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.

Management of neuroleptic-induced movement disorders: effects of physician training.

Residents given a specialized 4-hour course in managing extrapyramidal syndromes prescribed significantly lower neuroleptic doses and were more skilled at diagnosis of extrapyramidal syndromes than residents given standard psychopharmacology training. The results suggest that focused training in extrapyramidal syndromes should be part of residency curricula.

Drug abuse in schizophrenic patients: clinical correlates and reasons for use.

OBJECTIVE: This study aimed to 1) determine substance abuse prevalence and preference in a diverse sample of schizophrenic, schizoaffective, and schizophreniform inpatients, 2) compare drug-abusing and non-drug-abusing patients on demographic and clinical variables during the acute and stabilization phases of their hospital course, and 3) obtain data from patients on reasons for drug abuse and on acute state-related changes during periods of intoxication. METHOD: Eighty-three psychotic inpatients consecutively admitted to a New York City teaching hospital were evaluated. Sixty-eight had schizophrenia, 12 had schizoaffective disorder, and three had schizophreniform disorder diagnosed according to the Structured Clinical Interview for DSM-III-R. Each patient received ratings on the Brief Psychiatric Rating Scale, the Global Assessment Scale, and the Scale for the Assessment of Negative Symptoms at admission and at discharge, an evaluation of premorbid adjustment, and an extensive interview on drug and alcohol use. RESULTS: Forty (48%) of the patients received diagnoses of drug or alcohol abuse or dependence. The drug-abusing patients primarily used cannabis (N = 26), alcohol (N = 21), and cocaine (N = 14) and reported that they abused drugs to get "high," to relieve depression, and to relax. They had significantly fewer positive and negative symptoms at discharge, better sexual adjustment and worse school performance during adolescence, and more family histories of drug abuse than the non-drug-abusing patients. CONCLUSIONS: Schizophrenic patients who abuse drugs may represent a subgroup of patients with better prognoses and less severe clinical characteristics of schizophrenia, but their drug abuse may adversely affect global outcome.

Clinical nonrecognition of neuroleptic-induced movement disorders: a cautionary study.

Extrapyramidal side effects are a major limitation in the use of neuroleptics, and tardive dyskinesia is a special public health problem. Accurate clinical diagnosis of extrapyramidal syndromes is necessary for effective management. The authors compared clinicians' recognition of the major extrapyramidal syndromes in 48 psychotic inpatients with independent blind diagnoses by clinical researchers using standardized ratings. The major finding was a high rate of clinical underrecognition of all major extrapyramidal syndromes, especially tardive dyskinesia. The authors discuss the clinical predictors of nonrecognition of extrapyramidal side effects and recommend improved training in their detection.

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.

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.

A comparison of two adjunctive treatment strategies in acute mania.

A benzodiazepine-neuroleptic adjunctive treatment strategy in a cohort of acutely manic patients was compared with standard neuroleptic adjunctive treatment in a matched sample treated in the same hospital. Thirty newly hospitalized manic patients receiving low-dose neuroleptic (310 mg/day chlorpromazine equivalents) and benzodiazepines (1.6 mg/day lorazepam equivalents) were compared, retrospectively, with 30 statistically similar patients receiving standard dose neuroleptic adjunctive treatment (590 mg/day chlorpromazine equivalents; 0.09 mg/day lorazepam equivalents). The benzodiazepine-neuroleptic-treated group demonstrated significantly fewer seclusion and restraint episodes (p less than .05) and were comparable on other parameters. Treatment with the benzodiazepine-neuroleptic combination may lead to fewer inpatient complications than standard neuroleptic treatment alone.

Switching antipsychotic medications.

Compared with conventional antipsychotics, the so-called "atypical" antipsychotics promise improved side effect profiles and better control of the symptoms of schizophrenia. Therefore, most patients currently taking conventional antipsychotics could potentially benefit from a switch to an atypical antipsychotic. Often, the key issue in deciding whether to switch is the presence of countervailing factors that mitigate against the change. This paper discusses the indications and contraindications for switching antipsychotics, plus issues that require consideration before a switch is made. Also, the advantages and disadvantages of various switching techniques are discussed, with a particular focus on the newer antipsychotic olanzapine.

Long-term considerations after switching antipsychotics.

The so-called "atypical" antipsychotics are rapidly becoming the de facto standard pharmacologic treatment of schizophrenia. This article reviews some common psychopharmacologic and psychological issues that may arise after an outpatient with schizophrenia is switched to one of the newer antipsychotics. Important issues to consider in the first few months after switching include assessment of response to the new medication, dealing with subsequent psychological reactions, and management of an unsatisfactory response. Once the response is established, there are other pharmacologic and psychological issues that arise during the next year or two. Pharmacologic issues that emerge later on include the role of long-term combination antipsychotics, management of new side effects, and deciding whether and when to switch again. Some of the long-term psychological issues include changes in self-image that arise from being less visibly ill, sexuality and intimacy concerns, and recovery issues.

The distribution of body mass index among individuals with and without schizophrenia.

OBJECTIVE: The objective of this study was to estimate and compare the distributions of body mass index (BMI: kg/m2) among individuals with and without schizophrenia, and, thereby, place the weight gain-inducing effects of antipsychotic drugs into context. METHOD: Data sources were (1) the mental health supplement of the 1989 National Health Interview Survey (NHIS; N = 80,130 nonschizophrenic and 150 self-reported schizophrenic individuals), (2) baseline BMI data from a drug trial of the anti-psychotic ziprasidone supplied by Pfizer Inc (420 noninstitutionalized individuals with chronic psychotic disorders [DSM-IV schizophrenia or schizoaffective disorder]) and (3) data from the National Health and Nutrition Examination Survey III (NHANES III; N = 17,689 nonschizophrenic individuals) to act as a control group for the ziprasidone trial data. RESULTS: After age-adjusting BMI in each data set, the NHIS data revealed that men with schizophrenia have mean BMIs similar to those of men without schizophrenia (26.14 vs. 25.63, respectively). In contrast, women with schizophrenia in the NHIS data set had a significantly (p<.001) higher mean BMI than did women without schizophrenia (27.36 vs. 24.50, respectively). Moreover, each decile was higher for women with schizophrenia than for women without schizophrenia. Analysis of the ziprasidone and NHANES III data sets revealed that, on average, men with schizophrenia have mean BMIs comparable to those of men without schizophrenia (26.79 vs. 26.52, respectively). In these 2 data sets, women with schizophrenia also had a mean BMI similar to those of women without schizophrenia (27.29 vs. 27.39, respectively). CONCLUSION: Although there may be a small subpopulation of schizophrenic individuals who are underweight, individuals with schizophrenia were, on the whole, as obese as or more obese than individuals without schizophrenia, suggesting that weight gain induced by antipsychotic agents is an important concern for many individuals.

Lithium augmentation fails to reduce symptoms in poorly responsive schizophrenic outpatients.

BACKGROUND: Nearly one third of patients suffering from schizophrenia do not fully respond to antipsychotic medication. Safe, effective, and cost-efficient methods to reduce symptoms are clearly needed; therefore, lithium as an adjunct to fluphenazine decanoate was tested in a placebo-controlled trial in outpatients who were part of the Treatment Strategies of Schizophrenia (TSS) study. METHOD: Forty-one patients with DSM-III schizophrenia or schizoaffective disorder were assigned to either adjunctive lithium or placebo after at least 6 months of fluphenazine decanoate treatment to stabilize symptoms had failed. The trial was designed for 8 weeks of treatment, and patients assigned to placebo could afterward be administered lithium in an 8-week, open-label study. RESULTS: Assessment of the intent-to-treat analysis revealed no significant differences in demographic variables between the lithium and placebo groups. Although both groups showed significant (p = .00135) improvement as measured by total scores on the Brief Psychiatric Rating Scale (BPRS), there were no significant differences in response between the lithium and placebo groups. Patients originally treated with placebo added to neuroleptic did not have significantly greater improvement when receiving open-label adjunctive lithium. CONCLUSION: Although success with lithium augmentation therapy for persistent psychosis has been reported in the past, this study of well-characterized patients showed no benefit for this common strategy, thus indicating that care be used in utilizing lithium augmentation.

Cost of relapse in schizophrenia.

To estimate the national annual cost of rehospitalization for multiple-episode schizophrenia outpatients, and to determine the relative cost burden from loss of medication efficacy and from medication noncompliance, the yearly number of neuroleptic-responsive multiple-episode schizophrenia inpatients in the United States who are discharged back to outpatient treatment was estimated. The cohort at risk for future relapse and rehospitalization was determined. The research literature on the expected rates of relapse for schizophrenia patients on maintenance antipsychotic medication was reviewed; in particular, monthly relapse rates under the optimal medication conditions of compliant patients taking optimal doses of a depot neuroleptic (optimal neuroleptic dose) and under the less optimal conditions of patients stopping medication (medication noncompliant) was estimated. Using established noncompliance rates from the literature, it became possible to estimate a "real world" rehospitalization rate for this cohort, as well as the relative burden accruing from loss of medication efficacy and from medication noncompliance. Finally, cost estimates for index hospitalizations and rehospitalizations were derived from data on national expenditures for inpatient mental health care. The monthly relapse rates are estimated to be 3.5 percent per month for patients on maintenance neuroleptics and 11.0 percent per month for patients who have discontinued their medication. Postdischarge noncompliance rates in community settings are estimated to be 7.6 percent per month. These estimates were entered into a survival analysis model to determine the real world relapse rate of this cohort. An estimated 257,446 multiple-episode (> or = two hospitalizations) schizophrenia patients were discharged from short-stay (< or = 90 days) inpatient units in the United States during 1986. The estimated aggregate baseline inpatient cost for the index hospitalizations of this cohort was $2.3 billion (1993 dollars). Within 2 years after discharge, the aggregate cost of readmission approached $2 billion. Loss of neuroleptic efficacy accounted for roughly 60 percent of the rehospitalization costs and neuroleptic noncompliance for roughly 40 percent. The economic burden due to loss of efficacy is relatively higher during the first postdischarge year, whereas the burden from noncompliance is higher in the second year. Because loss of medication efficacy and medication noncompliance act synergistically on relapse, substantial inpatient cost savings can be realized by linking better pharmacologic treatments of schizophrenia with more effective strategies to manage medication noncompliance.

Selective effects of antipsychotic medications on eye-tracking performance in schizophrenia.

The potential impact of antipsychotic medications on eye-tracking impairments in schizophrenia has received little systematic attention. To address this issue, eye-tracking performance was studied in 19 neuroleptic-naive schizophrenic patients, 22 previously medicated schizophrenic patients who had not received antipsychotic drugs for at least 28 days, and 52 nonpsychiatric control subjects. Impairments were similar but generally more severe in previously treated than in neuroleptic-naive patients. An attention-facilitation manipulation improved eye-tracking performance in all groups. Ten neuroleptic-naive and 14 previously treated cases were retested after at least 3 weeks of treatment with antipsychotic medication. Short-term treatment with neuroleptics improved certain attention-related aspects of eye tracking involving saccadic eye movements such as anticipatory saccades, but it did not alter pursuit eye movements.

Relationships between medication treatments and neuropsychological test performance in schizophrenia.

Few investigations have assessed the neuropsychological effects of psychotropic medications on schizophrenic patients. In this study, 44 clinically stable schizophrenic inpatients were administered a battery of neuropsychological tests, and their performance was correlated with dosage of neuroleptic medication and benztropine. Neuroleptic dose was correlated with poorer performance on tests of psychomotor speed and attention, and with the number of perserverative errors on the Wisconsin Card Sort. Anticholinergic dose was associated with poorer verbal learning, verbal fluency, and motor speed. Both medication dosages were associated with poorer verbal recognition memory, but this association was strongly influenced by the performance of individuals on the highest medication doses. The findings, which were independent of clinical state and intelligence, indicate that higher doses of neuroleptic and anticholinergic medications are associated with poorer neuropsychological functioning in schizophrenia.

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.

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).