| 1 | J Clin Psychiatry 2007 -1 68 Suppl 1: 12-9 |
|---|---|
| PMID | 17286523 |
| Title | Discontinuing and switching antipsychotic medications: understanding the CATIE schizophrenia trial. |
| Abstract | A new standard in effectiveness research on schizophrenia medications has been established by the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. The study used an innovative approach to determining relative effectiveness of medications by using time until medication discontinuation or switch as the primary outcome criterion. The study is perhaps best known for the overall high proportion of subjects (74%) meeting all-cause discontinuation (ACD) criteria within the 18-month time frame of being assigned to their phase 1 antipsychotic. However, some of the drawbacks of the ACD approach are not well understood, in part because of unfamiliarity with the way ACD was assessed and problems with the use of hierarchical criteria to establish the primary reason for medication discontinuation. Using the time until ACD as an endpoint cannot by itself capture the complexity of the trajectory of a patient's response to a new medication. In particular, it is quite plausible that switching medications upon entering CATIE phase 1 would reduce some symptoms, which then would lead to a greater desire to make another medication switch. Using ACD criteria, a comparison with CATIE subjects who coincidentally remained on treatment with their preswitch medication would make it seem that switching was detrimental when in fact it could have been helpful. Another major limitation of the ACD was omitting the recording of the reason for stopping study medication whenever the ACD was considered to be a "patient-decision" discontinuation. This means that patient-initiated discontinuations could never be classified as a tolerability discontinuation. Since the ACD was done by the patients' clinicians, this approach may have underestimated the proportion of side effect discontinuations whenever the patient disagreed with his or her clinician. Moreover, retaining the "patient-decision" discontinuation subgroup in the attributable risk estimates of tolerability discontinuations further minimizes the attributable risk estimate of the role of side effects relative to other causes of discontinuation. For these assumptions to be valid would require the very optimistic assumption that CATIE clinicians never underestimated tolerability concerns in their patients. Otherwise, this mutually exclusive approach will lead to significant underestimation of the proportion of CATIE discontinuations caused by tolerability problems. It can be argued that excluding the "patient decision" subgroup from the attributable risk estimate of role of tolerability in medication discontinuation is a better approach to mitigate against these biases. A reanalysis using an adjusted N of 1061 evaluable subjects changes the attributable portion of tolerability discontinuations from 14.9% to 38.5%. Regarding specific side effect-medication pairs of interest, the attributable risk of extrapyramidal symptoms as a reason for discontinuing perphenazine increases from 8% to 21%, and weight-related discontinuations from olanzapine from 9% to 28%. Therefore, the clinical implications of the CATIE phase 1 findings may depend, in part, on the underlying assumptions of the ACD outcome measure. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Mol. Psychiatry 2008 Nov 13: 1001-10 |
| PMID | 17848916 |
| Title | Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide. |
| Abstract | Suicide is a major public health problem with approximately 1 million victims each year worldwide. Up to 90% of adults who commit suicide have at least one psychiatric diagnosis such as major depression, bipolar disorder (BPD), schizophrenia (SZ), substance abuse or dependence. A question that has remained unanswered is whether the biological substrates of suicide are distinct from those of the psychiatric disorders in which it occurs. The serotonin 2C receptor (5-HT 2C R) has been implicated in depression and suicide. We, therefore, compared the frequencies of its mRNA editing variants in postmortem prefrontal cortical specimens from subjects who committed suicide or who died from other causes. All suicides occurred in the context of either SZ or BPD. The non-suicide cases included subjects with either SZ or BPD as well as subjects with no psychiatric diagnosis. We identified 5-HT 2CR mRNA editing variations that were associated with suicide but not with the comorbid psychiatric diagnoses, and were not influenced by demographic characteristics (age and sex) and alcohol or drug use. These variations consisted of a significant increase in the pool of mRNA variants (ACD and ABCD) that encode one of the most prevalent and highly edited isoforms of 5-HT 2C R, that is, VSV (Val156-Ser158-Val160). Because the VSV isoform of 5-HT 2C R exhibits low functional activity, an increase in its expression frequency may significantly influence the serotonergic regulation of the brain. Thus, at least in patients with SZ or BPD, overexpression of the VSV isoform in the prefrontal cortex may represent an additional risk factor for suicidal behavior. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | J. Mol. Graph. Model. 2008 Jan 26: 834-44 |
| PMID | 17561422 |
| Title | Molecular modeling of histamine H3 receptor and QSAR studies on arylbenzofuran derived H3 antagonists. |
| Abstract | Histamine H3 receptors are presynaptic autoreceptors found in both central and peripheral nervous systems of many species. The central effects of these receptors suggest a potential therapeutic role for their antagonists in treatment of several neurological disorders such as epilepsy, schizophrenia, Alzheimer's and Parkinson's diseases. The purpose of this study was to identify the structural requirements for H3 antagonistic activity via quantitative structure-activity relationship (QSAR) studies and receptor modeling/docking techniques. A combination of partial least squares (PLS) and genetic algorithm (GA) was used in the QSAR approach to select the structural descriptors relevant to the receptor binding affinity of a series of 58 H3 antagonists. The descriptors were selected out of a pool of >1000 descriptors calculated by DRAGON, Hyperchem and ACD labs suite of programs. The resulting QSAR models for rat and human H3 binding affinities were validated using different strategies. QSAR models generated in the current work suggested the role of charge transfer interactions in the ligand-receptor interaction verified using the molecular modeling of the receptor and docking two antagonists to the binding site. The 3D model of human H3 receptor was built based on bovine rhodopsin structure and evaluated by molecular dynamics (MD) simulation in a mixed water-vacuum-water environment. The results were indicative of the stability of the model relating the observed structural changes during the MD simulation to the suggested ligand-receptor interactions. The results of this investigation are expected to be useful in the process of design and development of new potent H3 receptor antagonists. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Neuropsychobiology 2011 -1 63: 197-201 |
| PMID | 21422766 |
| Title | Quetiapine, olanzapine and haloperidol affect human plasma lipid peroxidation in vitro. |
| Abstract | Oxidative injury in schizophrenia may be caused not only by pathophysiological processes but partly also by treatment with antipsychotics. The purpose of the present study was to examine and to compare the effects of quetiapine (QUE), olanzapine (OLA) and haloperidol (HAL), at final concentrations corresponding to doses used for treatment of acute episodes of schizophrenia, on plasma lipid peroxidation in vitro, measured by the level of thiobarbituric acid-reactive substances (TBARS). Blood from 30 healthy volunteers was collected into ACD (citric acid/citrate/dextrose) solution. The drugs in form of active substances were dissolved in 0.01% dimethyl sulfoxide, added to plasma at the final concentrations [QUE (175 and 275 ng/ml), OLA (20 and 40 ng/ml), HAL (4 and 20 ng/ml)] and incubated for 1 and 24 h at 37 °C. The level of TBARS was measured spectrophotometrically (according to the Rice-Evans method, 1991). The comparative study in vitro showed that QUE causes a decrease in the TBARS level in plasma, whereas HAL increases the plasma TBARS level. After 24 h of incubation of plasma with QUE or HAL (at lower and higher concentrations),thedifferences in TBARS levels between the drugs were significant (p = 5.9 × 10??, p = 2.2 × 10??, respectively). QUE and OLA, contrary to the prooxidative action of HAL, did not induce oxidative stress; moreover, QUE has antioxidant properties. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | J Health Popul Nutr 2015 -1 33: 24 |
| PMID | 26825414 |
| Title | The opioid effects of gluten exorphins: asymptomatic celiac disease. |
| Abstract | Gluten-containing cereals are a main food staple present in the daily human diet, including wheat, barley, and rye. Gluten intake is associated with the development of celiac disease (CD) and related disorders such as diabetes mellitus type I, depression, and schizophrenia. However, until now, there is no consent about the possible deleterious effects of gluten intake because of often failing symptoms even in persons with proven CD. Asymptomatic CD (ACD) is present in the majority of affected patients and is characterized by the absence of classical gluten-intolerance signs, such as diarrhea, bloating, and abdominal pain. Nevertheless, these individuals very often develop diseases that can be related with gluten intake. Gluten can be degraded into several morphine-like substances, named gluten exorphins. These compounds have proven opioid effects and could mask the deleterious effects of gluten protein on gastrointestinal lining and function. Here we describe a putative mechanism, explaining how gluten could "mask" its own toxicity by exorphins that are produced through gluten protein digestion. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |