Off-label Use Of Second-generation Antipsychotics Research Articles

The prevalence of off-label use and supratherapeutic blood levels of outpatient psychotropic medication in suicidal adolescents.

Adolescents with mental disorders show an increased risk of suicidal phenomena. Vice versa, suicidality is a serious adverse event of psychotropic drug therapy in adolescents. There are only a few new psychotropic agents approved for this young age group. We evaluated the (pre-pandemic) prevalence of off-label use as well as detailed blood concentrations of outpatient psychotropic medication and sex differences in a clinical population of suicidal adolescents. The urine presence and serum levels of psychotropic substances of adolescents hospitalized due to their acute suicidality but without a known actual suicide attempt (i.e., no acute intoxication or serious self-injuries) were investigated routinely between 01.03.2017 and 31.01.2018. Urine (N = 205) and blood samples (N = 193) were taken at the beginning of closed inpatient admission, i.e., the results of the laboratory analysis reflect outpatient drug intake. The serum levels of psychopharmacological medication and OTC medication were measured. Our sample consists of 231 cases (boys: N = 54; girls: N = 177, ratio: 1:3.3), aged 12-17 years (average age: 15,4 years). The most prevalent psychiatric diagnoses were depressive episodes (54%) and adjustment disorders (25%), and girls were more often diagnosed with depressive disorders than boys (boy/girl ratio: 1:9.5, p < 0.0001). More than half of adolescents (56%) used at least one prescribed psychotropic drug at admission (24.8% ≥ two psychotropic drugs). Off-label use of second-generation antipsychotics was significantly more frequent than off-label use of antidepressants (85% vs. 31%, p < 0.01). Adolescents suffering from depressive disorders were significantly more often on-label treated than adolescents with neurotic or stress-related disorders (56% vs. 10%). Female cases with prescribed psychotropic drug use showed significantly more frequent supratherapeutic drug levels than male cases (5% vs. 27%, p < 0.05). Female adolescents may have an increased risk of supratherapeutic blood levels, especially when outpatient prescribed psychotropic drugs are off-label used. Measurement of blood levels of outpatient-prescribed psychotropic drugs could be used to enhance the safety and efficacy of the individual psychopharmacological treatment of adolescent suicidal patients. There is an urgent need for more real-world evidence on the effective treatment of adolescents with psychotropic drugs.

Metabolic adverse effects of off-label use of second-generation antipsychotics in the adult population: a systematic review and meta-analysis.

Prescription rates of second-generation antipsychotics (SGAs) are rapidly increasing for non-indicated (i.e., off-label) usage. SGAs used for approved indications are associated with significant metabolic adverse effects, including weight gain. The objective of this systematic review and meta-analysis is to evaluate the metabolic adverse effects of SGA use for off-label management of psychiatric illnesses in the adult population. We performed a systematic database search to identify randomized controlled trials (RCTs) that reported on weight and other metabolic outcomes with off-label use of SGAs among adults. Thirty-eight RCTs met inclusion criteria for this review; 35 of these studies, with a total of 4930 patients, were included in the quantitative meta-analysis. Patients treated with olanzapine, risperidone, and quetiapine were more likely to report weight gain as a side effect and experience clinically significant (≥7%) weight gain compared to those treated with a placebo. Among studies that reported weight as a continuous outcome, olanzapine was associated with significantly greater weight gain across all disorders (mean difference (MD) = 3.24 kg, 95% CI: 2.57-3.90 p = 0.001, N = 12 studies). Similar trends were noted with quetiapine and risperidone. A meta-regression analysis revealed a positive dose-response association between olanzapine dose and weight gain (regression coefficient: 0.36, p = 0.001). This review demonstrates that off-label use of SGAs, and particularly olanzapine, is associated with significant weight gain among adult patients. Our findings are concerning given the widespread off-label use of SGAs. Further studies are required to better understand the effects of off-label SGA use on other metabolic parameters. The study was registered with the PROSPERO international database of prospectively registered systematic reviews (PROSPERO #143186).

Tardive syndrome: An update and mini-review from the perspective of phenomenology.

Tardive syndrome (TS) is a group of movement disorders caused by the long-term use of dopamine receptor blocking agents. The phenotypic presentation of TS is diverse, ranging from the most well-characterized symptom of tardive dyskinesia to other symptoms, including dystonia, akathisia, myoclonus, parkinsonism, tremor, and tics. These tardive symptoms are distinct not only in their phenomenology but also in their clinical outcomes. However, our knowledge of the pathophysiology and management of TS is almost exclusively based on tardive dyskinesia. First-generation antipsychotics have a higher risk of inducing TS and have largely been replaced by second-generation antipsychotics with a lower risk of TS. However, patients with off-label use of second-generation antipsychotics are still at risk of developing TS. Thus, the management of TS remains a challenging and important issue for physicians. In this review, we update the information on the epidemiology, phenomenology, and treatment of TS from the perspective of the specific form of TS.

Metabolic Adverse Effects of Off-Label Use of Second-Generation Antipsychotics in the Adult Population: A Systematic Review and Meta-Analysis

Second generation antipsychotics (SGAs) are approved by the US Food and Drug Administration for treatment of schizophrenia, bipolar disorder, and refractory depression. Since the 1990’s, antipsychotic prescription has more than doubled, with off-label use disproportionately contributing. SGAs used “on-label’ have significant metabolic adverse effects (MAEs). Currently, there is no literature systematically investigating the MAEs of ‘off-label’ use to guide clinical decision-making practices.

Off-Label Use of Second-Generation Antipsychotics in Borderline Personality Disorder: A Survey of Italian Psychiatrists.

The guidelines for borderline personality disorder (BPD) treatment suggest non-pharmacological treatment as the first option, but second-generation antipsychotics (SGAs) are among the overprescribed medications. This study aimed to explore Italian psychiatrists' attitudes toward off-label use of SGAs in BPD. A randomly selected sample of Italian psychiatrists completed a questionnaire regarding off-label prescription of SGAs. Most respondents reported the off-label use of SGAs. Among the reasons supporting the prescription of SGAs, the presence of strong published data was the most determining factor (51.5%). The SGA olanzapine is considered the most appropriate, followed by quetiapine and aripiprazole. Although off-label prescription of SGAs represents a common clinical practice in accordance with a worldwide trend, the use of long-acting injection formulations was considered inappropriate by 69% of psychiatrists in our sample. Our results reiterate the discrepancy between everyday clinical practice and international recommendations, and show how relevant the literature is in off-label drug prescription.

Off-Label Use of Second-generation Antipsychotics in Bipolar Disorder: A Survey of Italian Psychiatrists.

Bipolar disorder (BD) is characterized by recurrent depressive and manic episodes. Lithium, valproate, lamotrigine, and some second-generation antipsychotics (SGAs) are the most typical pharmacological treatments for BD, the main goal being mood stabilization. However, despite these treatments, most patients continue to experience recurrent mood episodes and residual symptoms. Findings from several studies suggest that some SGAs may be beneficial beyond approved indications. The goal of the survey presented in this article was to examine Italian psychiatrists' attitudes concerning the off-label use of SGAs in depressive and maintenance phases of BD. A questionnaire about the off-label prescription of SGAs was e-mailed to 300 psychiatrists from Northern, Central, and Southern Italy affiliated with the Italian Society of Psychopharmacology (SINPF) to investigate the frequency of and motivation for off-label use of SGAs and evaluate the psychiatrists' attitude toward use of specific SGAs in BD; 202 questionnaires were completed. The respondents were equally distributed in terms of sex, and the mean age of respondents was 44.1 years. The majority of the sample reported use of SGAs for off-label indications either very often (16.7%), often (33.7%), or occasionally (34.7%). The main motivation for off-label use of the SGAs was the presence of published evidence (51.5%), followed by patients' nonresponse to previous treatment (37.1%). With regard to the use of specific SGAs in BD, off-label aripiprazole was considered appropriate for depressive episodes by 46% of the psychiatrists, followed by olanzapine which was considered appropriate by 33.7%. For maintenance treatment of BD, off-label asenapine was considered appropriate by 45% of the psychiatrists, followed by long-acting aripiprazole and olanzapine pamoate, which were considered appropriate by 37.1% and 23.8%, respectively. In summary, ~50% of Italian psychiatrists frequently (very often or often) prescribe SGAs for off-label indications. Given the relatively limited number of indicated effective treatments for BD, the use of some SGAs off-label may be considered appropriate when dealing with patients whose BD is resistant to medications with labeled indications for BD.

Trends in Off-Label Use of Second-Generation Antipsychotics in the Medicare Population From 2006 to 2012.

The study evaluated trends in the off-label use of second-generation antipsychotics in the Medicare population, a practice that has been identified as lacking adequate supporting evidence for many indications. Medicare claims data from 2006 to 2012 were used to identify beneficiaries who filled at least one prescription for any second-generation antipsychotic. Any use that was not associated with a medical claim for an approved indication in a given year was classified as off-label use. Rates of off-label use and of diagnoses associated with off-label use were compared over time. Fill counts standardized for 30-day supply and costs were compared by type of use. On the basis of a sample of 490,314 patient-years, the rate of off-label use among beneficiaries prescribed a second-generation antipsychotic declined from 51% to 45%. Fill counts were 16% lower for off-label users compared with on-label users. Off-label users had higher out-of-pocket costs but lower total costs for second-generation antipsychotics. Off-label users most commonly had claims related to dementia, minor depression, anxiety disorders, and other psychosis. The proportion of off-label users without any claims for the most common off-label uses of second-generation antipsychotics declined from 45% in 2006 to 30% in 2012. Off-label use of second-generation antipsychotics has declined, especially among persons without any of the common off-label conditions. The diagnoses accompanying off-label use did not systematically reflect changes in the evidence base for the use of these drugs, suggesting a mismatch between evidence supporting the use of off-label second-generation antipsychotics and prescribing practices.

Use of Administrative Data to Identify Off-Label Use of Second-Generation Antipsychotics in a Medicaid Population

OBJECTIVE The use of second-generation antipsychotics for conditions not approved by the U.S. Food and Drug Administration (FDA) is a prevalent phenomenon with important implications. The objective of this study was to determine the accuracy of administrative claims for identifying off-label use of second-generation antipsychotics in a Medicaid population in 2009. METHODS The authors estimated the sensitivity, specificity, positive predictive values (PPV), and negative predictive values of Medicaid claims data for detecting off-label use of second-generation antipsychotics in the electronic health records of 788 patients. Separate estimates were calculated for patients without schizophrenia and bipolar disorder, the two most long-standing FDA indications for use of second-generation antipsychotics, and for a subset of patients using a second-generation antipsychotic with indications for treatment-resistant depression. RESULTS Medicaid claims determined a lack of schizophrenia and bipolar disorder in the medical record with a sensitivity of 72% and a specificity of 85%. The prevalence of identifying neither diagnosis was 83%, which was associated with a predictive ability (PPV) of 96%. Among those using a second-generation antipsychotic with an indication for treatment-resistant depression, the sensitivity, specificity, and PPV of Medicaid claims for identifying off-label use were 41%, 86%, and 87%, respectively. CONCLUSIONS Medicaid claims data had high predictive ability for identifying users of second-generation antipsychotics who did not have documentation of schizophrenia or bipolar disorder in the medical record. The predictive utility of the claims was diminished when the analyses were limited to patients using a second-generation antipsychotic with an indication for treatment-resistant depression.

Characteristics and trends of low‐dose quetiapine use in two western state Medicaid programs

Medicaid programs are concerned about inappropriate, potentially hazardous, and costly off-label use of second-generation antipsychotics (SGAs). Several states are exploring policies aimed at managing low-dose quetiapine, commonly prescribed for off-label conditions. This study aimed to characterize longitudinal trends and patient characteristics associated with low-dose quetiapine in two state Medicaid programs. We further aimed to quantify changes in the use of quetiapine associated with a legal settlement that curtailed off-label promotion of this product. Using administrative data from two state Medicaid programs, Oregon and Colorado, we identified SGA initiators and determined patient level factors associated with receipt of low-dose SGAs. We evaluated changes in low-dose quetiapine initiation during and after a period in which quetiapine was being promoted illegally for off-label purposes. We identified 14,763 new SGA starts during the study period. Low-dose (versus therapeutic dose) SGA use was common in both states, representing 53% to 56% of initiators. Quetiapine was the most commonly used SGA in both states and both dose ranges. Diagnoses of schizophrenia, bipolar disorder, posttraumatic stress disorder, anxiety disorder, and use of newer sedative hypnotics were associated with lower likelihood of initiating low-dose quetiapine. Initiation of low-dose quetiapine as a proportion of all SGA initiation and of all quetiapine initiation significantly declined in Oregon following suspension of off-label promotional activities. Low-dose SGA and specifically low-dose quetiapine use remains common. Medicaid programs must set policies carefully to maximize the net safety of prescription use while optimizing disease management considering the potential for substitution effects.

Effects of an antipsychotic restriction policy in a veteran population

Introduction: Recent trials have failed to demonstrate differences in efficacy between first generation antipsychotics (FGAs) and second generation antipsychotics (SGAs). To reduce costs, many health care systems have restricted the availability of SGAs through use of prior authorizations. Restrictions for the off-label use of SGAs and the use of dual-antipsychotic therapy have also been implemented in many health care systems. At the South Texas Veterans Health Care System (STVHCS), a restricted drug request (RDR) method has been implemented to manage costs and improve patient safety. Risperidone, due to its lower cost and equal efficacy, is the first-line option of SGAs. If one wishes to prescribe an SGA other than risperidone, an RDR is submitted and reviewed by Veterans Integrated Service Network (VISN) pharmacists. Since the introduction of these policies at the STVHCS, the impact of the RDR has not been assessed. Rationale: The primary aim of this study was to determine the effects of the RDR policy on the care of STVHCS veterans as evidenced by changes in hospitalization rates of veterans with a denied request for an SGA due to initial criterion failure. Secondary outcomes included: impact of antipsychotic RDR denial on mental health as evidenced by changes in no-shows and cancellations for follow-up psychiatric appointments, psychiatric emergency department visits, presence of suicidal ideation, change in weight, hemoglobin A1c, number of psychotropic medications prescribed, and extrapyramidal symptoms. Methods: A retrospective chart review of veterans denied an initial SGA request was conducted from 3 months prior to denial to 3 months post request denial (index date). Data collected included: patient demographics, indication for SGA request, reason for SGA denial, length of time for request evaluation, number of psychiatric hospitalizations, number of no-shows and cancellations for mental health appointments, number of psychiatric emergency department visits, number of reports of suicidal ideation or attempts, weight, hemoglobin A1c lab results, presence of extrapyramidal symptoms, and number of prescribed psychotropic medications. The health care utilization data collected pre- and post-index date, were compared. Results were analyzed using Fisher's Exact, 2-tailed standardized t-tests, and descriptive statistics appropriately matched to data type. Results: Results for both primary and secondary outcomes were not statistically significant. No differences were found in the number of veterans hospitalized pre- versus post-index date [0/33 (0%) versus 2/33 (6%), p=0.492.] The most requested indication for an SGA was PTSD [22/33 (66.7%)] and the most frequently denied SGA was quetiapine [16/33 (48.5%)]. Conclusions: Although outcomes were not statistically significant, several valuable conclusions were drawn from this research. Positive outcomes from a RDR policy were seen by the limitations placed on inappropriate medication prescribing. Also, it was observed that the number of approvals for SGAs was almost three times higher than denials. A subsequent finding from this research is the apparent lack of metabolic monitoring for veterans prescribed SGAs. Further research on these observations, as well as conducting a pharmacoeconomic analysis on the RDR policy, would also be beneficial information for health care providers.

Ten Years of Antipsychotic Prescribing to Children: A Canadian Population-Based Study

To report the prescribing of antipsychotics to the youth population of the Canadian province of Manitoba during the course of a decade. Use of antipsychotics in children and adolescents (aged 18 years or younger) was described using data collected from the administrative health databases of Manitoba Health and the Statistics Canada census between the fiscal years of 1999 and 2008. The prevalence of antipsychotic use in this segment of the population increased with the introduction of the second-generation antipsychotics (SGAs) from 1.9 per 1000 in 1999 to 7.4 per 1000 in 2008. The male-to-female antipsychotic usage ratio increased from 1.9 to 2.7 as the male youth population represented the fastest-growing subgroup of antipsychotic users in the entire population of Manitoba. The total number of prescriptions also increased significantly despite the lack of approved indications in this population. Proportion of use remained equally split between high- and low-income users. More than 70% of antipsychotic prescriptions to children and adolescents were written by general practitioners. The most common diagnoses linked to antipsychotic use were attention-deficit hyperactivity disorder and conduct disorders. Use of antipsychotics in combination with methylphenidate increased from 13% to 43%. Extensive off-label use of SGAs has been observed in the youth population of Manitoba for treatment of aggressive behaviours across a range of diagnoses. It is important to monitor antipsychotic prescribing to children as more reports of significant adverse events associated with antipsychotics become available.

Off-Label Use of Second-Generation Antipsychotic Agents Among Elderly Nursing Home Residents

This study examined off-label and evidence-based use of second-generation antipsychotic agents among elderly nursing home residents and factors associated with off-label use. This study involved a retrospective, cross-sectional analysis of data from the 2004 National Nursing Home Survey (NNHS). The sample included nursing home residents 65 years and older who received second-generation antipsychotic agents. This study used an indication-based definition of off-label use established by the U.S. Food and Drug Administration (FDA). Evidence-based use included FDA-approved indications and indications for which the Agency of Healthcare Research and Quality found at least moderate strength of evidence of effectiveness. Descriptive statistics were used to examine the prevalence of off-label and evidence-based use. Multiple logistic regression was used to examine the patient and facility factors associated with off-label use of second-generation antipsychotics. According to the 2004 NNHS, 308,990 (23.5%) elderly nursing home residents received at least one second-generation antipsychotic agent. Of those using second-generation antipsychotics, 86.3% received them for off-label indications and 56.9% received them for an evidence-based use. Multivariate analysis found that age (> or =75 years), self-pay for nursing home care, diagnosis of dementia, and residing in a nonprofit nursing home were positively associated with off-label use, whereas receiving Medicaid benefits was negatively associated with such use. Although second-generation antipsychotics were frequently used for off-label indications, most of the usage was evidence based among elderly nursing home residents. However, the high level of non-evidence-based use combined with recent safety and efficacy data suggests an urgent need to address the evidence base for this vulnerable population.

Off-Label Use of Antipsychotic Medications in the Department of Veterans Affairs Health Care System

This study aimed to determine the prevalence of prescribing antipsychotics to adults without schizophrenia or bipolar disorder and to identify factors associated with such off-label use. Patients with at least one prescription for an antipsychotic medication from the Department of Veterans Affairs (VA) during fiscal year (FY) 2007 were identified in national VA administrative databases. Rates of off-label antipsychotic use were determined along with average doses. Multivariate logistic regression models identified sociodemographic and clinical characteristics associated with off-label use. Of the 279,778 individuals in FY 2007 who received an antipsychotic medication, 168,442 (60.2%) had no record of a diagnosis for which these drugs are approved. The most common mental illness diagnoses among patients given prescriptions for antipsychotics off label were posttraumatic stress disorder (PTSD, 41.8%), minor depression (39.5%), major depression (23.4%), and anxiety disorder (20.0%). Among VA patients with mental illness other than schizophrenia or bipolar disorder, the proportion who received prescriptions for antipsychotic medications ranged from a low of 9.1% among patients with adjustment reaction; to about 20% for those with depression, dementia, or PTSD; and to a high of 40.7% among patients with other psychoses. Doses were low, with over half of patients who received off-label quetiapine, risperidone, or first-generation antipsychotics receiving doses below those recommended for schizophrenia. In logistic regression models, patients diagnosed as having other psychosis or dementia had the highest odds of receiving an antipsychotic medication off label. Off-label use of antipsychotic medications was common. Given that these drugs are expensive, have potentially severe side effects, and have limited evidence supporting their effectiveness for off-label usage, they should be used with greater caution.