have important roles in mediating the interaction between group II mGluRs and their ligand, compared with the CH(2) group of 4, oxygen atom of 5, and sulfur atom of 6. (1R,2S,5S,6S)-2-Amino-6-fluoro-4-oxobicyclo[3.1. 0]hexane-2,6-dicarboxylic acid monohydrate ((+)-14, MGS0028) exhibited a remarkably high degree of agonist activity for mGluR2 (K(i) = 0.570 +/- 0.10 nM) and mGluR3 (K(i) = 2.07 +/- 0.40 nM) expressed in CHO cells but not mGluR4, 6, 7, 1a, or 5 expressed in CHO cells (K(i) = >100 000 nM). Furthermore, compound (+)-14 strongly inhibited phencyclidine (PCP)-induced head-weaving behavior (ED(50) = 0.090 microg/kg) and hyperactivity (ED(50) = 0.30 mg/kg) in rats. Thus, (+)-7 and (+)-14 are potent, selective, and orally active group II mGluR agonists and might be useful not only for exploring the functions of mGluRs but in the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Hum Psychopharmacol 2002 Aug 17: 305-7 |
| PMID | 12404676 |
| Title | Tardive dyskinesia and impaired glucose tolerance. |
| Abstract | The authors examined the role of impaired glucose metabolism in the pathophysiology of tardive dyskinesia in schizophrenic patients with and without persistent TD. Glucose tolerance and insulin levels were determined in 86 patients with persistent tardive dyskinesia and in 108 patients without tardive dyskinesia. Dyskinesias were assessed by the abnormal involuntary movement scale (AIMS) and extrapyramidal symptoms by the Simpson--Angus rating scale (SARS). Fasting blood glucose levels were significantly lower while the first and second hour glucose levels did not reveal any differences in patients with tardive dyskinesia compared with those without tardive dyskinesia. Insulin levels did not differ in these two groups. Our cross-sectional epidemiological study does not suggest hyperglycemia to be a risk factor for tardive dyskinesia. However, prospective long-term studies with multiple assessment points are needed to clarify the role of glucose metabolism in the development of tardive dyskinesia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Schizophr. Res. 2003 Jan 59: 67-71 |
| PMID | 12413644 |
| Title | Clinical characteristics and associated factors in antipsychotic-induced akathisia of Asian patients with schizophrenia. |
| Abstract | We studied the prevalence of akathisia and its relationship to a number of sociodemographic and clinical factors in a population of Chinese inpatients with schizophrenia. Six-hundred and forty-five patients were recruited for the study. Akathisia was assessed using the Barnes Akathisia Rating Scale (BARS), dyskinesia by the Abnormal Involuntary Movement Scale (AIMS) and extrapyramidal side effects (EPSE) were assessed by the Simpson-Angus Rating Scale (SARS). Only 35 (5%) patients were assessed to have akathisia. There was no gender or ethnic difference in the rates of akathisia. However, the majority of the patients (65%) were receiving an anticholinergic agent at the time of the study. Our findings of an overlap between TD and EPSE support the suggestion that there may be a common vulnerability for these movement disorders. The finding of a low rate of akathisia among our Asian patients suggests an inter-ethnic difference in the vulnerability for the development of akathisia. However, comparing our results with the rates reported from other countries may be hampered by the diagnostic and methodological differences across studies. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Isr J Psychiatry Relat Sci 2005 -1 42: 258-62 |
| PMID | 16618059 |
| Title | Psychiatric inpatients' reactions to the SARS epidemic: an Israeli survey. |
| Abstract | The threat of the potential spreading of the SARS epidemic caused significant stress to many individuals from non-affected countries. In this study, we investigated whether the SARS threat affected the subjective mood and behavior of Israeli patients with schizophrenia and compared their reactions with those noted in their clinical staff. Subjects were evaluated with a specially designed questionnaire and a modified form of the Spielberger Scale for State Anxiety. As compared to staff, patients had higher scores on the Modified Spielberger State Anxiety Scale. However, many responses (e.g., dysphoria) to the SARS threat did not differ from staff. Patients felt more protected by the authorities and some perceived the epidemic in a psychotic manner. It seems that patients attempt to reduce the effect of external stressors by living in an "autistic bubble" (in which outside threats cannot enter) or by denying the significance of these stressors and over-emphasizing the power of medical authorities to protect them. On the other hand, some patients also psychotically interpreted these stressors. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Psychiatry Res 2006 Sep 144: 57-63 |
| PMID | 16904189 |
| Title | Diagnostic validity of assessment scales for depression in patients with schizophrenia. |
| Abstract | The aim of this study was to examine the diagnostic validity of four commonly used assessment scales for depression in schizophrenia. The study population consisted of 84 inpatients meeting the DSM-IV criteria for schizophrenia. Depression in the study subjects was defined by the DSM-IV criteria for major depressive episode. The Positive and Negative Syndrome Scale (PANSS) and the Simpson-Angus Rating Scale (SARS) were used to differentiate depression from the negative and extrapyramidal symptom-related depressive phenomena in schizophrenia. The following four depression scales were assessed for their diagnostic validity as measures of depressive disorder in schizophrenia: the Calgary Depression Scale for schizophrenia (CDSS), the Beck Depression Inventory (BDI), the Hamilton Rating Scale for Depression (HAM-D), and the depression subscale of the PANSS (PANSS-D). Of 84 patients with schizophrenia, 32 were diagnosed as having comorbid depressive disorder. The areas under the Receiver Operating Characteristic (ROC) curves of the CDSS, HAM-D, PANSS-D, and BDI were 0.94, 0.89, 0.90, and 0.81, respectively. The area under the ROC curve of the CDSS was significantly greater than that of the BDI and tended to be more favorable than those for the HAM-D and the PANSS-D. Our study suggests that the CDSS may provide the best assessment for depression in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Bioorg. Med. Chem. Lett. 2008 Jun 18: 3386-91 |
| PMID | 18455394 |
| Title | The discovery of fused pyrrole carboxylic acids as novel, potent D-amino acid oxidase (DAO) inhibitors. |
| Abstract | The 'NMDA hypofunction hypothesis of schizophrenia' can be tested in a number of ways. DAO is the enzyme primarily responsible for the metabolism of d-serine, a co-agonist for the NMDA receptor. We identified novel DAO inhibitors, in particular, acid 1, which demonstrated moderate potency for DAO in vitro and ex vivo, and raised plasma d-serine levels after dosing ip to rats. In parallel, analogues were prepared to survey the SARS of 1. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Zh Nevrol Psikhiatr Im S S Korsakova 2008 -1 108: 28-33 |
| PMID | 18577931 |
| Title | [The use of nifedipine as a corrector of extrapyramidal side-effects of classical neuroleptics]. |
| Abstract | The aim of the article was to study efficacy and safety of nifedipine in the correction of extrapyramidal side-effects emerged during conventional neuroleptics therapy. Fifty-one patients diagnosed with paranoid schizophrenia received haloperidol in combination with nifedipine (25 patients) or haloperidol only (26 patients) during 26 weeks. Dynamics of psychopathological symptoms and extrapyramidal disorders were measured with PANSS, CGI, BARS, SARS and AIMS. Patients receiving haloperidol in combination with nifedipine had the lower AIMS scores indicating appearances of dyskinesia and less marked (on the trend to statistical significance) SARS scores measuring parkinsonian symptoms as compared to patients receiving monotherapy with haloperidol. The administration of nifedipine in combination with haloperidol did not reduce the therapeutic efficacy of the latter and did not lead to the increase of side-effects. The data obtained suggest that nifedipine may be used as a perspective corrector of extrapyramidal disorders caused by classical neuroleptics. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Parkinsonism Relat. Disord. 2009 Nov 15: 655-9 |
| PMID | 19346155 |
| Title | The current prevalence and factors associated with tardive dyskinesia among Filipino schizophrenic patients. |
| Abstract | To determine the prevalence of and the factors associated with tardive dyskinesia (TD) among Filipino patients with schizophrenia admitted at the National Center for Mental Health. Cross-sectional study. A total of 227 inpatients fulfilling the DSM-IV TR criteria for schizophrenia participated in the study. Demographic data including age, disease duration and medication intake were obtained. The Abnormal Involuntary Movement Scale (AIMS) and Simpson Angus Rating Scale (SARS) were performed on all patients. Odds of developing TD in relation to the different variables were computed. The association between study variables and development of TD was also evaluated using the Chi-square test. Our cohort of patients had a mean age of 40 (range: 19-73 years old), had a mean disease duration of 6 years, had a daily neuroleptic dose of 700 mg in chlorpromazine equivalent, and had a lifetime neuroleptic exposure of at least 5 years. The prevalence rate of TD was 20.3% (46 out of 227 patients). Fifty-three percent of patients had significant extrapyramidal features (SARS > or =3). TD was noted more in females and older age groups. The other factors associated with TD: were those patients with longer duration of illness and those patients with longer cumulative exposure to neuroleptic drugs. There was no association found with regard to the presence of diabetes mellitus type II, to the use of anticholinergic drugs, to the history of substance abuse and to the history of electroconvulsive therapy. Despite the predominant use of first-generation antipsychotic agents, the prevalence of TD among Filipino schizophrenic patients is similar to that reported among Asians, but lower than that reported among our Western counterparts. The results may be affected by differences in methodological, racial and genetic determinants. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Parkinsonism Relat. Disord. 2009 Nov 15: 655-9 |
| PMID | 19346155 |
| Title | The current prevalence and factors associated with tardive dyskinesia among Filipino schizophrenic patients. |
| Abstract | To determine the prevalence of and the factors associated with tardive dyskinesia (TD) among Filipino patients with schizophrenia admitted at the National Center for Mental Health. Cross-sectional study. A total of 227 inpatients fulfilling the DSM-IV TR criteria for schizophrenia participated in the study. Demographic data including age, disease duration and medication intake were obtained. The Abnormal Involuntary Movement Scale (AIMS) and Simpson Angus Rating Scale (SARS) were performed on all patients. Odds of developing TD in relation to the different variables were computed. The association between study variables and development of TD was also evaluated using the Chi-square test. Our cohort of patients had a mean age of 40 (range: 19-73 years old), had a mean disease duration of 6 years, had a daily neuroleptic dose of 700 mg in chlorpromazine equivalent, and had a lifetime neuroleptic exposure of at least 5 years. The prevalence rate of TD was 20.3% (46 out of 227 patients). Fifty-three percent of patients had significant extrapyramidal features (SARS > or =3). TD was noted more in females and older age groups. The other factors associated with TD: were those patients with longer duration of illness and those patients with longer cumulative exposure to neuroleptic drugs. There was no association found with regard to the presence of diabetes mellitus type II, to the use of anticholinergic drugs, to the history of substance abuse and to the history of electroconvulsive therapy. Despite the predominant use of first-generation antipsychotic agents, the prevalence of TD among Filipino schizophrenic patients is similar to that reported among Asians, but lower than that reported among our Western counterparts. The results may be affected by differences in methodological, racial and genetic determinants. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | BMC Psychiatry 2014 -1 14: 166 |
| PMID | 24903304 |
| Title | Severity of psychotic episodes in predicting concurrent depressive and anxiety features in acute phase schizophrenia. |
| Abstract | Considering that depressive and anxiety symptoms are common in schizophrenia, this study investigated whether the severity of a psychotic episode in an acute phase schizophrenia cohort is predictive of concurrent depressive and anxiety features. Fifty one recently hospitalised patients suffering from acute phase schizophrenia participated prospectively in a cross-sectional study. The severity of the psychotic episode, the depressive features and the anxiety features were measured by the Structured Clinical Interview for Positive and Negative Syndrome Scale (SCI-PANSS), the Calgary Depression Scale for schizophrenia (CDSS), the Hamilton Anxiety Rating Scale (HAM-A) and the Staden schizophrenia Anxiety Rating Scale (S-SARS). The total SCI-PANSS-scores were adjusted to exclude appropriately the depression or anxiety items contained therein. To examine akathisia as potential confounder, the Barnes Akathisia Scale was also applied. The relationships were examined using linear regressions and paired t-tests were performed between lower and higher scores on the SCI-PANSS. A higher adjusted total SCI-PANSS-score predicted statistically significantly higher scores for depressive features on the CDSS (p < 0.0001) and for anxiety features on the HAM-A (p = 0.05) and the S-SARS (p < 0.0001). The group that scored more or equal to the median (=99) of the adjusted total SCI-PANSS, scored significantly higher (p < 0.0001) on the CDSS, the HAM-A and the S-SARS than the group scoring below it. Akathisia measured distinctly different (p < 0.0001) from both the anxiety measures. The study suggests that the severity of a psychotic episode in acute phase schizophrenia predicts the severity of concurrent depressive and anxiety features respectively. |
| SCZ Keywords | schizophrenia, schizophrenic |