Lack of insight in schizophrenia: impact on treatment adherence.

People with schizophrenia commonly lack insight, that is, they are unaware of their illness and the consequences thereof. One of the most important consequences of lack of insight is a failure to recognise the need for treatment, leading to treatment nonadherence. With several scales that now enable objective measurement of insight, it is possible to examine correlates of insight change, including course of illness and treatment adherence. Specific interventions, both pharmacological and psychotherapeutic, have been developed to enhance illness insight and treatment adherence. The extent to which second-generation antipsychotic medications, including a recently released long-acting formulation, improve insight and/or enhance treatment adherence remains to be determined.

A wellness class for inpatients with psychotic disorders.

OBJECTIVE: The purpose of this project was to educate inpatients with psychotic disorders, many of whom were taking second-generation antipsychotics, about lifestyle changes they can make to combat weight gain. METHOD: All inpatients on a Veterans Affairs acute inpatient schizophrenia treatment unit were invited to a 30-minute, didactic presentation given by a medical student and a psychology student under the supervision of the primary investigator. The topics covered included the health benefits of maintaining an ideal body weight by selecting foods according to the USDA Food Pyramid, determining adequate food portions, choosing healthy meals outside the home, and beginning and adhering to an exercise program. Subjects completed a 13-item quiz concerning their knowledge of food and nutrition before and after the presentation to determine its efficacy in teaching patients the material. RESULTS: Fifty patients completed both the pre- and post-presentation tests. The mean percentage of correct answers on the pre-test was 85.6%, which rose to 89.3% on the post-test. This difference of 3.7% was statistically significant (t = 2.43, df = 49, p < 0.02), and the mean percent of improvement was 6.1%. CONCLUSIONS: This study demonstrates that psychotic individuals are able to benefit from educational presentations about nutrition and a healthy lifestyle. A statistically significant improvement in test scores suggests that subjects gained an understanding of basic concepts related to food choices and fitness.

A videotape intervention to enhance the informed consent process for medical and psychiatric treatment research.

OBJECTIVE: This study evaluated a brief educational video designed to enhance the informed consent process for people with serious mental and medical illnesses who are considering participating in treatment research. METHOD: Individuals with schizophrenia who were being recruited for ongoing clinical trials, medical patients without self-reported psychiatric comorbidity, and university undergraduates were randomly assigned to view either a highly structured instructional videotape about the consent process in treatment research or a control videotape that presented only general information about bioethical issues in human research. Knowledge about informed consent was measured before and after viewing. RESULTS: Viewing the experimental videotape resulted in larger gains in knowledge about informed consent. Standardized effect sizes were large in all groups. CONCLUSIONS: The videotape was thus an effective teaching tool across diverse populations, ranging from individuals with severe chronic mental illness to university undergraduates.

Possible association of QTc interval prolongation with co-administration of quetiapine and lovastatin.

BACKGROUND: QTc interval prolongation can occur as a result of treatment with both conventional and novel antipsychotic medications and is of clinical concern because of its association with the potentially fatal ventricular arrhythmia, torsade de pointes. METHODS: One case is described in which a patient with schizophrenia, who was being treated for dyslipidemia, developed a prolonged QTc interval while taking quetiapine and lovastatin. RESULTS: QTc returned to baseline when the lovastatin dose was reduced. CONCLUSIONS: QTc prolongation associated with antipsychotic medication occurs in a dose-dependent manner. We therefore hypothesize that the addition of lovastatin caused an increase in plasma quetiapine levels through competitive inhibition of the cytochrome P(450) (CYP) isoenzyme 3A4. Our case highlights the potential for a drug interaction between quetiapine and lovastatin leading to QTc prolongation during the management of dysipidemia in patients with schizophrenia.

The neurocognitive effects of low-dose haloperidol: a two-year comparison with risperidone.

BACKGROUND: Neurocognitive deficits are core features of schizophrenia that are linked to functional outcome for the disorder. Recent studies and reviews have concluded that newer antipsychotic medications are better for neurocognitive deficits than conventional antipsychotic medications; however, one difficulty in interpreting this literature is that the comparisons have mainly been with high doses of conventional medications. This study examined the neurocognitive effects of low-dose haloperidol compared with risperidone over a 2-year period. METHODS: Sixty-two patients were randomly assigned to medication (starting at 6 mg of each medication) and administered neurocognitive batteries six times over the course of follow-up. At 6 months, the mean dose of haloperidol was 5.0 mg, and the mean dose of risperidone was 6.0 mg. Neurocognitive data were reduced into cluster scores and a global summary score. RESULTS: We found no significant overall differences in treatment effects on the cluster scores or the global score. The global score revealed a significant group by time interaction, reflecting the fact that the haloperidol group tended to improve initially and then stay stable, whereas the risperidone group improved more gradually over the follow-up period. CONCLUSIONS: This study did not provide support for neurocognitive advantages of a newer antipsychotic medication over a low-dose conventional medication. We speculate that conventional medications may have neurocognitive benefits at low doses that are neutralized or reversed at higher doses.

Maintenance treatment of schizophrenia with risperidone or haloperidol: 2-year outcomes.

OBJECTIVE: Most controlled studies comparing second-generation and conventional antipsychotics have focused on the acute treatment of schizophrenia. The authors compared symptom outcomes, side effects, and social adjustment in stable schizophrenia outpatients who received 2 years of maintenance treatment with risperidone or haloperidol. METHOD: This was a 2-year, randomized, double-blind comparison of 6 mg of risperidone versus haloperidol in 63 patients with stabilized DSM-IV schizophrenia. Study patients also received 15 months of standard behavioral skills training or enhanced training with a case manager who promoted patients' use of their skills in the community. RESULTS: The risk of psychotic exacerbations and the risk of leaving the study were similar for both drug treatment groups. However, patients who received both risperidone and the enhanced community-based skills training were more likely to remain in the study than those in the other treatment groups. Patients demonstrated significant improvement in score on the Brief Psychiatric Rating Scale over time with both medications. There were no between-group differences in cluster scores for thought disturbance, hostile-suspiciousness, and withdrawal-retardation. A significant between-group difference favoring risperidone was found for the anxious-depression cluster. Risperidone resulted in significantly greater reductions in tremor and akathisia and greater improvements in most items on the SCL-90-R. CONCLUSIONS: When compared with patients given a low dose of haloperidol, risperidone-treated patients experienced similar improvements in positive and negative symptoms and similar risks of psychotic exacerbations. However, risperidone-treated patients appeared to feel subjectively better, as indicated by less anxiety and depression and fewer extrapyramidal side effects.

Supplementing clinic-based skills training with manual-based community support sessions: effects on social adjustment of patients with schizophrenia.

OBJECTIVE: Although skills training is a validated psychosocial treatment for schizophrenia, generalization of the skills to everyday life has not been optimal. This study evaluated a behaviorally oriented method of augmenting clinic-based skills training in the community with the aim of improving opportunities, encouragement, and reinforcement for outpatients to use their skills in their natural environment. METHOD: Sixty-three individuals with schizophrenia were randomly assigned to 60 weeks of clinic-based skills training alone or of clinic-based skills training supplemented with manual-based generalization sessions in the community. Patients were also randomly assigned to receive either haloperidol or risperidone. Therapists' fidelity to the manuals was measured. Patients' acquisition of the skills from pre- to posttraining was evaluated. The primary outcome measures were the Social Adjustment Scale-II and the Quality of Life Scale. RESULTS: Seventy-one percent of the patients completed the trial. Only six participants experienced psychotic exacerbations during the trial. There was no evidence of a differential medication effect on social functioning. Social functioning improved modestly in both psychosocial conditions over time; participants who received augmented skills training in the community showed significantly greater and/or quicker improvements. CONCLUSIONS: Given judicious and effective antipsychotic medication that limited exacerbations to less than 10% during the trial, a wide range of outpatients with schizophrenia demonstrated substantial learning of illness management and social skills in the clinic. When clinic-based skills training was augmented by in vivo training and consultation, transfer of the skills to everyday life was enhanced. These benefits were established regardless of the medications prescribed.

Physical health monitoring of patients with schizophrenia.

OBJECTIVE: Schizophrenia is associated with several chronic physical illnesses and a shorter life expectancy, compared with life expectancy in the general population. One approach to improving the health of patients with schizophrenia is to improve the monitoring of physical health that occurs in psychiatric settings. The authors discuss a consensus panel's recommendations for improving the physical health monitoring of patients with schizophrenia who are treated in outpatient settings. METHOD: A consensus meeting including psychiatric and other medical experts assembled on October 17-18, 2002, to evaluate the existing literature and to develop recommendations for physical health monitoring of patients with schizophrenia. Conference participants reviewed the literature in the following areas: 1) weight gain and obesity; 2) diabetes; 3) hyperlipidemia; 4) prolongation of the QT interval on the ECG; 5) prolactin elevation and related sexual side effects; 6) extrapyramidal side effects, akathisia, and tardive dyskinesia; 7) cataracts; and 8) myocarditis. Experts for each topic area formulated monitoring recommendations that were discussed by all of the participants until a consensus was reached. RESULTS: Consensus recommendations included regular monitoring of body mass index, plasma glucose level, lipid profiles, and signs of prolactin elevation or sexual dysfunction. Information from monitoring should guide the selection of antipsychotic agents. Specific recommendations were made for cardiac monitoring of patients who receive medications associated with QT interval prolongation, including thioridazine, mesoridazine, and ziprasidone, and for monitoring for signs of myocarditis in patients treated with clozapine. Patients who receive both first- and second-generation antipsychotic medications should be examined for extrapyramidal symptoms and tardive dyskinesia. Patients with schizophrenia should receive regular visual examinations. CONCLUSIONS: The conference participants recommended that mental health care providers perform physical health monitoring that typically occurs in primary care settings for their patients who do not receive physical health monitoring in those settings. This change in usual practice is recommended on the basis of the conference participants' belief that this additional monitoring will result in the earlier detection of common, serious risk factors that could, without detection and intervention, contribute to impaired health of patients with schizophrenia.

Alteration of branch site consensus sequence and enhanced pre-mRNA splicing of an NMDAR1 intron not associated with schizophrenia.

Aberrant splicing of pre-mRNA is recognized to account for a significant minority of disease-causing mutations. The N-methyl-D-aspartate receptor (NMDA) subunit gene R1 (NMDAR1) is alternatively spliced to produce eight length variants. In an examination of the NMDAR1 as a candidate gene in schizophrenia, a presumed microdeletion/insertion (del/ins) was observed in intron 10 of an African-American male near a weak putative branch-site consensus sequence. Although exon 10 is not known to be alternatively spliced, the del/ins was posited to alter splicing efficiency. If splicing were abolished and intron retention occurred, an in-frame translation product of more than 250 amino acids was predicted. To explore splicing efficiency, mini genes were examined through primer-extension analyses in NIH293 embryonic kidney cell cultures. Rather than disruption of splicing, the del/ins allele exhibited a fivefold enhancement in splicing. In an association analysis with additional schizophrenic cases and unaffected controls, all of African-American descent, the mutant allele was observed at equivalent frequencies. A family study also did not support cosegregation of the variant allele with psychiatric disease.

Schizophrenia and obesity: impact of antipsychotic medications.

Obesity is an epidemic in this country and much of the rest of the developed world. It is a major contributor to a range of metabolic disorders responsible for much of the medical morbidity and mortality that burden our society. The combination of the costs to society of the chronic illness of schizophrenia with the costs of obesity and the chronic illnesses associated with it, e.g., metabolic disorders, diabetes, dyslipidemias, and cardiovascular disease, represents a major public health problem. Obesity in schizophrenia is accentuated even further largely through illness-related factors, like poor dietary conditions and more sedentary lifestyles, and particularly because many of the psychiatric medications (antipsychotics, mood stabilizers, and antidepressants) used to combat this devastating illness themselves result in weight gain that, if untreated, may result in the usual obesity-associated morbidity and mortality. This article is intended to review some of the physiology of obesity and obesity-related metabolic disorders, the risks to schizophrenia patients engendered by obesity, the evidence for weight gain associated with the antipsychotic drugs, and the possible mechanisms involved in antipsychotic medication-associated weight gain.

The effects of novel antipsychotics on glucose and lipid levels.

BACKGROUND: The novel antipsychotics are extensively used based on their favorable extrapyramidal side effect profiles. However, accumulating evidence suggests that these agents, particularly clozapine and olanzapine, have serious side effects of their own, including weight gain and elevated glucose and triglyceride levels. The goal of this study is to compare the effects of novel antipsychotics clozapine, olanzapine, risperidone, and quetiapine and typical antipsychotics haloperidol and fluphenazine on glucose and lipid levels. METHOD: The charts of 590 patients were retrospectively reviewed. Of those, 215 patients had adequate laboratory data for inclusion. Glucose and lipid level data from 2 1/2 years before and after initiation of the target antipsychotic were included. Covariates, including patients' age, the duration of antipsychotic treatment, other medications that may affect glucose or lipid levels, and the initial laboratory values, were controlled for in the analyses. RESULTS: Glucose levels were increased from baseline for patients treated with clozapine, olanzapine, and haloperidol. There were statistically and clinically significant differences among the medications' effects on lipid profiles (p < .05). Those receiving clozapine and olanzapine demonstrated statistically significant increases in triglyceride levels compared with the other groups. Over one third of patients treated with any of the novel antipsychotics had clinically meaningful triglyceride elevations. CONCLUSION: It has been shown that novel antipsychotics are associated with weight gain. This risk factor along with others, such as elevated glucose and triglyceride levels, compounds the risk for coronary artery disease. Routine monitoring of glucose and lipid levels during treatment with novel antipsychotics should be advocated.

Clinical predictors of response to clozapine treatment in ambulatory patients with schizophrenia.

BACKGROUND: Despite the advent of new atypical antipsychotics, clozapine remains an important option in the treatment of patients with poor response to conventional antipsychotics. Clinicians would be well served if clinical characteristics could be identified that predict a favorable response to clozapine. A few studies addressing this issue have reported inconsistent results. METHOD: The association of clinical characteristics with a sustained response was investigated in 37 partially treatment-refractory outpatients with a DSM-III-R diagnosis of chronic schizophrenia who had been assigned to clozapine treatment in a double-blind, haloperidol-controlled, long-term (29-week) study of clozapine. Response was defined as a 20% decrease of the Brief Psychiatric Rating Scale (BPRS) psychosis factor score sustained over 2 consecutive ratings. Differences between responders and nonresponders with regard to selected baseline variables were analyzed with t tests and chi2 tests. In addition, Cox regression analyses were performed to identify variables that best predicted a response to clozapine treatment. RESULTS: Clozapine responders were rated as less severely ill, showed a lesser degree of negative symptoms, and demonstrated fewer extrapyramidal side effects at baseline as compared with nonresponders. In addition, higher BPRS total scores--after controlling for the effects of the other variables--were associated with a response. CONCLUSION: In a cohort of partially treatment-refractory outpatients, a favorable response to clozapine was associated with characteristics describing less severely ill patients. The history of patients did not affect their response to clozapine.

Sexual side effects of novel antipsychotic medications.

BACKGROUND: The novel antipsychotic medications offer a more favorable extrapyramidal side effect profile than conventional agents. It is uncertain that the novel antipsychotics have a benefit in terms of sexual side effects. METHODS: We prospectively administered a survey of sexual functioning to 25 male patients with DSM-IV schizophrenia, taking conventional and novel antipsychotics. Contrasts were made between three treatment groups: clozapine (CLOZ), risperidone (RIS), and a combined haloperidol/fluphenazine (HAL/FLU) group. RESULTS: A decrease in overall sexual functioning was reported in all medication groups (40-71%). The majority of subjects taking RIS or HAL/FLU reported a decline in one or more aspects of sexual functioning. Examining specific aspects of sexual functioning revealed that, a decline in sexual interest was significantly less common on CLOZ compared to RIS (0 vs. 64%; chi(2)=6.1, df=1, p=0.01) or HAL/FLU (0 vs. 67%; chi(2)=5.2, df=1, p=0.02), while a decline in the erectile frequency was significantly more common on RIS compared to CLOZ (40 vs. 93%; chi(2)=6.2, df=1, p=0.01) or HAL/FLU (50 vs. 93%; chi(2)=4.8, df=1, p=0.03) (0%). For enjoyment of orgasm and ejaculatory volume, significantly fewer CLOZ compared to RIS subjects reported a decline (20 vs. 86%; chi(2)=7.4, df=1, p=0.01). CONCLUSIONS: Sexual side effects are common clinically pertinent adverse effects associated with both novel and conventional antipsychotic medications. They deserve increased attention in clinical work and future research with emerging antipsychotic drugs.

Understanding the new and evolving profile of adverse drug effects in schizophrenia.

This article has reviewed the emerging side-effect profiles of second-generation antipsychotic medications. Although these medications have favorable extrapyramidal side-effect profiles, clinicians must be aware of their propensity to cause weight gain, glucose and lipid abnormalities, and cardiac and sexual side effects. If clinicians are proactive about warning patients about these side effects and appropriately monitoring them, further morbidity and mortality may be prevented in this patient population. Initial choices of medication should be made based on the relative side-effect profiles in light of a particular patient's medical status. In the future, new treatments may be developed, with even fewer side effects.