Discontinuation Of Antipsychotic Treatment Research Articles

T54. TAILOR – TAPERED DISCONTINUATION VERSUS MAINTENANCE THERAPY OF ANTIPSYCHOTIC MEDICATION IN PATIENTS WITH NEWLY DIAGNOSED SCHIZOPHRENIA SPECTRUM DISORDERS IN REMISSION OF PSYCHOTIC SYMPTOMS

BackgroundSchizophrenia spectrum disorders have major implications for the individuals, their families and society.Antipsychotic medication is the cornerstone in the treatment of psychotic symptoms and is effective in the reduction of psychotic symptoms and of relapse after remission of psychotic symptoms. This is the reason for recommending maintenance treatment with antipsychotic medication in national and international guidelines for the treatment of schizophrenia, one year after remission of psychotic symptoms in first episode psychosis.The aim of the study is to investigate the effect of tapered discontinuation versus maintenance therapy with antipsychotic medication in patients with newly diagnosed schizophrenia or persistent delusional disorder and with minimum three months remission of psychotic symptoms, and to find minimal effective dose of antipsychotic medication. Negative symptoms, cognitive impairments and the side effects of antipsychotic medication can cause a serious and long-term burden for patients and can reduce their quality of life. The TAILOR study will investigate these important aspects.MethodsThe study is a randomized multicenter single blinded clinical trial. The aim is to include 250 patients from the outpatient early intervention program, OPUS, a 2 years manualized psychiatric treatment programme. At baseline patients must have 3 months remission of psychotic symptoms as documented by the SAPS (Schedule for Assessment of Positive Symptoms in Schizophrenia).The patients will be randomized to either tapered discontinuation or dose reduction of antipsychotic medication or treatment as usual stratified according to substance abuse. The intervention will last for 1 year, and follow up interviews will be made after 1,2 and 5 years.The patients will receive a user-developed mobile phone application to make daily registrations.ResultsThe study has been including patients since May 2017.The first data is expected in 2019.DiscussionThe TAILOR trial will contribute to knowledge about the effect of tapering/discontinuation of antipsychotic medication in early phases of schizophrenia spectrum disorders and hopefully the results may guide future clinical treatment regimens of antipsychotic medication.The trial is a complex medical intervention, and it raises ethical, practical and organizational challenges.When designing the TAILOR trial ethical questions were raised regarding blinding and the design of the intervention. In the trial only the researchers are blinded, neither clinicians nor patients, because they should be attentive of the high risk of relapse in the discontinuation group. The design gives the clinicians the possibility to adjust the dose of the antipsychotic medication to ensure sufficient treatment. Therefore, the trial only includes assessor blinding and the groups might end up being more similar than intended.In general, it is of ethical consideration that the trial participants in the tapering/discontinuation group will be subjected to a higher risk of relapse. On the other hand, it seems unethical if research were not to discover the group of patients who can discontinue antipsychotic medication without relapsing.Practical challenges will be sufficient recruitment or patient motivation and dropout.

F143. PREDICTORS OF RELAPSE: PATIENT, DISEASE, COGNITIVE, AND FUNCTIONAL CHARACTERISTICS WITH COMT GENE VAL158MET POLYMORPHISM IN A 2-YEAR FOLLOW-UP

BackgroundSchizophrenia is a severe and chronic mental illness characterized by continual relapses that may require hospitalization, changes in medications, arrests, emergency room hospitalizations, self-harm or suicidal behavior. Research has shown that costs associated with treatment received following relapse may constitute the largest share of treatment costs psychiatric illnesses. Although, demographic and clinical characteristics associated with relapse have been examined in previous research, information about potential predictors of relapse are limited. The aim of this study was to evaluate the effect of patient and disease characteristics, cognitive, functioning, and COMT gene polymorphism (rs4680) on relapse during 2-year following completion of an inpatient rehabilitation and cognitive treatment.MethodsData were taken from a COMT genotype and response to cognitive remediation study of schizophrenia in the United States conducted between 07/2005 and 10/2015 for inpatients with schizophrenia who were also participating in psychiatric rehabilitation. Patients with and without relapse 2 years following completion of the study were compared on clinical, demographic, cognitive, functional and COMT genotype characteristics. The COMT gene rs4680 polymorphism was genotyped using a DNA sequence detection system. Relapse or events identified as treatment failures include: arrest, psychiatric re-hospitalization, suicide, discontinuation of antipsychotic treatment due to inadequate efficacy, treatment supplementation with another antipsychotic due to inadequate efficacy, discontinuation of antipsychotic treatment due to safety or tolerability, or increase in the level of psychiatric services. Baseline (end of study, start of 2-year follow-up) predictors of subsequent relapse were also assessed. Univariate Analsyis and Cox’s regression was used to examine the effect of potential predictors on outcome.ResultsOf 140 subjects with eligible data, 91 (65.00%) relapsed during the 2-year follow-up period. Patients who relapsed were younger (< 45 years), higher number of previous hospitalizations, shorter chronicity of illness (< 10 years), PANSS baseline score of >4 on the core PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content), higher negative symptom factor, substance use, PSP score of < 60 and lower MCCB composite T score (> 2 SD below the mean). Univariate analysis shows that COMT rs4680 gene variants were different between relapse and stable groups. The COMT rs4680 gene had an interaction with PANSS baseline core item scores and MCCB composite score. Number of previous antipsychotic trials did not predict relapse.DiscussionThere is a high relapse rate within 2 years in chronic schizophrenia. Behavioral symptoms, aided by genetic and environmental factors common to this population (homelessness, unemployment, and social isolation) frequently lead to treatment failure. Knowing potential triggers of relapse can help in developing resources for this population to reduce treatment failures and associated costs.

Prediction of Relapse After Discontinuation of Antipsychotic Treatment in Alzheimer's Disease: The Role of Hallucinations.

In Alzheimer's disease, antipsychotic medications are often used for a period, with relief of symptoms, and then discontinued, after which relapse may occur. The authors sought to determine which neuropsychiatric symptoms predict relapse. In the Antipsychotic Discontinuation in Alzheimer's Disease trial, 180 patients with Alzheimer's disease and symptoms of agitation or psychosis were treated with risperidone for 16 weeks, after which patients who responded (N=110) were randomly assigned to continue risperidone for 32 weeks, to continue risperidone for 16 weeks followed by switch to placebo for 16 weeks, or to receive placebo for 32 weeks. As reported previously, discontinuation of risperidone was associated with a two- to fourfold increased risk of relapse over 16-32 weeks. In planned post hoc analyses, the authors examined associations between the 12 symptom domains in the Neuropsychiatric Inventory (NPI) and relapse in the first 16-week phase after randomization. Compared with patients with mild hallucinations or no hallucinations, patients with severe hallucinations as a presenting symptom at baseline had a higher likelihood of relapse (hazard ratio=2.96, 95% CI=1.52, 5.76). This effect was present for the subgroup with auditory hallucinations, but not the subgroup with visual hallucinations. Among patients with baseline hallucinations, 13 of 17 (76.5%) who discontinued risperidone relapsed, compared with 10 of 26 (38.5%) who continued risperidone (p<0.02). This group difference remained significant for severe (77.8%) compared with mild (36%) hallucinations. NPI domain scores after the initial open-treatment phase were not associated with relapse. Patients with severe baseline hallucinations were more likely to relapse after randomization, and the presence of baseline hallucinations was associated with a higher risk of relapse after discontinuation of risperidone compared with continued risperidone treatment. For patients with hallucinations, particularly auditory hallucinations, antipsychotic discontinuation should be approached cautiously because of high relapse risk.

Antipsychotic discontinuation linked to greater risk of symptom recurrence

Discontinuation of antipsychotic treatment after functional recovery from a single psychotic episode was associated with a high rate of symptom recurrence in an open‐label, nonrandomized study. Resumption of antipsychotic treatment in these patients was associated with clinical remission and a lack of further relapses, the study found.

Comparative effectiveness of long-acting injectable risperidone vs. long-acting injectable first-generation antipsychotics in bipolar disorder

ObjectiveThe aim of this study was to compare the treatment effectiveness between long-acting injectable risperidone and long-acting injectable first-generation antipsychotics among patients with bipolar disorder. MethodWe conducted a retrospective cohort study using Taiwan's National Health Insurance Research Database. Patients with bipolar disorder aged 15 years or higher, who were newly administered long-acting injectable antipsychotics between June 1, 2004 and December 31, 2011 were included. The clinical outcome indexes were hospitalization for any mood, manic/mixed, or depressive episodes. In addition, the all-cause discontinuation of long-acting injectable antipsychotic treatment was also assessed. ResultsA total of 3916 patients with bipolar disorder were extracted. Compared with risperidone, the use of first-generation antipsychotics was associated with a higher rate of hospitalization for any mood episode and major depressive episode. However, there was no statistically significant difference in treatment discontinuation rate between risperidone and first-generation antipsychotics. LimitationsInformation for the severity of mood symptoms, social support, life style, neurological and metabolic adverse effect was not available in this database. In addition, we only measured severe mood episodes with hospitalization as our outcome index. It may not be possible to generalize our findings to mild mood episodes. ConclusionsOur findings suggested that patients treated with long-acting injectable risperidone might be superior to first-generation antipsychotics in the rate of psychiatric hospitalization.

Antipsychotic Withdrawal After FEP Recovery Linked to Relapse

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessAntipsychotic Withdrawal After FEP Recovery Linked to RelapseMark MoranMark MoranSearch for more papers by this authorPublished Online:4 Feb 2016https://doi.org/10.1176/appi.pn.2016.2a9AbstractFirst-episode treatment programs should establish a medication-withdrawal strategy with systematic follow-up for patients inclined to discontinue medication, researchers say.Antipsychotic discontinuation following functional recovery in patients after a first episode of psychosis (FEP) appears to be associated with a very high rate of relapse compared with those who maintain antipsychotic treatment, according to a report in the Journal of Clinical Psychiatry (December 8, 2015). Moreover, the time to relapse was faster for those who discontinued medication compared with those who relapsed on maintenance treatment, wrote researchers at the University of Cantabria, Spain.“In clinical practice, physicians very often face the dilemma of discontinuing or maintaining antipsychotics in those patients who have fully recovered from their initial episode of psychosis,” they wrote. “In those individuals who are willing to discontinue medication, a planned medication withdrawal strategy with follow-up should be established to prevent unrestrained treatment disengagement. Clinicians should provide accurate information to patients and relatives concerning the risks and benefits of withdrawing medication.”Comments Sought on Reclassification of ECT DevicesThe FDA is proposing new guidance for the regulation of ECT devices that could affect the clinical practice of ECT and its availability. The deadline for public comments on the draft guidance is March 28. The APA Task Force on ECT has prepared a summary of the draft guidance (including how to contact the FDA and the link to the FDA draft guidance). The FDA takes public comments very seriously, so even a brief communication is valuable.Study participants were drawn from an ongoing longitudinal intervention study for FEP in Spain. Inclusion criteria for the study were receiving 18 months of treatment with antipsychotics, meeting clinical remission criteria for 12 months and functional recovery criteria for six months, and being stabilized on the lowest antipsychotic dose for three months. A total of 46 individuals opted to discontinue medication, and 22 remained on maintenance medication; the primary outcome measures were relapse rate at 18 and 36 months and time to relapse.In the discontinuation group, 31 patients (27 relapses and four cases of deterioration in symptoms) relapsed. In contrast, among patients in the maintenance group, just seven patients relapsed over the three-year period. The average time to relapse in the maintenance group was 608 days compared with 209 days for those who relapsed in the discontinuation group.“[T]he rate of symptom recurrence in functionally recovered FEP patients following the self-elected discontinuation of treatment is extremely high,” the researchers stated. “Relapsed individuals had a greater severity of symptoms and lower functionality [during the three-year follow-up period] compared with those patients who did not relapse during the follow-up.” ■“Clinical Outcome After Antipsychotic Treatment Discontinuation in Functionally Recovered First-Episode Nonaffective Psychosis Individuals: A 3-Year Naturalistic Follow-Up Study” can be accessed here. ISSUES NewArchived

Pharmacy switch of antipsychotic medications: patient's perspective.

Background and aimSeveral studies have raised concerns over consequences of brand-to-generic and generic-to-generic pharmacy-generated medication substitutions in psychiatric and non-psychiatric patients. The purpose of this retrospective study was to assess behavioral and emotional responses of patients with schizophrenia to antipsychotic medication substitution performed by pharmacies.MethodsA group of Polish ambulatory patients with schizophrenia (n = 196) chronically treated with antipsychotic medications were asked whether antipsychotic medication substitution had been proposed by a pharmacist in the last 12 months. Ninety-nine patients answering positively were administered more questions addressing the patient’s emotional and behavioral response to the pharmacy proposal.ResultsThe most important findings of the present study can be summarized as follows: (1) approximately half of the patients were confronted with a pharmacy proposal to switch their antipsychotic medications in the last 12 months, (2) one quarter of these patients did not accept the pharmacy switch, (3) a substantial proportion of patients (>40 %) did not receive any explanation from a pharmacist offering medication substitution, (4) pharmacy-generated substitution proposals were mainly associated with negative patient attitudes and negative emotional responses, (5) substitution proposals provoked an unscheduled psychiatric visit in approx. 10 % of patients, (6) despite the negative attitudes reported by patients, the pharmacy switch rarely led to treatment discontinuation, but did provoke a change in drug dosing in 7 % of patients accepting the switch.ConclusionsA pharmacy proposal to switch their antipsychotic medications is a relatively common experience of Polish ambulatory patients with schizophrenia. Pharmacy-generated substitution proposals are mainly associated with negative patient attitudes, but rarely lead to antipsychotic treatment discontinuation in this group of patients.

Time to discontinuation of antipsychotic drugs in a schizophrenia cohort: influence of current treatment strategies.

Rates of discontinuation of antipsychotic treatment for patients with schizophrenia are high and evidence is limited by selective inclusion and high attrition in randomized controlled trials. To study time to discontinuation of antipsychotic treatment for patients with schizophrenia. All patients with schizophrenia (n = 396) discharged between 2005 and 2011 were followed until discontinuation (clinician or patient decided) of antipsychotic treatment or other endpoints. Univariate and multivariate survival analyses (with time on antipsychotic treatment as the dependent variable) using time-dependent variables were performed. Clozapine displayed lower risk for all-cause (p < 0.001), clinician-decided (p = 0.012) and patient-decided (p = 0.039) discontinuation versus olanzapine oral treatment in the multivariate Cox regression. Second-generation long-acting injection antipsychotics (LAI) (p = 0.015) and first-generation long-acting injection antipsychotics (p = 0.013) showed significantly lower risks for patient-decided discontinuation than olanzapine oral. Higher effectiveness of clozapine and LAI treatment versus oral olanzapine were identified in a clinical cohort of patients with schizophrenia.

12‐month longitudinal cognitive functioning in patients recently diagnosed with bipolar disorder

Although cognitive deficits are observed in the early stages of bipolar disorder, the longitudinal course of neuropsychological functioning during this period is unknown. Such knowledge could provide etiologic clues into the cognitive deficits associated with the illness, and could inform early treatment interventions. The purpose of the present study was to evaluate cognitive change in bipolar disorder in the first year after the initial manic episode. From an initial pool of 65 newly diagnosed patients with bipolar disorder (within three months of the end of the first manic or mixed episode) and 36 demographically similar healthy participants, 42 patients [mean age 22.9 years, standard deviation (SD) = 4.0] and 23 healthy participants [mean age 22.9 years (SD = 4.9)] completed baseline, six-month, and one-year neuropsychological assessments of multiple domains including processing speed, attention, verbal and nonverbal memory, working memory, and executive function. Patients also received clinical assessments, including mood ratings. Although patients showed consistently poorer cognitive performance than healthy individuals in most cognitive domains, patients showed a linear improvement over time in processing speed (p = 0.008) and executive function (p = 0.004) relative to the comparison group. Among patients, those without a history of alcohol/substance abuse or who were taken off an antipsychotic treatment during the study showed better improvement. The early course of cognitive functioning in bipolar disorder is likely influenced by multiple factors. Nevertheless, patients with bipolar disorder showed select cognitive improvements in the first year after resolution of their initial manic episode. Several clinical variables were associated with better recovery, including absence of substance abuse and discontinuation of antipsychotic treatment during the study. These and other factors require further investigation to better understand their contributions to longitudinal cognitive functioning in early bipolar disorder.

Treatment of first-episode non-affective psychosis: a randomized comparison of aripiprazole, quetiapine and ziprasidone over 1 year

Discontinuation of antipsychotic treatment at early phases increases the risk of poor adherence to maintenance drug therapy. Differences among antipsychotics in terms of effectiveness may determine a good adherence to treatment. The aim of this study is to compare the clinical effectiveness of aripiprazole, ziprasidone and quetiapine in the treatment of first-episode schizophrenia spectrum disorders at 1 year. From October 2005 to January 2011 a prospective, randomized, open-label study was undertaken. Two hundred two first-episode drug-naïve patients were randomly assigned to aripiprazole (N = 78), ziprasidone (N = 62), or quetiapine (N = 62) and followed up for 1 year. The primary effectiveness measure was all-cause of treatment discontinuation. In addition, an analysis based on intention-to-treat principle was conducted in the analysis for clinical efficacy. The overall dropout rate at 1 year was 13.37 %. The treatment discontinuation rate differed significantly between treatment groups (aripiprazole = 43.6 %, ziprasidone = 66.1 % and quetiapine = 82.3 %) (χ 2 = 22.545; p < 0.001). Insufficient efficacy in the group of quetiapine is the most important reason for differences in discontinuation rates between agents (χ 2 = 19.436; p < 0.001). The mean time to all-cause discontinuation was significantly different between groups (LogRank = 30.732 p < 0.001). The profile of extrapyramidal symptoms varies between treatments. Patients on ziprasidone were more likely to be prescribed antidepressants. First episode patients treated with quetiapine have a higher risk of treatment discontinuation at midterm due to insufficient efficacy. Establishing differences between SGAs may help clinicians on prescribing decision for treatment of individuals presenting with first-episode non-affective psychosis.

Withdrawal Symptoms and Rebound Syndromes Associated with Switching and Discontinuing Atypical Antipsychotics: Theoretical Background and Practical Recommendations

With the widespread use of atypical or second-generation antipsychotics, switching treatment has become current practice and more complicated, as the pharmacological profiles of these agents differ substantially despite their similarity in being 'atypical'. All share the ability to block dopamine D₂ receptors, and most of them also block serotonin 5-HT2A receptors. Apart from these common features, some atypical antipsychotics are also able to block or stimulate other dopamine or serotonin receptors, as well as histaminergic, muscarinergic or adrenergic receptors. As a result of the varying receptor affinities, in switching or discontinuing compounds several possible pitfalls have to be considered, including the occurrence of withdrawal and rebound syndromes. This article reviews the pharmacological background of functional blockade or stimulation of receptors of interest in regard to atypical antipsychotics and the implicated potential withdrawal and rebound phenomena. A MEDLINE search was carried out to identify information on withdrawal or rebound syndromes occurring after discontinuation of atypical antipsychotics. Using the resulting literature, we first discuss the theoretical background to the functional consequences of atypical antipsychotic-induced blockade or stimulation of neurotransmitter receptors and, secondly, we highlight the clinical consequences of this. We then review the available clinical literature on switching between atypical antipsychotics, with respect to the occurrence of withdrawal or rebound symptoms. Finally, we offer practical recommendations based on the reviewed findings. The systematic evaluation of withdrawal or rebound phenomena using randomized controlled trials is still understudied. Knowledge of pharmacological receptor-binding profiles may help clinicians in choosing adequate switching or discontinuation strategies for each agent. Results from large switching trials indicate that switching atypical antipsychotics can be performed in a safe manner. Treatment-emergent adverse events during or after switching are not always considered to be, at least in part, associated with the pre-switch antipsychotic. Further studies are needed to substantiate the evidence gained so far on different switching strategies. The use of concomitant medication, e.g., benzodiazepines or anticholinergic drugs, may help to minimize symptoms arising from the discontinuation or switching of antipsychotic treatment.

The nature of relapse in schizophrenia

BackgroundMultiple relapses characterise the course of illness in most patients with schizophrenia, yet the nature of these episodes has not been extensively researched and clinicians may not always be aware of important implications.MethodsWe critically review selected literature regarding the nature and underlying neurobiology of relapse.ResultsRelapse rates are very high when treatment is discontinued, even after a single psychotic episode; a longer treatment period prior to discontinuation does not reduce the risk of relapse; many patients relapse soon after treatment reduction and discontinuation; transition from remission to relapse may be abrupt and with few or no early warning signs; once illness recurrence occurs symptoms rapidly return to levels similar to the initial psychotic episode; while most patients respond promptly to re-introduction of antipsychotic treatment after relapse, the response time is variable and notably, treatment failure appears to emerge in about 1 in 6 patients. These observations are consistent with contemporary thinking on the dopamine hypothesis, including the aberrant salience hypothesis.ConclusionsGiven the difficulties in identifying those at risk of relapse, the ineffectiveness of rescue medications in preventing full-blown psychotic recurrence and the potentially serious consequences, adherence and other factors predisposing to relapse should be a major focus of attention in managing schizophrenia. The place of antipsychotic treatment discontinuation in clinical practice and in placebo-controlled clinical trials needs to be carefully reconsidered.

Erratum

Erratum Samtani MN, Sheehan JJ, Fu D-J, Remmerie B, Sliwa JK, Alphs L. Management of antipsychotic treatment discontinuation and interruptions using model-based simulations. Clin Pharmacol. 2012;4:25–40. The video abstract was not included on page 25 for this paper.Read the original article

Management of antipsychotic treatment discontinuation and interruptions using model-based simulations.

BackgroundMedication nonadherence is a well described and prevalent clinical occurrence in schizophrenia. These pharmacokinetic model-based simulations analyze predicted antipsychotic plasma concentrations in nonadherence and treatment interruption scenarios and with treatment reinitiation.MethodsStarting from steady state, pharmacokinetic model-based simulations of active moiety plasma concentrations of oral, immediate-release risperidone 3 mg/day, risperidone long-acting injection 37.5 mg/14 days, oral paliperidone extended-release 6 mg/day, and paliperidone palmitate 117 mg (75 mg equivalents)/28 days were assessed under three treatment discontinuation/interruption scenarios, ie, complete discontinuation, one week of interruption, and four weeks of interruption. In the treatment interruption scenarios, pharmacokinetic simulations were performed using medication-specific reinitiation strategies.ResultsFollowing complete treatment discontinuation, plasma concentrations persisted longest with paliperidone palmitate, followed by risperidone long-acting injection, while oral formulations exhibited the most rapid decrease. One week of oral paliperidone or risperidone interruption resulted in near complete elimination from the systemic circulation within that timeframe, reflecting the rapid elimination rate of the active moiety. After 1 and 4 weeks of interruption, minimum plasma concentrations were higher with paliperidone palmitate than risperidone long-acting injection over the simulated period. Four weeks of treatment interruption followed by reinitiation resulted in plasma levels returning to predicted therapeutic levels within 1 week.ConclusionDue to the long half-life of paliperidone palmitate (25–49 days), putative therapeutic plasma concentrations persisted longest in simulated cases of complete discontinuation or treatment interruption. These simulations may help clinicians better conceptualize the impact of antipsychotic nonadherence on plasma concentrations, and the impact of medication-specific reinitiation strategies after intermittent nonadherence.

P-1263 - Antipsychotic treatment for patients with schizophrenia; patient-decided and clinician-decided discontinuations

Introduction Antipsychotic maintenance treatment for patients with schizophrenia has been demonstrated to be the single most important modifiable factor to prevent unplanned readmissions. Effectiveness studies have indicated different risk for drug discontinuation between current antipsychotics. Objectives & aims To evaluate time until discontinuation of antipsychotic treatment, and specifically to investigate if differences between the prescribed antipsychotics could be detected. Methods 396 patients with schizophrenia were included in an open cohort study and followed through treatment until all antipsychotics prescribed at inclusion were discontinued, predictors for time to discontinuation were analysed with univariate and multivariate Cox survival analyses with time until discontinuation as the dependent variable and antipsychotic monotherapy as the predictor variable. The analysis was controlled for common confounders. Results 65.7% of the patients were men, mean age was 42.4 years, and 12.9% were first-episode patients. 287 were prescribed antipsychotic monotherapy. In the multivariate Cox analysis with time to all-cause discontinuation only clozapine was significant different from olanzapine, Adjusted Hazard Rate (AHR) 0.17 (0.07,0.45) (p = 0.0003), this was also the case for the prediction of time to clinician-decided discontinuation, AHR (0.20 (0.06,0.70) (p = 0.012). In the analysis with time to patient-decided discontinuation as the dependent variable also Second Generation Antipsychotic Long-Acting Injectables (LAI) (AHR 0.26 (0.09,0.77) (p = 0.015) and First Generation Antipsychotic (LAI) (AHR 0.35 (0.16,0.80) (p = 0.013) had significant lower risk for discontinuation. Conclusions Clinicians and patients discontinued clozapine at a lower rate than olanzapine, patients also discontinued LAI formulations at a lower rate than olanzapine.

A Case of Neurotoxic Syndrome With the Use of Long-Acting Risperidone and Subsequent Olanzapine and Paroxetine

To the Editor: Administration of medications that affect brain dopamine and serotonin neurotransmission are occasionally associated with neurotoxic, behavioral, and autonomic syndromes, variously described as the neuroleptic malignant syndrome (NMS) and the toxic serotonin syndrome.1 We describe such a syndrome with the use of long-acting risperidone and subsequent olanzapine and paroxetine. Case report. Ms A, a 38-year-old woman, presented to our emergency department in 2009 for difficulty with swallowing and talking and profound drooling of saliva. She had a history of paranoid schizophrenia and amphetamine and heroin dependence and had had a severe head injury 15 months previously for which she underwent temporal craniectomy (with evidence of a right temporal lobe gliosis on follow-up computed tomography scans). For the past year, she was being treated with long-acting risperidone injection 37.5 mg intramuscularly every 2 weeks, lithium carbonate 250 mg bid, and oral risperidone 3 mg, taken at night. She was observed to have extrapyramidal symptoms, which were treated with benztropine. In an attempt to reduce these symptoms, these medications were stopped, and she was prescribed olanzapine 10 mg, taken at night, and paroxetine 20 mg, taken in the morning. Benztropine was continued. Over the next month, she developed progressive dysphagia, severe sialorrhea, occasional low-grade fever, frequent and profuse sweating, unsteadiness of gait, falls, and progressively slowed movements. Over the course of hospitalization, we observed the following: muscle rigidity (lead-pipe, all 4 extremities), coarse tremors of the hands, tachycardia, labile blood pressure, severe nausea, and tongue fasciculations. She had no cognitive, psychotic, or affective symptoms. There was no evidence of agitation, myoclonus, hyperreflexia, incoordination, shivering, or diarrhea (Sternbach criteria for serotonin syndrome2). Findings of laboratory investigations were all within normal limits except for mildly elevated liver function tests. Serum creatine kinase level was 40 U/L. She met DSM-IV research criteria for NMS (333.92).3 She was treated with benztropine 4 mg/d, and all other medications were stopped. All symptoms resolved within 8 days. Two days prior to discharge, she had paranoid thinking. In light of her history and emerging symptoms, olanzapine 5 mg at night was instituted. There was no reemergence of physical or psychiatric symptoms on follow-up. This case provides several insights into the symptomatology and pathophysiology of NMS and serotonin syndrome. The patient developed NMS/serotonin syndrome symptoms on treatment with a combination of paroxetine and olanzapine. There were no features of NMS/serotonin syndrome in the preceding months when she was being treated with oral and depot risperidone and lithium carbonate, although she did have significant extrapyramidal symptoms. The patient met DSM-IV criteria for NMS. However, she did not have the symptoms of severe NMS, such as a marked creatine phosphokinase elevation, hyperthermia, and an altered sensorium. The fact that she was on treatment with an atypical antipsychotic and that her symptoms were detected early probably accounted for this. Several of the patient's symptoms could also be explained by a serotonin syndrome.1 Nausea, for example, is not a typical feature of NMS but is frequently seen in serotonin syndrome. Abrupt discontinuation of antipsychotic treatment is a well-recognized although rare predisposing factor for the development of NMS. Although her medications were stopped, the patient was on depot risperidone treatment and would have had therapeutic plasma concentrations for several weeks. Risperidone has high antagonistic D2 receptor affinity, and the institution of olanzapine would have had a similar effect, although olanzapine is a relatively weaker D2 antagonist than risperidone.4 This would have resulted in a hypodopaminergic state, which is one of the postulated mechanisms for the development of NMS.5 Paroxetine is a potent and specific inhibitor of 5-HT reuptake,6 whereas olanzapine has high antagonistic affinity at 5-HT2A receptors and low agonistic affinity at 5-HT1A receptors.4 This would have resulted in significantly increased serotonergic neurotransmission at the 5-HT1A receptor. Hyperstimulation of the 5-HT1A receptor in the brain stem and spinal cord has been implicated in the pathophysiology of both the serotonin syndrome and NMS.7 In addition, there is substantial evidence that the serotonin system inhibits dopaminergic function at the level of the origin of the dopamine system in the midbrain as well as at the terminal dopaminergic fields in the forebrain.8 Furthermore, studies suggest that traumatic brain injury patients show an increase in serotonergic and noradrenergic neurotransmission and a dysfunction in mesolimbic and mesocortical dopaminergic neurotransmission.5,9 The net effect of all these actions in this patient would have been a greatly increased serotonergic neurotransmission and a greatly decreased dopaminergic neurotransmission. This could explain the pathophysiology of the toxidrome in this case and explain the symptom overlap between NMS and serotonin syndrome that this patient displayed. This case highlights the need for caution and vigilance in the use of selective serotonin reuptake inhibitor–atypical antipsychotic combinations, particularly in patients with preexisting brain injury.

Actitud respecto a la medicación antipsicótica como factor predictivo de la suspensión del tratamiento antipsicótico en el período inicial de la psicosis de inicio temprano

Antipsychotic drug discontinuation is a key risk factor in psychotic relapses. Clinical relapse is related to poor outcome, especially in the earlier stages of psychotic illness. The attitude toward treatment during the acute phase of a first episode of psychosis has been proposed as one of the main determinants of treatment discontinuation. However, the relationship between attitude toward antipsychotic medication and treatment discontinuation in the adolescent population has not been properly assessed.Adolescents, aged 12-18 years old, consecutively admitted to an adolescent unit with a first lifetime admission for a first episode of psychosis were asked to participate in a randomized, flexible-dose, 6-month controlled trial of olanzapine vs. quetiapine. Attitude toward antipsychotic medication was assessed using the 10-item Drug Attitude Inventory (DAI). The outcome variable was all-cause treatment discontinuation over the 6-month follow- up. The study sample was composed of 42 patients [34 boys (82.9%), eight girls (17.1%), mean age ± SD: 16.1±1.3].Of the 42 patients, only 29 (69%) continued the medication throughout the entire 6-month follow-up, while 13 (31%) discontinued the medication. DAI scores were greater than zero at all assessments, indicating that the general attitude of the patients toward medication was positive. Higher DAI scores at baseline were related to lower all-cause treatment discontinuation [adjusted hazard ratio (HR) = 0.81 (95% CI: 0.68-0.96), P=0.016], while DAI scores at 15 days were unrelated to treatment discontinuation [adjusted HR=1.0 (95% CI: 0.82-1.23), P=0.998].A better attitude toward antipsychotic medication at a first lifetime psychiatric admission for a first early-onset psychotic episode was significantly related to lower all-cause antipsychotic treatment discontinuation.

Antipsychotic treatment discontinuation in previously untreated patients with schizophrenia: 36-month results from the SOHO study

Data from the 3-year, prospective, observational SOHO study were used to compare the effectiveness (in terms of treatment discontinuation) and the tolerability of olanzapine, risperidone, other atypicals and typical antipsychotics in 1009 previously untreated outpatients with schizophrenia who started monotherapy at baseline. Kaplan–Meier survival analysis estimated the time to treatment discontinuation by the treatment group, Cox proportional hazards regression models identified the variables associated with treatment discontinuation (adjusted for baseline differences between treatment groups), and logistic regression models compared the tolerability profiles of the different treatment groups. Of the 931 patients analyzed, 31.9% discontinued the medication initiated at baseline during the 3-year follow-up. Olanzapine had the lowest rate of discontinuation (28.9%), followed by other atypical (34.0%), risperidone (36.2%) and typical antipsychotics (44.5%). Compared to olanzapine, risk of treatment discontinuation was higher with typical antipsychotics (hazard ratio [HR] 1.75; 95% confidence interval [CI] 1.11, 2.78) or risperidone (HR 1.36; 95% CI 1.02, 1.82). A higher baseline Clinical Global Impression (CGI) positive score was associated with a higher risk of treatment discontinuation (HR 1.18; 95% CI 1.06, 1.30). Olanzapine was associated with a lower frequency of extrapyramidal symptoms than other antipsychotics, fewer prolactin-related adverse events than risperidone and other atypical antipsychotics, but greater weight gain than typicals and risperidone. For all analyses, comparison with the other atypical group is limited due to its small sample size ( n = 50). In conclusion, treatment effectiveness and tolerability varied among antipsychotic medications in previously untreated patients with schizophrenia. The results should be interpreted conservatively given the observational study design.

Attitude Toward Antipsychotic Medication as a Predictor of Antipsychotic Treatment Discontinuation in First-Episode Early-Onset Psychosis

BackgroundAntipsychotic drug discontinuation is a key risk factor in psychosis relapses. Clinical relapse is related to poor outcome, especially in the earlier stages of psychotic illness. The attitude toward treatment during the acute phase of a first episode of psychosis has been proposed as one of the main determinants of treatment discontinuation. However, the relationship between attitude toward antipsychotic medication and treatment discontinuation in the adolescent population has not been properly assessed. MethodsAdolescents, aged 12–18 years old, consecutively admitted to an adolescent unit with a first lifetime admission for a first episode of psychosis were asked to participate in a randomized, flexible-dose, 6-month controlled trial of olanzapine versus quetiapine. Attitude toward antipsychotic medication was assessed using the 10-item Drug Attitude Inventory (DAI). The outcome variable was all-cause treatment discontinuation over the 6-month follow-up. The study sample was composed of 42 patients (34 boys [82.9%], 8 girls [17.1%]; mean age [SD], 16.1 [1.3]). ResultsOf the 42 patients, only 29 (69%) continued the medication throught the entire 6-month follow-up, while 13 (31%) discontinued the medication. DAI scores were greater than zero at all assessments, indicating that the general attitude of the patients toward medication was positive. Higher DAI scores at baseline were related to lower all-cause treatment discontinuation (adjusted hazard ratio [HR] = 0.81 [95% CI, 0.68–0.96], P=.016), while DAI scores at 15 days were unrelated to treatment discontinuation (adjusted HR = 1.0 [95% CI, 0.82–1.23], P=.998). ConclusionsA better attitude toward antipsychotic medication at a first lifetime psychiatric admission for a first early-onset psychotic episode was significantly related to lower all-cause antipsychotic treatment discontinuation.

The Schizophrenia Outpatient Health Outcomes (SOHO) study: 3-year results of antipsychotic treatment discontinuation and related clinical factors in Spain

IntroductionThis article presents the long-term results in terms of antipsychotic medication maintenance and factors influencing it in a representative sample of patients with schizophrenia recruited in the SOHO study within Spain. MethodsThe SOHO was a prospective, 3-year observational study of the outcomes of schizophrenia treatment in outpatients who initiated therapy or changed to a new antipsychotic performed in 10 European countries with a focus on olanzapine. The Kaplan–Meier method was used to analyse the time to treatment discontinuation and the Cox proportional hazards model to investigate correlates of discontinuation. Results and conclusionsIn total, 1688 patients were included in the analyses. Medication maintenance at 3years varied with the antipsychotic prescribed, being highest with clozapine (57.6%, 95% CI 39.2–74.5), followed by olanzapine (48.3%, 95% CI 45.1–51.5); and lowest with quetiapine (19.0%, 95% CI 13.0–26.3). Treatment discontinuation was significantly less frequent with olanzapine than with risperidone (p=0.015), depot typical (p=0.001), oral typical antipsychotics (p<0.001) or quetiapine (p<0.001); but not than with clozapine (p=0.309). Longer maintenance was also associated with higher social abilities and better cognitive status at baseline; in contrast, a shorter time to discontinuation was associated with the need for mood stabilisers during follow-up. This study emphasises the different value of antipsychotics in day-to-day clinical practice, as some of them were associated with longer medication maintenance periods than others. This study has some limitations because of possible selection and information biases derived from the non-systematic, non-randomised allocation to treatments and the existence of unobserved covariates that may influence the outcome.