Antipsychotic pharmacogenomics in first episode psychosis: a role for glutamate genes.

Genetic factors may underlie beneficial and adverse responses to antipsychotic treatment. These relationships may be easier to identify among patients early in the course of disease who have limited exposure to antipsychotic drugs. We examined 86 first episode patients (schizophrenia, psychotic bipolar disorder and major depressive disorder with psychotic features) who had minimal to no prior antipsychotic exposure in a 6-week pharmacogenomic study of antipsychotic treatment response. Response was measured by change in Brief Psychiatric Rating Scale total score. Risperidone monotherapy was the primary antipsychotic treatment. Pharmacogenomic association studies were completed to (1) examine candidate single-nucleotide polymorphisms (SNPs) in genes known to be involved with glutamate signaling, and (2) conduct an exploratory genome-wide association study of symptom response to identify potential novel associations for future investigation. Two SNPs in GRM7 (rs2069062 and rs2014195) were significantly associated with antipsychotic response in candidate gene analysis, as were two SNPs in the human glutamate receptor delta 2 (GRID2) gene (rs9307122 and rs1875705) in genome-wide association analysis. Further examination of these findings with those from a separate risperidone-treated study sample demonstrated that top SNPs in both studies were overrepresented in glutamate genes and that there were similarities in neurodevelopmental gene categories associated with drug response from both study samples. These associations indicate a role for gene variants related to glutamate signaling and antipsychotic response with more broad association patterns indicating the potential importance of genes involved in neuronal development.

Pretargeted radioimmunotherapy (PRIT) for treatment of non-Hodgkin's lymphoma (NHL).

Pretargeted radioimmunotherapy (PRIT) was first investigated in a series of phase I and phase II studies in patients with adenocarcinoma using a pancarcinoma antibody, NR-LU-10. The principles and schema developed were then applied to an initial study in patients with non-Hodgkin's lymphoma (NHL). The PRIT approach used is a multi-step delivery system in which an antibody is used to target streptavidin to a tumor-associated antigen receptor, and subsequently, biotin is used to target the 90Y radioisotope to the tumor localized streptavidin. In the NHL study, a chimeric, IgG1, anti-CD20 antibody (Rituximab) was conjugated to streptavidin (SA) and administered to patients. Thirty-four hours later, a clearing agent, synthetic biotin-N-acetyl-galactosamine, was administered to remove non-localized conjugate from the circulation. Finally, a DOTA-biotin ligand, labeled with 111In for imaging and/or 90Y for therapy was administered. Ten patients with relapsed or refractory NHL were studied, and seven received 30 or 50 mCi/m(2) 90Y DOTA-biotin. Preliminary studies using 186Re labeled conjugate confirmed that it localized to tumor and that the clearing agent removed >95% of the conjugate from the circulation. Radiolabeled biotin localized well to tumor. Unbound radiobiotin was rapidly excreted from the whole body and normal organs. The mean tumor dose calculated was 29+/-23 cGy/mCi 90Y, and the mean tumor to whole body dose ratio was 38:1. Only grade I/II non-hematologic toxicity was observed. Hematologic toxicity was also not severe; i.e. five of the seven patients who received 30 or 50 mCi/m(2) of 90Y-DOTA-biotin experienced only transient grade III (but no grade IV) hematologic toxicity. Although six of 10 patients developed humoral immune responses to the streptavidin, these were delayed and transient and hence may not preclude retreatment. Six of seven patients who received 30 or 50mCi/m(2) 90Y achieved objective tumor regression, including three complete and one partial response. The estimate of tumor to whole body dose ratio (38:1) achieved with PRIT in these NHL patients is higher than that achieved in other studies using conventional RIT. Toxicity was mild and tumor response encouraging. PRIT clearly deserves additional study in patients with NHL.

Cationic liposome-mediated E1A gene transfer to human breast and ovarian cancer cells and its biologic effects: a phase I clinical trial.

PURPOSE: Preclinical studies have demonstrated that the adenovirus type 5 E1A gene is associated with antitumor activities by transcriptional repression of HER-2/neu and induction of apoptosis. Indeed, E1A gene therapy is known to induce regression of HER-2/neu-overexpressing breast and ovarian cancers in nude mice. Therefore, we evaluated the feasibility of intracavitary injection of E1A gene complexed with DC-Chol cationic liposome (DCC-E1A) in patients with both HER-2/neu-overexpressing and low HER-2/neu-expressing breast and ovarian cancers in a phase I clinical trial. PATIENTS AND METHODS: An E1A gene complexed with DCC-E1A cationic liposome was injected once a week into the thoracic or peritoneal cavity of 18 patients with advanced cancer of the breast (n = 6) or ovary (n = 12). RESULTS: E1A gene expression in tumor cells was detected by immunohistochemical staining and reverse transcriptase-polymerase chain reaction. This E1A gene expression was accompanied by HER-2/neu downregulation, increased apoptosis, and reduced proliferation. The most common treatment-related toxicities were fever, nausea, vomiting, and/or discomfort at the injection sites. CONCLUSION: These results argue for the feasibility of intracavitary DCC-E1A administration, provide a clear proof of preclinical concept, and warrant phase II trials to determine the antitumor activity of the E1A gene.

Medication supervision and adherence of persons with psychotic disorders in residential treatment settings: a pilot study.

BACKGROUND: Little is known about risk factors for and predictors of medication nonadherence within residential facilities. This pilot study examined the association between medication adherence and level of supervision and other environmental and clinical variables among patients with schizophrenia and related psychotic disorders living in supported housing. METHOD: A convenience sample of 74 adult residents with schizophrenia and related psychotic disorders (DSM-IV criteria) living in 4 supported housing facilities in New York City were assessed by their treating psychiatrist for medication cessation during the previous month. Demographic characteristics, medications, supervision, global function as measured by the Global Assessment of Functioning (GAF), and substance abuse were also assessed. A priori hypotheses were that regimen complexity would be directly and medication supervision would be inversely related to medication nonadherence. RESULTS: In multivariate models, lack of direct medication supervision, negative medication attitude, and lower GAF score were associated with increased medication nonadherence in the recent past. CONCLUSION: This pilot study suggests that direct supervision of medication is associated with better adherence in residential treatment settings. This finding is relevant for mental health service planners and clinicians working in these settings.

Which side effects really matter? Screening for common and distressing side effects of antipsychotic medications.

As a class, the newer antipsychotics are less likely to cause EPS but continue to have a range of other, non-EPS, side effects. Most standardized scales for side effects of antipsychotics emphasize the physical findings of the motor abnormalities of extrapyramidal symptoms (EPS). There is a need for screening instruments that include both EPS and non-EPS side effects. This article discusses the development of a screening instrument called the Approaches to Schizophrenia Communication (ASC). Initially derived from other subjective screening measures, the ASC was specifically designed to address the following issues pertaining to side effect evaluation of antipsychotics: 1) to cover all common and distressing side effects from antipsychotics, not just EPS, and 2) to screen for perceived distress, rather than the objective severity of the side effect. These two characteristics of the ASC make it possible for it to be given directly to the patient (the ASC Self-Report Version) or to be administered by mental health clinicians who do not have to be extensively trained in side-effect assessments (the ASC Clinician Interview version).

An innovative approach to clinical communication in schizophrenia: the approaches to schizophrenia communication checklists.

Side effects from antipsychotic medications can have a profound effect on patients' lives and may adversely affect their willingness to comply with treatment. Identification of side effects through improved communication between psychiatrists, other members of the healthcare team, and their patients might increase treatment compliance. The Approaches to Schizophrenia Communication (ASC) Steering Group developed two simple, practical checklists for use in the busy clinical setting. The ASC-Self-Report (ASC-SR) checklist is completed by the patient and comprises a list of the more common or clinically important side effects of antipsychotic treatment. The ASC-Clinic (ASC-C) checklist is completed by both clinician and patient together, being used as the basis for a semi-structured interview. In a multicenter pilot study set up to evaluate the utility of checklists, 86% of patients responding considered the ASC-SR to be useful in communicating their problems to psychiatrists and other members of the healthcare team. All healthcare team respondents found both checklists to be helpful when discussing side effect problems with their patients. Moreover, 41% and 47% of healthcare team respondents reported that the ASC-SR and ASC-C, respectively, had assisted them in identifying side-effect problems not previously acknowledged. Preliminary evaluation of the ASC-SR and ASC-C in this multicenter pilot study suggests that both tools were user-friendly, encouraged communication between patients and healthcare professionals about antipsychotic drug side effects, and could readily integrated into everyday clinical practice.

Prevalence and correlates of diabetes in national schizophrenia samples.

People with schizophrenia may be at increased risk for Type II diabetes because of the side effects of antipsychotic medication, poorer overall physical health, less healthy lifestyles, and poorer health care. The present study uses data bases collected by the Schizophrenia Patient Outcomes Research Team (PORT) to assess the prevalence and demographic and clinical correlates of diabetes within large populations of persons receiving treatment for schizophrenia. In the Schizophrenia PORT, Medicaid and Medicare data from 1991 and more recent interview data were collected regarding the comorbidity of schizophrenia and diabetes: prevalence, quality of life, physical health, and services utilization and costs. The study found that rates of diagnosed diabetes exceeded general population statistics well before the widespread use of the new antipsychotic drugs. Risk factors for diabetes were similar to those observed in the general population. The linkage of diabetes to poor physical health, medical morbidity, and increased service use and cost requires attention. This study of diabetes in the early 1990s suggests that even before the widespread use of the atypical antipsychotic drugs, diabetes was a major problem for persons with schizophrenia.

High-dose busulfan, melphalan and thiotepa as consolidation for non-inflammatory high-risk breast cancer.

The purpose of this study was to evaluate the toxicity and efficacy of high-dose busulfan, melphalan and thiotepa (Bu/Mel/TT) in patients with high-risk non-inflammatory breast cancer defined as stage II disease > or =10 lymph nodes (n = 52) or stage III (n = 69), and prognostic factors for treatment outcome. One hundred and twenty-one patients (median age, 46 years) were treated with high-dose Bu (12 mg/kg), Mel (100 mg/m2) and TT (500 mg/m2) (HDC) followed by autologous stem cell infusion (ASCI). One hundred patients were initially treated with surgery followed by standard adjuvant chemotherapy prior to HDC/ASCI. Twenty-one patients with stage III disease had inoperable tumors at diagnosis and were treated with neoadjuvant chemotherapy and surgery before HDC/ASCI. Transplant-related mortality was 6%. The probabilities of event-free survival (EFS) at 3 and 5 years (median follow-up of 36 months) from transplant were, for all patients: 0.62-0.60; stage II: 0.71-0.67: stage III: 0.55-0.55 (for stage III adjuvant and neoadjuvant groups: 0.60-0.60 and 0.42-0.42, respectively). Multivariate analysis did not identify variables associated with poor outcome. The efficacy of Bu/Mel/TT is similar to other HDC regimens reported for patients with high-risk non-inflammatory breast cancer. Bu/Mel/TT has high activity in stage II disease and a moderate benefit in stage III operable tumors.

Interferon alpha-2a and 13-cis-retinoic acid in patients with metastatic renal cell cancer.

Treatment of patients with metastatic renal cell cancer (RCC) with interferon-alpha-2a (IFN) and 13-cis-retinoic acid (CRA) was first reported to be tolerable on an outpatient basis and to yield a 30% objective response rate. We sought to confirm these preliminary results by conducting a phase II trial of therapy with IFN/CRA in patients with bidimensionally measurable RCC. Twenty-five patients were enrolled. The median age was 58 (range, 47-75 years) and the median Karnofsky performance status was 90 (range 60-100). Seventeen patients (60%) had undergone prior nephrectomy and none had received prior systemic therapy. Treatment consisted of oral CRA at 1 mg/kg/day and IFN self-administered by subcutaneous injection at 3 MU/day with weekly escalation to 6 and 9 MU/day. Treatment was well tolerated, with cheilitis, influenza-like symptoms, and fatigue the most common toxicities. Severe toxicity was reversible and consisted of grade 4 cheilitis in one patient and grade 3 malaise/fatigue in two patients. One complete and four partial responses were observed, for an objective response rate of 20% (95% confidence interval, 4-36%). We conclude that treatment with CRA/IFN for RCC is tolerable on an outpatient basis and induces objective responses in some patients. The contribution, if any, of CRA to the responses observed will be determined in ongoing randomized phase III trials.

Pretargeted radioimmunotherapy (PRIT) for treatment of non-Hodgkin's lymphoma (NHL): initial phase I/II study results.

Pretargeted radioimmunotherapy (PRIT) was investigated in patients with non-Hodgkin's lymphoma (NHL). The PRIT approach used in this study is a multi-step delivery system in which an antibody is used to target streptavidin to a tumor associated antigen receptor, and subsequently biotin is then used to target 90Y radioisotope to the tumor localized streptavidin. A chimeric, IgG1, anti-CD20 antibody, designated C2B8 or Rituximab, was conjugated to streptavidin (SA) and administered to patients with NHL. Thirty-four hours later, a clearing agent, synthetic biotin-N-acetyl-galactosamine, was administered to remove non-localized conjugate from the circulation. Finally, a DOTA-biotin ligand, labeled with 111In for imaging and/or 90Y for therapy was administered. Ten patients with relapsed or refractory NHL were studied. In three patients, the C2B8/SA conjugate was radiolabeled with a trace amount of 186Re in order to assess pharmacokinetics and biodistribution using gamma camera imaging. Seven patients received 30 or 50 mCi/m2 90Y DOTA-biotin. Re-186 C2B8/SA images confirmed that the conjugate localized to known tumor sites and that the clearing agent removed > 95% of the conjugate from the circulation. Radiolabeled biotin localized well to tumor. Unbound radiobiotin was rapidly excreted from the whole body and normal organs. The mean tumor dose calculated was 29 +/- 23 cGy/mCi 90Y and the average whole body dose was 0.76 +/- 0.3 cGy/mCi 90Y, resulting in a mean tumor to whole body dose ratio of 38:1. Only grade I/II non-hematologic toxicity was observed. Hematologic toxicity was also not severe; i.e., five of the seven patients who received 30 or 50 mCi/m2 of 90Y-DOTA-biotin experienced only transient grade III (but no grade IV) hematologic toxicity. Although six of ten patients developed humoral immune responses to the streptavidin, these were delayed and transient and hence may not preclude retreatment. Six of seven patients who received 30 or 50mCi/m2 90Y achieved objective tumor regression, including three complete and one partial response. The estimate of tumor to whole body dose ratio (38:1) achieved with PRIT in these NHL patients is higher than has been achieved in other studies using conventional RIT. Toxicity was mild and tumor response encouraging. PRIT clearly deserves additional study in patients with NHL.

Predicting medication noncompliance after hospital discharge among patients with schizophrenia.

OBJECTIVE: The study sought to identify predictors of noncompliance with medication in a cohort of patients with schizophrenia after discharge from acute hospitalization. METHODS: Adult psychiatric inpatients with schizophrenia or schizoaffective disorder for whom oral antipsychotics were prescribed (N=213) were evaluated at hospital discharge and three months later to assess medication compliance. Comparisons were made between patients who reported stopping their medications for one week or longer and patients who reported more continuous medication use. RESULTS: Of the 213 patients, about a fifth (19.2 percent) met the criterion for noncompliance. Medication noncompliance was significantly associated with an increased risk of rehospitalization, emergency room visits, homelessness, and symptom exacerbation. Compared with the compliant group, the noncompliant group was significantly more likely to have a history of medication noncompliance, substance abuse or dependence, and difficulty recognizing their own symptoms. Patients who became medication noncompliant were significantly less likely to have formed a good therapeutic alliance during hospitalization as measured by inpatient staff reports and were more likely to have family members who refused to become involved in their treatment. CONCLUSIONS: Patients with schizophrenia at high risk for medication noncompliance after acute hospitalization are characterized by a history of medication noncompliance, recent substance use, difficulty recognizing their own symptoms, a weak alliance with inpatient staff, and family who refuse to become involved in inpatient treatment.

Phase II trial of yttrium-90-DOTA-biotin pretargeted by NR-LU-10 antibody/streptavidin in patients with metastatic colon cancer.

A Phase II study of yttrium-90-tetra-azacyclododecanetetra-acetic acid-biotin (90Y-DOTA-biotin) pretargeted by NR-LU-10 antibody/streptavidin (SA) was performed. The primary objectives of the study were to evaluate the efficacy and safety of this therapy in patients with metastatic colon cancer. Twenty-five patients were treated with a single dose of 110 mCi/m2 (mean administered dose, 106.5 +/- 10.3 mCi/m2) of 90Y-DOTA-biotin. There were three components of the therapy. Patients first received NR-LU-10/SA on day 1. A clearing agent (biotin-galactose-human serum albumin) was administered approximately 48 h after the NR-LU-10/SA to remove residual circulating unbound NR-LU-10/SA. Lastly, 24 h after administration of clearing agent, patients received biotin-DOTA-labeled with 110 mCi/m2 90Y. All three components of the therapy were administered i.v. Both hematological and nonhematological toxicities were observed. Diarrhea was the most frequent grade 4 nonhematological toxicity (16%; with 16% grade 3 diarrhea). Hematological toxicity was less severe with 8% grade 3 and 8% grade 4 neutropenia and 8% grade 3 and 16% grade 4 thrombocytopenia. The overall response rate was 8%. Two partial responders had freedom from progression of 16 weeks. Four patients (16%) had stable disease with freedom from progression of 10-20 weeks. Despite the relatively disappointing results of this study in terms of therapeutic efficacy and toxicity, proof of principle was obtained for the pretargeting approach. In addition, valuable new information was obtained about normal tissue tolerance to low-dose-rate irradiation that will help to provide useful guidelines for future study designs.

Clinical optimization of pretargeted radioimmunotherapy with antibody-streptavidin conjugate and 90Y-DOTA-biotin.

UNLABELLED: Pretargeted radioimmunotherapy (PRIT) was evaluated using an antibody-streptavidin conjugate, followed by a biotin-galactose-human serum albumin clearing agent and 90Y-dodecane tetraacetic acid (DOTA)-biotin as the final step for therapy. The objective was to develop a clinical protocol that could show an improved tumor-to-red marrow therapeutic ratio compared with conventional radioimmunotherapy (RIT) and at the same time preserve the efficiency of tumor targeting. METHOD: Forty-three patients with adenocarcinomas reactive to NR-LU-10 murine monoclonal antibody received the 3 components. Doses and timing parameters were varied to develop an optimized schema. In some patients, the conjugate was radiolabeled with 186Re as an imaging tracer to assess biodistribution of the conjugate and effectiveness of the clearing agent. 111In-DOTA-biotin was coinjected with 90Y-DOTA-biotin for quantitative imaging. Safety, biodistribution, pharmacokinetics, dosimetry, and antiglobulin formation were evaluated. RESULTS: The optimal schema was defined as a conjugate dose of 125 microg/mL plasma volume followed at 48 h by a clearing agent in a 10:1 molar ratio of clearing agent to serum conjugate. The therapeutic third step was 0.5 mg radiobiotin administered 24 h later. No significant adverse events were observed after administration of any of the components. The mean tumor-to-marrow absorbed dose ratio when using the optimized PRIT schema was 63:1, compared with a 6:1 ratio reported previously for conventional RIT. Antiglobulin to murine antibody and to streptavidin developed in most patients. CONCLUSION: This initial study confirmed that the PRIT approach is safe and feasible and achieved a higher therapeutic ratio than that achieved with conventional RIT using the same antibody.

Antipsychotic-induced weight gain: a comprehensive research synthesis.

OBJECTIVE: The purpose of this study was to estimate and compare the effects of antipsychotics-both the newer ones and the conventional ones-on body weight. METHOD: A comprehensive literature search identified 81 English- and non-English-language articles that included data on weight change in antipsychotic-treated patients. For each agent, a meta-analysis and random effects metaregression estimated the weight change after 10 weeks of treatment at a standard dose. A comprehensive narrative review was also conducted on all articles that did not yield quantitative information but did yield important qualitative information. RESULTS: Placebo was associated with a mean weight reduction of 0.74 kg. Among conventional agents, mean weight change ranged from a reduction of 0.39 kg with molindone to an increase of 3.19 kg with thioridazine. Among newer antipsychotic agents, mean increases were as follows: clozapine, 4.45 kg; olanzapine, 4.15 kg; sertindole, 2.92 kg; risperidone, 2.10 kg; and ziprasidone, 0.04 kg. Insufficient data were available to evaluate quetiapine at 10 weeks. CONCLUSIONS: Both conventional and newer antipsychotics are associated with weight gain. Among the newer agents, clozapine appears to have the greatest potential to induce weight gain, and ziprasidone the least. The differences among newer agents may affect compliance with medication and health risk.

Compliance and the rehabilitation alliance.

Expectations for the treatment of schizophrenia have historically been modest, with emphasis on eliminating positive symptoms and keeping patients out of the hospital. Noncompliance with traditional antipsychotic agents, which have limited efficacy and are associated with numerous adverse side effects, has contributed to these low expectations. The atypical antipsychotics can improve compliance because of their better safety, efficacy, and tolerability and thus help raise treatment expectations from mere removal of symptoms to fuller rehabilitation. This rehabilitation can even include the reintegration of patients with schizophrenia into the community. Compliance with any drug regimen, however, does not in itself guarantee the return to a normal life for patients with schizophrenia. Instead, compliance must occur within a rehabilitation alliance--a supportive network that includes the patient, the treating physician, family members and friends, and other caregivers.