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Discontinuation from Schizophrenia Treatment is Driven by Poor Symptom Response: A Pooled Post-hoc Analysis of Four Atypical Antipsychotics
Hong Liu-Seifert, PhD, David H. Adams, PhD, Bruce J. Kinon, MD Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
liu-seifert_hong@lilly.com adamsda@lilly.com bj_kinon@lilly.com
Regular Research Article Running head: Reasons for Discontinuation
Address correspondence and reprint requests to Dr. Hong Liu-Seifert, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Drop Code 4133, Indianapolis, IN 46285. Telephone: (317) 433-0662; Fax: (317) 276-7100 email: liu-seifert_hong@lilly.com.
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ABSTRACT Background: Antipsychotic treatment discontinuation can interrupt therapeutic progress and lead to illness exacerbation. Treatment discontinuation results from controlled clinical trials were utilized to explore reasons for this phenomenon. Methods: This was a post-hoc, pooled analysis of four randomized, double-blind clinical trials, 24-28 weeks in duration, enrolling 1627 patients with schizophrenia or a related disorder. Analyses were conducted combining all atypical antipsychotic treatment groups in the studies. Results: A majority of patients (53%) discontinued early from antipsychotic treatment. Poor psychiatric response/symptom worsening was the most frequent reason for discontinuation, which was substantially more common than discontinuation due to medication intolerability. This phenomenon was corroborated by inadequate symptom improvement in patients who discontinued compared to completers, based on the PANSS total scores. Discontinuation due to poor response was apparently, predominantly linked to patient perception as compared to physician conclusion alone (80% vs. 20%). Discontinuation due to patient perception of poor response appeared to occur particularly early in the treatment course. Patients who discontinued due to medication intolerability showed a rate of response comparable to that of completers. Conclusions: Treatment discontinuation may lead to illness exacerbation, undermining therapeutic progress. In these studies, poor response to treatment and worsening of underlying psychiatric symptoms, and to a lesser extent, intolerability of medication were the primary contributors to treatment discontinuation. Our findings suggest that adherence may be enhanced by effective symptom control as objectively measured, as well as subjectively
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perceived. Such strategies may improve patient engagement in long-term therapy and increase likelihood of achieving treatment goals.
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BACKGROUND Treatment adherence is a significant issue in the clinical management of schizophrenia. Early treatment discontinuation in patients with schizophrenia or schizophrenia-like disorders is strikingly common, with prevalence estimates of treatment discontinuation in antipsychotic drug trials ranging from 25%-75% and rates of nonadherence appear to be even higher in naturalistic uncontrolled settings [1,2,3,4]. The consequences of early treatment discontinuation are significant, making medication adherence a critical determinant of the patient’s overall health outcome. Discontinuation of a prescribed antipsychotic is associated with symptom exacerbation [5], relapse [5,6], increased hospitalization [5,6], poor long-term course of illness [7], and higher economic costs of treatment [8]. As many as 75% of patients who stop taking their antipsychotic medication experience significant symptom exacerbation over the course of a year compared with only 25% of those who consistently take their medication [5,6]. There are many factors associated with early treatment discontinuation. These can be separated into treatment-related reasons such as inadequate response and adverse events, patient-related reasons such as insight and attitude, and environmental elements such as family support and transportation availability [5,9,10]. Treatment-emergent adverse events are one of the more frequently cited reasons for noncompliance with antipsychotic medications [5,9]. The health belief model suggests that a patient’s likelihood of adhering to their prescribed medication is a product of an implicit and subjective assessment of the relative costs and benefits of adherence in relation to personal goals and constraints [3,9,11].
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Recently, treatment discontinuation has been used as a measure of treatment ineffectiveness in schizophrenia [12,13,14]. The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial is a large, randomized, controlled trial that evaluates the effectiveness of atypical and conventional antipsychotic medications in patients with schizophrenia over an 18-month period [14]. The primary outcome variable in this trial is the time to treatment discontinuation for any reason. In this context, treatment discontinuation reflects both patient and clinician views of efficacy and tolerability. The significant impact of treatment adherence on clinical outcome and increasing use of treatment continuation as a proxy for overall treatment effectiveness make it important to better understand the reasons for treatment discontinuation. Randomized, controlled clinical trials provide information on reasons for discontinuation of prescribed medication that may help to shed light on what happens in the naturalistic settings of clinical care. We, therefore, undertook a secondary analysis of controlled trials of olanzapine for schizophrenia and schizophrenia-like illnesses with treatments collapsed to explore the reasons for treatment discontinuation. Our goal was to better understand the role that efficacy and tolerability plays in treatment discontinuation, along with the relative role of patient and clinician perception.
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METHODS
Patient Population This was a post-hoc, pooled analysis of clinical trials within the Eli Lilly and Company database. The study selection criteria were: 1) randomized, double-blind, active-controlled, 2) duration of 24 to 28 weeks, and 3) schizophrenia, schizophreniform disorder, or schizoaffective disorder. Four studies met these criteria. The 4 studies included 1627 patients treated with olanzapine, risperidone, quetiapine, or ziprasidone. None of the studies included a placebo arm. Patients were men and women between the ages of 18 and 75. All protocols were approved by the ethical review boards responsible for individual study sites. All patients gave written, informed consent prior to entering the study. The pooled analysis included 1 trial comparing olanzapine and risperidone [15], 1 trial comparing olanzapine and quetiapine [16], and 2 trials comparing olanzapine and ziprasidone [17,18]. Study Designs Study 1 was a 28-week, multi-center study of olanzapine (10-20 mg/day, n=172) versus risperidone (4-12 mg/day, n=167) in inpatients and outpatients meeting diagnostic criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder according to the DSM-IV [15]. The study was conducted at 38 sites in Europe, South Africa, and the United States. Patients had an initial score on the Brief Psychiatric Rating Scale (BPRS) of at least 42. Patients started olanzapine therapy at 15 mg/day once daily for the first 7 study days and then titration was permitted to optimize an individual patient’s outcome (range 10-20 mg). Consistent with risperidone labeling, patients began
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risperidone titration at a dosage of 1 mg twice daily on Day 1, 2 mg twice daily on Day 2, and then 3 mg twice daily on Days 3 through 7. After the first week, titration was permitted to optimize an individual patient’s outcome (range 4-12 mg/day). Concomitant psychotropic medications were not allowed during the study with the exception of limited benzodiazepines/hypnotics and approved antiparkinsonian medications. Study 2 was a 6-month, multicenter study comparing the efficacy of olanzapine (10-20 mg/day, n=171) with quetiapine (300-700 mg/day, n=175) in outpatients meeting diagnostic criteria for schizophrenia and schizoaffective disorder according to the DSMIV who had poor functioning and prominent negative symptoms [26]. The study was conducted at 29 sites in the United States. Patients had a score ≤ 60 on the Global Assessment of Functioning (GAF) and a score ≥4 on at least 3 or ≥5 on at least 2 of the 7 negative scale items on the Positive and Negative Syndrome Scale (PANSS). Patients were started on olanzapine therapy at 10 mg/day for the first 14 days and then investigators adjusted patients up to their clinically optimal dose (10-20 mg/day). Patients were started on quetiapine therapy at 50 mg/day on Day 1, 100 mg/day on Day 2, 200 mg/day on Day 3, and then 300 mg/day on Days 4-14. The quetiapine dose was then adjusted in 100 mg increments up to individual patient’s clinically optimal dose (300-700 mg/day). Concomitant psychotropic medications were generally not allowed during the study with the following exceptions: antidepressants if a patient had been on a stable dose for 30 days prior to study enrollment and remained on a stable dose during the study, limited benzodiazepines/hypnotics, and approved antiparkinsonian medications. Study 3 was a multicenter, 28-week study of olanzapine (10-20 mg/day, n=277) and ziprasidone (80-160 mg/day, n=271) in inpatients or outpatients meeting diagnostic
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criteria for schizophrenia according to the DSM-IV [17]. The study was conducted at 78 sites in Europe, Mexico, Puerto Rico, South America, and the United States. Patients had an initial score of at least 42 on the BPRS and a score ≥4 on one of the PANSS positive items in addition to a Clinical Global Impressions-Severity score ≥4. Patients were started on olanzapine at 10 mg once daily for 7 days and then adjusted in increments up to the patient’s individual optimal dose (10-20 mg/day). Patients were started on ziprasidone at 10 mg twice daily for 3 days, 40 mg twice daily for 4 days, and then adjusted in increments up to the patient’s individual optimal dose (80-160 mg/day). Concomitant psychotropic medications were not allowed during the study with the exception of limited benzodiazepines/hypnotics and approved antiparkinsonian medications. Medications known to prolong the QTc interval were prohibited. Study 4 was a multicenter, 24-week, fixed-dose study of olanzapine (10, 15, or 20 mg/day, n=202) and ziprasidone (80, 120, or 160 mg/day, n=192) in inpatients or outpatients meeting diagnostic criteria for schizophrenia or schizoaffective disorder according to the DSM-IV with concurrent depressive symptoms [18]. The study was conducted at 40 sites in the United States. Patients had a score ≥16 on the MontgomeryÅsberg Depression Rating Scale (MADRS) and ≥4 on Item 2 (reported sadness). Ziprasidone treatment was initiated at 20 mg twice a day for 3 days, then 40 mg twice a day for 6 days, and then up-titrated to the randomly assigned dosage. Concomitant psychotropic medications were generally not allowed during the study with the following exceptions: antidepressants if a patient had been on a stable dose for 30 days prior to study enrollment and remained on a stable dose during the study, limited benzodiazepines/hypnotics, and approved antiparkinsonian medications. Medications
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known to prolong the QTc interval were prohibited. Assessments The primary objective of the present analysis was to assess the pattern and reasons for treatment discontinuation/continuation by pooling the 4 studies and collapsing all treatment groups. Clinical trial investigators in all 4 studies were required to record reason and date of discontinuation when patients left the trial before completing the study. A clinical report form with a checklist of potential reasons for discontinuation was used. The reasons for discontinuation are listed below: 1) Adverse Event (AE)-with the event specified. 2) Entry Criteria Not Met-checked when a patient had been inappropriately enrolled in the trial based on specific entry criteria. 3) Lack of Efficacy (LOE)-Patient Perception-the patient perception was that symptom improvement was not adequate for continued use of the randomized medication. 4) Lack of Efficacy (LOE)Physician Perception-the physician perception was that symptom improvement was not adequate for continued use of the randomized medication. 5) Lack of Efficacy (LOE)Patient and Physician Perception. 6) Lost to Follow-up-a patient did not come to a scheduled visit and subsequently was unable to be contacted by phone or mail. 7) Noncompliance-patients who intentionally missed all doses for a number of consecutive days specified for each trial or who regularly took more than the prescribed amount of medication. 8) Personal Conflict-the patient’s decision for a variety of personal reasons such as work conflict, lack of transportation, change of location, or unwillingness to fill out questionnaires. 9) Physician Decision-physician decided that a patient should be discontinued due to reasons other than lack of efficacy or satisfactory response. Examples include investigator sites closing and patients deemed unreliable. 10) Sponsor Decision-
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the sponsor, Eli Lilly and Company, decided that a patient should be discontinued following consultation by the investigator treating the patient. 11) Clinical Relapse-Study 2 only-clinical relapse was based on predefined criteria including an increase in the following positive symptoms of schizophrenia: delusions, conceptual disorganization, hallucinatory behavior, or suspiciousness as measured by PANSS; an increase in self depreciation as measured by the Calgary Depression Scale for Schizophrenia; or hospitalization for any psychiatric condition. 12) Satisfactory Response-Study 1 and Study 2 only. For the present analysis, discontinuation due to lack of efficacy based on either patient or physician perception was grouped together and used as a measure of discontinuation due to poor symptom response to treatment (termed poor response). Discontinuation due to psychiatric adverse events (e.g. emergent psychosis or depression) along with “Clinical Relapse” (Study 2 only-see above description) was used as a measure of discontinuation due to symptom worsening. These 2 categorizations, poor response and symptom worsening, represent a continuum of treatment inefficacy. In contrast, discontinuation due to non-psychiatric adverse events was considered discontinuation due to medication intolerability. The psychopathology of schizophrenia was measured by visitwise analysis of mean total scores on the PANSS [19]. The PANSS is a 30-item scale that was designed to capture numerous symptoms of schizophrenia including delusions, grandiosity, blunted affect, poor attention, and poor impulse control. Statistical Methods The analyses in this research were conducted combining all the treatment groups
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in the 4 clinical studies. The differences in PANSS total scores between study completers and discontinued patients were tested using Analysis of Variance (ANOVA) with term for group (completed vs. discontinued) at all timepoints that were common for all studies (Weeks 2, 4, 6, 8, 16, 20, and 24). In addition, PANSS total scores were also compared among completers and patients who discontinued due to various reasons such as poor response/symptom worsening, intolerability to medication, and others using ANOVA with term for group. Logistic regression analysis was applied to test if early response predicts study completion with the independent variable as change in PANSS total at Week 2. A similar model was used with the predictor as a categorical variable defined as an improvement of 20% or greater in PANSS total from baseline to 2 weeks. Time to discontinuation due to poor response was assessed by Kaplan-Meier estimators for patient perception and physician perception. Patient perception was based on discontinuation by patient perception of poor response either alone or in consensus with physician perception. Physician perception was based on physician perception alone. For patients who discontinued due to adverse events, the actual event was identified for all but 6 patients. All statistical tests are based on a two-tailed significance level of .05.
RESULTS Table 1 summarizes the study sample at baseline across the 4 studies with treatment groups combined. A majority of patients were male (64.4%), Caucasian (53.3%), and had a diagnosis of schizophrenia (78.5%). The patient mean age was 39.5±10.8 years and the mean age of illness onset was 23.5±8.3 years. The mean baseline PANSS total score was 91.27±19.72 and 49.8% of patients had been
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hospitalized prior to the study. Reasons for Discontinuation A majority of patients (53%; 866/1627) discontinued early from these 4 studies. The reasons for discontinuation are summarized in Figure 1. The most common reason for early treatment discontinuation was poor response/psychiatric symptom worsening (36% of the discontinuations; 315/866) which was 3 times the rate of patient discontinuation due to medication intolerability (12%; 106/866). In particular, poor response accounted for 19% (164/866) of patient discontinuation and symptom worsening 17% (151/866). The most common psychiatric adverse events (symptom worsening) cited for treatment discontinuation were psychosis (n=35), suicide ideation, attempts, or completion (n=18), schizophrenia/schizoaffective/schizophreniform disorder (n=17), and depression (n=12). The most frequent non-psychiatric adverse events (medication intolerability) cited for treatment discontinuation were sedation (n=7), somnolence (n=7), abnormal ECG (n=6), vomiting (n=5), dizziness (n=4), dystonia (n=3), fatigue (n=3), liver function test abnormal (n=3), and weight increased (n=3). The rates of and reasons for discontinuation cross the 4 studies were fairly consistent and are shown in Table 2. Symptom Response: Completers vs. Patients who Discontinued In order to objectively examine the association between poor clinical outcome and treatment discontinuation independently of the checklist used at patient departure, PANSS total scores at each assessment were compared between patients who completed the study and those who discontinued early. There was no significant difference in baseline PANSS total scores between the patients who completed and those who
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discontinued treatment (91.4+/-19.2 and 91.1+/-20.2, respectively; p=.744). However, at each time point after treatment had begun, patients who completed the study had significantly lower PANSS total scores than patients who discontinued prior to the end of the study (p<.001, Figure 2). Although both groups showed significant clinical improvement compared to baseline (p<.001 at each timepoint), patients who discontinued early from the study appeared to have a slower initial rate of improvement and less improvement overall as compared to those patients who completed the study. In view of the above results, it was of interest to determine if early response predicted study completion. Symptom improvement from baseline to 2 weeks as measured by mean change in PANSS total score was significantly predictive of study completion (regression coefficient estimate 0.02, p<.001). Further, defining early response as a 20% or greater improvement in PANSS total score at 2 weeks, 28.9% of patients (431 of 1492 available at Week 2) met the criteria. Based on this criteria, early response was associated with an approximately 80% greater likelihood of completing the study (odds ratio 1.76, confidence interval (1.4, 2.21), p<.0001). PANSS total scores at each assessment were also compared among completers and patients who discontinued treatment early due to poor response/worsening, intolerability to medication, and “other”, respectively. “Other” reasons for discontinuation were the same as described in Figure 1 and as described in detail in the Methods section. There was a cross-group significant difference from Week 0 through Week 6 and also at Week 20 (p<.05; Figure 3). In contrast to patients who discontinued due to poor response or symptom worsening, patients who discontinued due to medical adverse events showed comparable improvement in PANSS total scores to study
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completers, suggesting that adverse events do not interfere with symptom response, but prevent an otherwise effective treatment. The baseline characteristics of patients who discontinued early due to poor response or symptom worsening are described in Table 3. This group of patients reported prior hospitalization significantly more frequently than all other patients (56.8%; 179/315 vs. 48.2%; 632/1312; p=.007). In addition, these patients were significantly more often Caucasian when compared with all other patients (64.4%; 203/315 vs. 50.7%; 665/1312; p<.001). Other baseline characteristics were similar between patients who discontinued due to poor response or symptom worsening and the rest of the study population. Patient Perception Discontinuation due to poor response was further characterized to determine whether the patient or physician concluded that symptom response was not adequate for medication continuation. Discontinuation due to patient perception of poor response was defined as discontinuation due to patient perception of poor response (lack of efficacy) either alone or in consensus with physician conclusion. Physician perception was based on physician perception of poor response alone. Patient perception accounted for 80% (132/164) of discontinuation of treatment due to poor response (Figure 4.A). In addition, the time to discontinuation was much sooner when patient perception in comparison to physician perception of poor response was the reason for discontinuation (Figure 4.B). However, when PANSS total scores were compared between the groups that discontinued due to poor response by patient perception and by physician perception, the clinical performance was similar between the two groups (Figure 4.C; the only significant
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difference in PANSS scores between the groups was at Week 4, p=.02).
DISCUSSION
Premature treatment discontinuation was very common in these four schizophrenia clinical trials. The most common reason for early treatment discontinuation was poor symptom response/psychiatric symptom worsening which was substantially more common than discontinuation due to medication intolerability. Patients who discontinued early from the study due to poor response or symptom worsening had a slower initial rate of improvement and less improvement overall compared to those patients who completed the study. In contrast, patients who discontinued due to medication intolerability were showing comparable symptom improvement to study completers up until discontinuation. Discontinuation due to poor response was overwhelmingly linked to patient perception of response compared to physician observation alone. Discontinuation due to patient perception of poor response appeared to occur particularly early in the treatment course. The substantial rate of premature discontinuation from these studies likely reflects the great challenge of treatment adherence in the clinical treatment of patients with schizophrenia. Discontinuation by more than half of the patients in these trials is within the broad range of previous reports of antipsychotic discontinuation (25%-75%) and is in line with reports of medication adherence in naturalistic settings [1,2,3,4]. Both the present study and other analysis of clinical trials likely underestimate the true incidence
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and likely the associated burden of antipsychotic nonadherence in the long-term course of therapy since the studies are time-limited and treatment of schizophrenia is a life-long consideration. Studies of older typical antipsychotics indicate that about 75% of patients discontinue their medication within 2 years [5]. Perhaps the most interesting and important result of our analysis is that treatment discontinuation due to inadequate control of psychiatric symptoms appeared three times as likely as discontinuation due to medication intolerability. This was an unexpected finding of this systematic study since adverse events are a commonly cited reason for medication nonadherence [5,9]. Patients who discontinued had less improvement
compared to study completers using an objective rating scale (PANSS) suggesting that this patient group has a real deficit in medication response. However, even patients who discontinued achieved response to a certain extent, suggesting that there is a critical level of response needed to keep patients on treatment. Patients appeared to be especially likely to give up on treatments that did not provide a rapid therapeutic response as a 20% early response resulted in an approximately 80% greater likelihood of remaining on therapy. Although the notion that a substantial delay in antipsychotic response is common in the field of psychiatry [20], Agid et al. [21] recently reported the results of a meta-analysis of double-blind, controlled trials that suggests antipsychotic response starts within the first week of therapy and accumulates over time. In addition, antipsychotic response within the first week of treatment has been reported to predict response after 6 weeks, at least for haloperidol [22]. The present study expands upon these findings by suggesting that early response also predicts treatment continuation. Therefore, patient
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perception of efficacy early on in treatment may be a major contributor to engagement in treatment and adherence with the treatment plan. One possible explanation for the inadequate treatment response of patients who discontinued treatment early due to poor response or symptom worsening may be that they are intrinsically less responsive to treatment. For some patients, treatment resistance may represent an intrinsic part of the schizophrenic illness, at least with current antipsychotic medications [23]. The current study provides limited data to address this possibility. In support of this hypothesis, patients who discontinued treatment early due to poor response or symptom worsening reported prior hospitalization significantly more than all other patients. Treatment-resistant patients often require extensive periods of hospitalization and older studies commonly used frequent hospitalization as an indicator of treatment resistance, although this may not be accurate in all cases [24]. On the other hand, other baseline characteristics that might be associated with treatment resistance such as duration of illness and baseline illness severity were similar between patients who discontinued due to poor response or symptom worsening and the rest of the study population. Standardized criteria for treatment resistance have been more recently described [25,26]. Further studies using defined criteria for treatment resistance are needed to better determine if patients who discontinue treatment due to poor response or symptom worsening are truly treatment resistant. Alternatively, these patients may discontinue early because of a suboptimal early treatment response and perceived lack of efficacy, and may possibly benefit from an early active clinician-initiated attempt to bolster engagement in order to maintain treatment adherence.
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Interestingly, patients who discontinued due to medication intolerability were showing comparable symptom improvement compared to study completers prior to their discontinuation. It should be noted that some of the adverse events were not considered severe; nonetheless, they were costly to patients by derailing patients from the potential benefit of the treatment. Had these patients continued their treatment to study completion, they would have likely had a clinically successful treatment. Therefore, adverse events should be viewed as a significant barrier to treatment efficacy and must be addressed on an individual patient basis. Weight gain is a potential adverse event of atypical antipsychotic treatment that has been cited by patients as highly distressing [27], and has been proposed to be a factor in medication non-adherence [3]. However, weight gain has rarely been directly investigated as a factor in medication discontinuation or adherence. In the present studies, weight gain was infrequently reported as a reason for discontinuation (3 patients; 0.2%). However, weight gain in more naturalistic treatment settings may be a more important factor in patient adherence to medication than reported here for clinical trials. In addition to the deficit in treatment response as measured by PANSS scores, there was also a subjective component to the poor response reported by some patients. While patient perception of poor response was responsible for treatment discontinuation much more frequently than physician perception of poor response, patients who discontinued due to patient perception of poor response and patients who discontinued due to physician perception of poor response had similar PANSS scores, highlighting a subjective aspect of patient perception of treatment effectiveness. This suggests that patients are aware of whether they are getting better and may not be as willing as
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physicians to allow more time for symptom improvement if they perceive early in treatment that their symptom response is less than optimal. These results are consistent with the health belief model that suggests a patient’s likelihood of adhering to their prescribed medication is a product of an implicit and subjective assessment of the relative costs and benefits of adherence in relation to personal goals and constraints [3,9,11]. These results highlight the importance for active engagement of the patient early in treatment with a clear understanding of the patient’s expectations and treatment goals. A limitation of the present analysis is that the reasons for discontinuation on the checklist used to categorize discontinuation in the 4 clinical trials may have not optimally captured the primary reason for discontinuation in all cases. For instance, a relatively high number of patients discontinued due to “personal conflicts” which included a variety of specific reasons and were not analyzed in this study. Categorizing all of these reasons as personal conflicts may have prevented identifying additional barriers to medication adherence and may mask an underlying patient concern regarding efficacy, tolerability, or novel reasons that caused patients to lack the motivation to make the necessary commitment to continue. Finally, discontinuation due to physician perception of response may have been underrepresented since physician versus patient perception was only captured in regards to poor symptom response and was not assessed in regards to symptom worsening (psychiatric adverse events). Although, discontinuation due to psychiatric adverse events was ultimately a physician decision, it cannot be concluded that patients did not play a role in this decision. Therefore, discontinuation due to symptom worsening was not considered in the analysis of discontinuation due to patient and physician perception of response.
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An additional limitation of the present study is that it is based on clinical trials that may not reflect more naturalistic patient treatment settings. Patients enrolled in the trials were much more homogeneous than the patient population seen in routine clinical care because of restrictions on patient enrollment. For instance, in the trials patients with alcohol and substance dependence were excluded and patients generally did not receive polypharmacy. In addition, clinical trials require that patients be motivated to participate in the trial so these patients may have different implicit motivation and beliefs regarding treatment than patients in other settings. As a consequence, the rates of and reasons for discontinuation reported in this study may not be generalizable to typical outpatient settings. With these caveats, the systemic investigation of reasons for early discontinuation in the present study may still help to develop strategies to improve patient engagement in long-term therapy. Conclusion In these studies, as in clinical management of patients with schizophrenia, treatment discontinuation was strikingly common. Poor response to treatment and worsening of underlying psychiatric symptoms, and to a lesser extent, intolerability of medication were the most common reasons for treatment discontinuation. Both a real inadequacy of treatment response, as well as patient perception of failure to improve, contributed to early treatment discontinuation. Improved treatment adherence in schizophrenia can reduce the risk of relapse and its morbid consequences and perhaps promote higher functioning through better therapeutic engagement and building upon improvement. This study suggests that adherence may be enhanced by effective symptom control as objectively measured, as well as subjectively perceived.
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COMPETING INTERESTS All authors are employees of Eli Lilly and Company.
AUTHORS’ CONTRIBUTIONS Dr. Hong Liu-Seifert made substantial contributions to the analysis design, data analysis, and critical revision of the manuscript. Dr. David Adams made substantial contribution to the interpretation of data, drafting, and critical revisions to the manuscript. Dr. Bruce Kinon made substantial contributions to the individual study designs, analysis design, and critical revisions to the manuscript. All authors have given final approval of the manuscript.
ACKNOWLEDGEMENT This work was sponsored by Eli Lilly and Company. Appreciation is expressed to Binbin Zhang for technical assistance and to Jan Short for editorial assistance with the manuscript.
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FIGURE LEGENDS Figure 1. Flowchart of early treatment discontinuation. Values are the summary of reasons for discontinuation from all 4 studies. Poor Response was based on “Lack of Efficacy”. Symptom Worsening was based on “Psychiatric Adverse Events” and a priori protocol defined “Clinical Relapse” (HGJB only). Figure 2. Visitwise PANSS total scores between patients who completed the study and those who discontinued early. Values are means cross all treatments and studies. *p<.001 between group difference. Completers (Com), Discontinued (D/C). Figure 3. Visitwise PANSS total scores between patients who completed the study and those who discontinued early due to various reasons. Values are means cross all treatments and studies. *p<.05 between group difference. Completers (Com), Poor response/symptom worsening (Pr/W), Intolerability to Medication (IM).
Figure 4. Patient and physician perception of efficacy. A. Discontinuation due to poor response by perception. Patient perception was based on discontinuation by patient perception of poor response either alone or in consensus with physician perception. Physician perception was based on physician conclusion alone. B. Time to discontinuation (D/C) due to poor response by perception. C. Visitwise PANSS total scores between patients who discontinued early due to poor response by patient perception and those by physician perception. *p<.05. Physician perception (Phy per), Patient perception (Pt per).
28
Table 1. Patient and disease characteristics
Characteristic Age (mean ± SD)
Study 1 (n=339) 36.21 ± 10.73
Study 2 (n=346) 41.05 ± 9.58 228(65.9) 179(51.7)
Study 3 (n=548) 39.10 ± 11.8 352(64.2) 239(43.6)
Study 4 (n=394) 41.59 ± 9.74 248(62.9) 197(50.0)
Total (N=1627)
39.53 ± 10.85 1048(64.4) 868(53.3)
Sex (Male %) Race (Caucasian %) Diagnosis (%) Schizophrenia Schizoaffective Schizophreniform Age of Onset Illness (yrs ± SD) PANSS Total (mean±SD) Prior Hospitalization (%) Hospitalization days (mean ± SD)* Illness Duration (yrs ± SD)
220(64.9) 253(74.6)
277(81.7) 52(15.3) 10(2.9) 23.51 ± 7.48 96.08 ± 16.55 337(99.4) 23.12 ± 43.89 12.57 ± 9.75
230(66.5) 116(33.5) -23.36 ± 8.21 84.83 ± 14.03 180(52.0) 55.45 ± 77.13 17.68 ± 9.50
548(100) --23.37 ± 8.27 100.9 ± 20.18 105(19.2) 16.10 ± 37.4 15.80 ± 11.63
223(56.6) 171(43.4) -23.71 ± 8.93 79.35 ± 17.51 189(48.0) 41.12 ± 44.10 17.84 ± 10.59
1278(78.5) 339(20.84) 10(0.6) 23.48 ± 8.26
91.27 ± 19.72 811(49.8) 33.58 ± 54.31 16.02 ± 10.75
* Mean hospitalization days for group of patients reporting prior hospitalization.
29
Table 2. Reasons for discontinuation by study
Reason for Discontinuation n (%) Overall discontinuation Poor response or worsening Intolerability to medication Other reasons* Poor response by patient perception Poor response by physician perception
*Other reasons for discontinuation included criteria not met, lost to follow-up, noncompliance, personal conflict, physician decision, satisfactory response, and sponsor decision.
Study 1 (n=339) 161(47.5) 67(41.6)
Study 2 (n=346)
Study 3 (n=548)
Study 4 (n=394)
Total (N=1627)
190(54.9) 268(48.9) 247(62.7) 78(41.0) 99(36.9) 71(28.7)
866(53.2) 315(36.4)
19(11.8)
16(8.4)
31(11.6)
40(16.2)
106(12.2)
75(46.6) 40(76.9)
96(50.5) 18(85.7)
138(51.5) 136(55.1) 46(80.7) 28(82.4)
445(51.4) 132(80.5)
12(23.1)
3(14.3)
11(19.3)
6(17.6)
32(19.5)
30
Table 3. Baseline characteristics of patients who discontinued due to poor response or symptom worsening
Characteristic Age (mean ± SD) Study 1 (n=67)
36.17 ± 11.14
Study 2 (n=78)
39.56 ± 9.36
Study 3 (n=99)
38.58 ± 11.95
Study 4 (n=71)
41.77 ± 9.91 53(74.6) 48(67.6)
Total (N=315)
39.03 ± 10.84 211(67.0) 203(64.4)
Sex (Male %) Race (Caucasian %)* Diagnosis (%) Schizophrenia Schizoaffective Schizophreniform Age of Onset Illness (yrs ± SD) PANSS Total (mean±SD)
43(64.2) 54(80.6)
57(73.1) 48(61.5)
58(58.6) 53(53.5)
57(85.1) 8(11.9) 2 (3.0) 22.80 ± 6.69 95.48
54(69.2) 24(30.8)
99(100) --22.44 ± 7.62
39(54.9) 32(45.1)
249(79.8) 64(20.5) 2 (0.6) 22.36 ± 7.18
-21.63 ± 6.85
-22.63 ± 7.43
86.60
105.83
82.01
93.50 ± 20.35
± 15.31 Prior Hospitalization (%)* Hospitalization days (mean ± SD) † Illness Duration (yrs ± SD)
35.75 ± 54.52 13.25 65(97.0)
± 15.60
45(57.7)
± 22.04
27(27.3)
± 16.82
42(59.2) 179(56.8)
73.11
24.96
49.14
46.66 ± 76.40
± 113.67
17.93 ± 9.53
± 69.32
16.13
± 50.12
19.13 16.65 ± 10.99
± 10.47
± 12.02
± 10.83
*Significantly different from all other patients (prior hospitalization, p=.007; Caucasian race, p<.0001).
† Mean hospitalization days for group of patients reporting prior hospitalization.
Figure 1
All Patients 1627
Completers 761 of 1627 (47%) Poor Response or Worsening 315 of 866 (36%)
Discontinued 866 of 1627 (53%)
Intolerability to Medication 106 of 866 (12%)
Other Reasons
Criteria Not Met (12%) Lost to Follow-up (12%) Noncompliance (2%) Personal Conflict (20%) Physician Decision (4%) Satisfactory Response (0.2%) Sponsor Decision (1%)
Poor Response 164 of 866 (19%)
Symptom Worsening 151 of 866 (17%)
Figure 1
Figure 2
100 Mean score of PANSS Total 90 80 70 60 50 0 2 4 6 weeks
Com (N): 761 759 759 760 760 D/C (N): 865 733 578 475 376 759 160 760 89 757 40
* * * * * *
COMPLETERS DISCONTINUED
*
8 10 12 14 16 18 20 22 24 26 28
Figure 2
Figure 3
100 Mean score of PANSS Total 90 80 70 60 50 0
Com (N): 761 PR/W (N): 315 IM (N): 106 Other (N): 444
* * * * *
Poor Response/Worsening Intolerability to Medication D/C Due to Other Reasons COMPLETERS
2
759 289 82 362
4
759 229 65 284
6
760 190 53 232
8 10 12 14 16 18 20 22 24 26 28 weeks
760 144 40 192 759 63 15 82 760 38 11 40 757 22 5 13
Figure 3
Figure 4
A.
80%
% of Patients Discontiued due to Poor Response
100 80 60 40 20 0
B.
(132 out of 164)
Percent of Patients Staying on Treatment
100%
95% D/Cdue to Patient Perception 90% D/Cdue to Physician Perception
20% (32 out of 164)
85%
80% 0 4 8 12 16 20 24 28
Patient Perception
Physician Perception
Weeks
C.
Mean total score of PANSS
115 105 95 85 75 65 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
*
PHYSICIAN PERCEPTION PT PERCEPTION
weeks
Phy per (N): 32 31 26 20 12 Pt per (N): 132 122 95 82 63 8 21 2 17 1 7
Figure 4