Course, Natural History and Prognosis​

Presentation

Course, Natural History and Prognosis​

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Course, Natural History and Prognosis​
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Schizophrenia is a heterogeneous disease with many dimensions
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Schizophrenia progression may lead to functional decline​
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Key message: Schizophrenia is a progressive and recurring disease characterized by multiple psychotic relapses. Following a relapse, patients often fail to recover to baseline health and this may lead to functional decline​

Background​
The majority of patients with schizophrenia experience recurring psychotic relapses. Clinical deterioration may occur in the context of these relapses, meaning that patients may not recover from subsequent psychotic episodes as quickly or as fully as they did from previous episodes, and they may also experience greater degrees of residual symptomology and disability​

The process of relapse, treatment failure, and incomplete recovery leads  to a debilitating, chronic course of illness in many patients, and  to persistent disturbances and deficits in perceptions, thought processes, and cognition​

Patients accumulate morbidity in the form of residual or persistent symptoms and functional decline  compared with their premorbid status. The process of accruing morbidity in the context of exacerbations and (relative) remissions has been attributed to progression of the illness and described as “clinical deterioration”​

Although the majority of patients with schizophrenia exhibit a severe pattern of deterioration, different degrees and different temporal sequences do occur. Despite these variations, the deterioration process predominantly occurs during the early phases of the illness  (prepsychotic prodromal period and during the first 5–10 years after the initial episode)​

  1. Lieberman JA et al. Biol Psychiatry. 2001;50:884–97.​
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Typical Course of Schizophrenia​
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Relapses, characterized by acute psychotic exacerbation, can have a negative impact on psychosocial functioning​
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Key message: Relapses, characterized by acute psychotic exacerbation, can have a negative impact on psychosocial functioning​

Background​
Review article examining the evidence for illness progression after relapse in patients with schizophrenia​

Reports on indirect evidence obtained from retrospective, naturalistic, and brain-imaging studies, as well as a few prospective studies examining pre- and post-relapse treatment response​

Findings suggest that the treatment response after relapse is variable, with many patients responding rapidly, while others exhibit protracted impairment of response and a subgroup displays emergent refractoriness​

Relapses, characterized by acute psychotic exacerbation, may have serious psychosocial implications — in addition to the risk of self-harm and harm to others, relapses may cause patients and families distress, jeopardize friendships and relationships, disrupt education or employment, diminish personal autonomy, contribute to stigma, and add to the economic burden of treating schizophrenia​

  1. Emsley R, et al. Schizophr Res. 2013;148(1–3):117–121.​
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Relapse and treatment – Emergent adverse effects have substantial impact on patient quality of life​
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Key messages: Relapse and treatment-emergent adverse effects (such as weight gain and hyperprolactinemia) have substantial impact on patient quality of life​

​Background​
The impact of schizophrenia, treatments for schizophrenia, and treatment-related adverse events on patients with schizophrenia were assessed using health state descriptions and a time trade-off instrument​

Health state descriptions for stable schizophrenia, extrapyramidal symptoms (EPS), hyperprolactinemia, diabetes, weight gain, and relapse were developed, based on a review of the literature and expert opinion​

The quality of life impact of each health state was elicited using a time trade-off instrument administered by interview to 49 stable patients with schizophrenia and 75 healthy volunteers​

Regression techniques were employed to examine the importance of subject characteristics on health-related utility scores​

Clinical vignettes were used to obtain feedback on the impact of various treatment-related adverse events on patient quality of life​

Stable schizophrenia was the base case, and each of the other clinical situations demonstrated a decrease in patient feelings on overall quality of life​

Each of the treatment-related adverse events and relapse showed decreasing utility, from weight gain (lowest impact on quality of life) to relapse (highest impact on quality of life) ​

  1. Briggs A, et al. Health Qual Life Outcomes. 2008;6:105.​
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Many patients experience symptoms that are not fully controlled with treatment​
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Please note, this slide builds​

Key message: Many patients experience symptoms that are not fully controlled with treatment, with social withdrawal and impoverished thought being the two most common negative symptoms, and disordered thought and bizarre behavior the two most common positive symptoms. Between 47–60% of patients experience positive symptoms that are not fully controlled by treatment. ​

​Background​
In a large, multinational, cross-sectional survey, psychiatrists in the US and five European countries (France, Germany, Italy, Spain, and the United Kingdom) who prescribed antipsychotics for ≥15 patients with schizophrenia within the preceding 3 months, provided data on their patients’ demographic and clinical characteristics, their antipsychotic prescribing practices and drug attributes influencing treatment choice​

Data were collected from 872 physicians on 6523 patients (85% European, 15% US). Most patients were aged 25–44 years, 63% were men, and 66% were outpatients​

Inadequate control was reported more frequently for negative (71–77%) than positive (47–60%) symptoms​​

  1. Lecrubier Y, et al. Eur Psychiatry. 2007;22(6):371–379.​
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Symptoms that are not fully controlled are significantly associated with impaired global functioning ​
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Key message: In a study of patients in remission, those with residual symptoms had significantly worse global functioning that those without residual symptoms. ​

​Background
Patients (aged 18–65) in remission with and without residual symptoms were compared regarding psychopathology, functioning and side effects (using t tests). ​

399 patients with a schizophrenia spectrum disorder were evaluated within a naturalistic study ​

236 patients (59%) of patients were in remission at discharge with 94% of them had at least one residual symptom ​

Residual symptoms were defined as any symptom present at the time point of remission, therefore a PANSS item with a symptom severity of >1 (=at least borderline mentally ill) was defined to be a residual symptom​

Remission was defined using the consensus criteria by Andreasen et al. (2005) as a PANSS score of 3 or less of the following items: delusions (P1), unusual thought contents (G9), hallucinatory behavior (P3), conceptual disorganisation (P2), mannerism/posturing (G5), blunted affect (N1), social withdrawal (N4) and lack of spontaneity (N6)​

Global functioning was assessed using the Global Assessment of Functioning Scale (GAF), and ratings were assessed by trained clinicians at baseline and subsequently every 2 weeks until discharge and at the 1-year follow-up​

  1. Schennach R, et al. Eur Arch Psychiatry Clin Neurosci. 2015;265(2):107–16.​
  2. Andreasen et al. Am J Psychiatry 2005;162(3):441–449​
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Disorganization, a common residual symptom,1 is associated with impaired community functioning ​
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Key message: Conceptual disorganization is a common residual symptom in patients with schizophrenia, and is a reliable predictor of several aspects of community functioning, as measured by the Life Skills Profile (which was specifically designed to assess constructs of relevance to survival and adaptation in the community)​

Background1​
Conceptual disorganization is a common residual symptom in patients with schizophrenia1 ​

Conceptual disorganization occurred in 42% of patients with remission, and was the second most common residual symptom after blunted affect (which occurred in 49% of patients)1​

Background2​
Neurocognitive and symptom data (collected as part of an earlier study) were used to predict the community functioning of 50 patients (aged 17–60) with schizophrenia​
Using the Life Skills Profile, staff of a community mental health program assessed community functioning while blind to the earlier symptom ratings and neurocognitive performance2​

  • The Life Skills Profile was designed specifically to assess constructs of relevance to survival and adaptation in the community​
  • The 39 items of the scale measure five key dimensions: self-care (grooming, hygiene, budgeting, food preparation, etc.); nonturbulence (degree of offensiveness, violence, intrusiveness, anger control, etc.); social contact (friendships, interpersonal interests and activities, etc.); communication (conversational skills, inappropriate gesturing, etc.); and responsibility (cooperativeness, responsibility regarding personal property and medication, etc.)2​

Disorganization symptoms are more strongly related than formal cognitive test scores to community functioning2​

  1. Schennach R, et al. Eur Arch Psychiatry Clin Neurosci. 2015;265(2):107–16.​
  2. Norman RM, et al. Am J Psychiatry. 1999;156(3):400–5.​
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Positive symptoms of schizophrenia are inversely correlated with ability to function​
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Key message: Increase in positive symptoms is directly correlated with a reduction in functional capacity. The correlation between positive symptoms and depression is predictive of impairment in real-world performance measures (as measured by interpersonal skills, community activities, work skills) ​

​Background​
Cross-sectional data was examined from a study of the course of neuropsychological and adaptive life skills patients with schizophrenia (age 50–85) (N=78)​

Functional capacity was examined with a performance-based measure (UCSD Performance-Based Skills Assessment), and case managers rated real-world adaptive functions (i.e., interpersonal skills, work skills, and community activities)​

Real-world functional performance was examined using the Specific Level of Function Scale, which is a 43-item caretaker report of a patient’s behavior and functioning across the following domains: physical functioning (e.g., vision, hearing), personal care skills (e.g., eating, grooming), interpersonal skills (e.g., initiating, accepting and maintaining social contacts; effectively communicating), social acceptability (e.g., absence of verbal and physical abuse, absence of repetitive behaviors), community activities (e.g., shopping, using telephone, paying bills, use of leisure time, use of public transportation) and work skills (e.g., employable skills, level of supervision, punctuality)​

Severity of schizophrenia symptoms was assessed by the Positive and Negative Syndrome Scale (PANSS), which was completed after a structured interview​

Self-reports of depression were obtained from the patients by using the second edition of the Beck Depression Inventory​

Confirmatory path analyses were conducted to determine which of the variables predicted or mediated the relationship with the functional outcome domains from the Specific Level of Function Scale. The goodness of fit of these models was tested statistically and compared with several comparison models. In these analyses, the Specific Level of Function Scale domains were used as the outcome variables​

 

  1. Bowie CR, et al. Am J Psychiatry. 2006;163(3):418–25.​
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Primary negative symptoms of schizophrenia can impact domains of functioning directly1 ​
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Key message: Negative symptoms and cognitive deficits can cause patients functional impairment. Primary negative symptoms of schizophrenia can impact different domains of functioning directly, including interpersonal relations, use of common objects and activities, and instrumental role functioning. 

Background
The sample included 1,427 patients (aged 18–65) with schizophrenia who completed the baseline visit in the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) schizophrenia study1

Symptoms were assessed by the Positive and Negative Syndrome Scale and Calgary Depression Scale, extrapyramidal side effects with the Simpson–Angus scale, and real-world functional status with the Heinrichs–Carpenter Quality of Life Scale (QLS)1

  • Primary negative symptoms were assessed using the negative symptom factor score from the Positive and Negative Syndrome Scale (PANSS), which includes the following items: blunted affect, emotional withdrawal, poor rapport, apathetic social withdrawal, lack of flow, motor retardation and active social avoidance

The intrapsychic foundations subdomain of the QLS has been cited to have conceptual overlap with certain negative symptoms, therefore it was not included in the analyses1 ​

Pearson’s product-moment correlations were computed to examine the zero-order relationship between negative symptoms and each domain of functioning, including interpersonal relations (social), instrumental role functioning (vocational), and use of common objects and activities (recreational). The potential influence of various clinical variables on negative symptom severity was examined using correlation analysis1 ​

Negative symptoms were significantly correlated with each domain of functioning, including interpersonal relations (r =-0.42, P < 0.001), instrumental role functioning (r=-0.24, P < 0.001), and use of common objects and activities (r =-0.30, P < 0.001); for all domains assessed, greater negative symptom burden was associated with poorer functioning1

  1. Fervaha G, et al. Eur Psychiatry. 2014;29(7):449–55.​
  2. Lehman AF, et al. [APA Practice Guidelines] 2010. ​
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Take home points​
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Schizophrenia Is a Progressive and Cyclical Disease Characterized by Multiple Psychotic Relapses​
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The development of psychotic symptoms marks the formal onset of first-episode schizophrenia. It is common for some time to pass in a prodromal phase before the patient is brought in for medical attention and diagnosed with schizophrenia1​

During the course of the illness, patients will experience subsequent psychotic relapses, and patients often fail to recover to the same degree as they had prior to the most recent episode. This process of relapse, treatment failure, and incomplete recovery leads many patients to a debilitating, chronic course of illness1​

Patients accumulate morbidity in the form of residual or persistent symptoms and functional decline when compared to their premorbid status1​

Although the majority of patients with schizophrenia exhibit a severe pattern of deterioration, different degrees and different temporal sequences do occur. Despite these variations, the deterioration process predominantly occurs during the early phases of the illness1​

With treatment, some patients achieve symptomatic remission following a first episode2​

However, others may go on to experience clinical progression and deterioration in the years following a first episode, reaching a plateau during the chronic phase2,3​

  1. Lieberman JA, Perkins D, Belger A, et al. The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry. 2001;50(11):884-897.​
  2. Lieberman JA, Jarskog LF, Malaspina D. Preventing clinical deterioration in the course of schizophrenia: the potential for neuroprotection. J Clin Psychiatry. 2006;67(6):983-990.​
  3. Agius M, Goh C, Ulhaq S, McGorry P. The staging model in schizophrenia, and its clinical implications. Psychiatr Danub. 2010;22(2):211-220.​
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Early, Continuous Treatment of Schizophrenia Improves Treatment Outcomes​
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Patients within the first 2 years of their first psychotic episode (N=77), treated with continuous antipsychotic medication and psychosocial interventions, were assessed during the first year after hospital discharge​

Data shown on this slide demonstrate that patients can achieve symptomatic remission and good functional outcomes, and recover from their illness​​

  1. Ventura J, Subotnik KL, Guzik LH, et al. Remission and recovery during the first outpatient year of the early course of schizophrenia. Schizophr Res. 2011;132(1):18-23.​
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Poor Treatment Outcomes Early in the Course of Schizophrenia Led to Measurable Neurological Damage​
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Patients in their first episode of schizophrenia or schizoaffective disorder (n=107) as well as control participants (n=20) were longitudinally followed for up to 6 years. Cortical structures were examined using high resolution magnetic resonance imaging (MRI) in both patients and healthy controls. In addition, clinical assessments of psychopathology and treatment outcomes were recorded​

This figure depicts the total ventricular volume change in patients with poor outcomes and good outcomes vs control participants. Ventricular volume change in patients with poor outcomes increased over time and were significantly different from those of patients with good outcomes (F=9.69, P=0.0028) and control participants (F=4.69, P=0.03)​

  1. Lieberman J, Chakos M, Wu H, et al. Longitudinal study of brain morphology in first episode schizophrenia. Biol Psychiatry. 2001;49(6):487-499. ​
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A Variety of Symptom Clusters Contribute to Functional Impairment​
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Some Patients With Schizophrenia May Achieve Recovery ​ With Effective Treatment​
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In a 3-year observation study of adults with schizophrenia (n=6642), the frequency and predictors of patient outcomes were assessed1​

  • The average age upon entry was 40.2 years (standard deviation=12.9 years), and mean duration of illness was 11.8 years (standard deviation=11.0 years)​
  • Long-lasting symptomatic remission was defined as achieving a level of severity that was mild or less (ie, a score of <4 on the scale from 1 to 7) in the CGI-SCH positive, negative, cognitive, and overall severity scores, plus no inpatient admission for a minimum period of 24 months maintained until the 36-month visit​
  • 33% achieved long-lasting symptomatic remission​
  • Long-lasting functional remission was defined as fulfilling the following 3 criteria for a minimum period of 24 months and maintaining until the 36-month visit: (1) a positive occupational/vocational status (ie, paid or unpaid full- or part-time employment, being an active student, or being a housewife); (2) living independently; and (3) having active social interactions (ie, having more than 1 social contact during the last 4 weeks or having a spouse or partner)​
  • 13% achieved long-lasting functional remission​
  • Long-lasting adequate quality of life was defined as achieving an EQ-5D VAS score ≥70 for a minimum period of 24 months and maintaining it until the 36-month visit​
  • 27% achieved long-lasting adequate quality of life​

Participants with first-episode psychosis (N=109) were recruited and followed for a mean of 10.5 years post-index admission to examine predictors of outcome2​

  • Poor outcomes were defined as fulfilling all of the following criteria: mentally ill in the last year; mentally ill for at least 5 of the previous 10 years; employed for less than 2 of the last 10 years; and did not work at all in the last year. The criteria were broadened to also include participants who died from an unnatural cause of death​
  • A total of 64 out of 103 (62%) patients at the end of the trial were rated as having a poor outcome based on these criteria​
  1. Novick D, Haro JM, Suarez D, Vieta E, Naber D. Recovery in the outpatient setting: 36-month results from the Schizophrenia Outpatients Health Outcomes (SOHO) study. Schizophr Res. 2009;108(1-3):223-230.​
  2. White C, Stirling J, Hopkins R, et al. Predictors of 10-year outcome of first-episode psychosis. Psychol Med. 2009;39(9):1447-1456.​
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Patients With Schizophrenia Who Achieved Symptomatic Remission Had Significantly Better Personal and Social Functioning​
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76 Patients with schizophrenia were categorized by their remission status​

Cross-sectional symptomatic remission was defined according to the symptom-severity remission criteria proposed by Andreasen et al (2005); however, patients hospitalized in the previous 6 months were not considered to have fulfilled the remission criteria​

The majority (69.7%) were not in remission​

Social functioning was evaluated with the Global Assessment of Functioning (GAF) (Endicott et al, 1976) and the Personal and Social Performance (PSP) scale​

Subjective quality of life was assessed with the World Health Organization Quality of Life measure—Abbreviated Version (WHOQOL—Bref), a generic self-report quality of life (QoL) instrument providing 4 unweighted domain measurements: physical, psychological, social relationships, and environment​

The neurocognitive test battery encompassed the domains of processing speed (Wechsler Memory Scale [WMS]—Mental Tracking; Trail Making Test Part A [TMT-A]); executive functions (Digit Span; Trail Making Test Part B [TMT-B]); and verbal learning and memory (California Verbal Learning Test [CVLT])​

Social functioning scores were significantly higher in remitted patients​

As a group, remitted patients showed statistically significant better functioning in all the functioning domains of the PSP except disturbing and aggressive behaviors. Only 15 patients scored ≥70 on the PSP, reflecting mild or no functioning difficulties; however, of this number, only 8 patients with a PSP total score of ≥70 were in remission​​

  1. Brissos S, Dias VV, Balanzá-Martinez V, Carita AI, Figueira ML. Symptomatic remission in schizophrenia patients: relationship with social functioning, quality of life, and neurocognitive performance. Schizophr Res. 2011;129(2-3):133-136.​
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Patients With Schizophrenia Who Achieved Symptomatic Remission Had Significantly Better Self-Reported Quality of Life​
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76 Patients with schizophrenia were categorized by their remission status​

Cross-sectional symptomatic remission was defined according to the symptom-severity remission criteria proposed by Andreasen et al (2005); however, patients hospitalized in the previous 6 months were not considered to have fulfilled the remission criteria​

The majority (69.7%) were not in remission​

Social functioning was evaluated with the Global Assessment of Functioning (GAF) (Endicott et al, 1976) and the Personal and Social Performance (PSP) scale​

Subjective quality of life was assessed with the World Health Organization Quality of Life measure—Abbreviated Version (WHOQOL—Bref), a generic self-report quality of life (QoL) instrument providing 4 unweighted domain measurements: physical, psychological, social relationships, and environment​

The neurocognitive test battery encompassed the domains of processing speed (Wechsler Memory Scale [WMS]—Mental Tracking; Trail Making Test Part A [TMT-A]); executive functions (Digit Span; Trail Making Test Part B [TMT-B]); and verbal learning and memory (California Verbal Learning Test [CVLT])​

Remitted patients self-reported significantly better QoL in all domains compared with nonremitted patients​

 

  1. Brissos S, Dias VV, Balanzá-Martinez V, Carita AI, Figueira ML. Symptomatic remission in schizophrenia patients: relationship with social functioning, quality of life, and neurocognitive performance. Schizophr Res. 2011;129(2-3):133-136.​
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Symptomatic Remission in Schizophrenia Led to Significantly Better Insight and Fewer Depressive Symptoms​
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76 Patients with schizophrenia were categorized by their remission status​

Cross-sectional symptomatic remission was defined according to the symptom-severity remission criteria proposed by Andreasen et al (2005); however, patients hospitalized in the previous 6 months were not considered to have fulfilled the remission criteria​

The majority (69.7%) were not in remission​

Social functioning was evaluated with the Global Assessment of Functioning (GAF) (Endicott et al, 1976) and the Personal and Social Performance (PSP) scale​

Subjective quality of life was assessed with the World Health Organization Quality of Life measure—Abbreviated Version (WHOQOL—Bref), a generic self-report quality of life (QoL) instrument providing 4 unweighted domain measurements: physical, psychological, social relationships, and environment​

The neurocognitive test battery encompassed the domains of processing speed (Wechsler Memory Scale [WMS]—Mental Tracking; Trail Making Test Part A [TMT-A]); executive functions (Digit Span; Trail Making Test Part B [TMT-B]); and verbal learning and memory (California Verbal Learning Test [CVLT])​

Depressive symptoms were significantly lower, and insight was significantly better in remitted patients

  1. Brissos S, Dias VV, Balanzá-Martinez V, Carita AI, Figueira ML. Symptomatic remission in schizophrenia patients: relationship with social functioning, quality of life, and neurocognitive performance. Schizophr Res. 2011;129(2-3):133-136.​
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Excess mortality in severe mental illness
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Schizophrenia: A broad range of symptoms​
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Patients with schizophrenia experience a broad range of symptoms including positive, negative, and cognitive symptoms.1,2 Mood symptoms, such as, depression, anxiety, anger, hostility, and aggression, may also be present.1

Positive symptoms​
Positive symptoms appear to reflect an excess or distortion of normal functions, and include distortions in:1,2

  • thought content (delusions)​
  • perception (hallucinations)​
  • language and thought process (disorganised thought/speech)​
  • self-monitoring of behaviour (grossly disorganised or catatonic behaviour)​

Negative symptoms​
Negative symptoms reflect a decline in, or loss of, normal functions, and include:1,2

  • diminished emotional expression and a decrease in motivated self-initiated, purposeful activities (avolition)​
  • alogia (diminished speech output)​
  • anhedonia (decreased ability to experience pleasure from positive stimuli)​
  • asociality (apparent lack of interest in social interactions)

Cognitive symptoms​
Cognitive symptoms are considered to be a key component of schizophrenia,3 and include impairments in:1

  • attention​
  • episodic memory​
  • executive functions (including language function)​
  • working memory​
  • processing speed​
  • inhibitory capacity

Clinical manifestations of patients with schizophrenia are very variable.5 Individuals with schizophrenia experience their own distinct combination of symptoms with a degree of severity that varies between patients and throughout the course of the illness, such that no two cases of schizophrenia are ever exactly the same.4,6

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition (DSM-5). © 2013 American Psychiatric Association, Arlington, VA. 99–102. ​
  2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition. Text Revision (DSM-IV-TR™). © 2000 American Psychiatric Association, Washington, DC. 299–302. ​
  3. Wilk CM, Gold JM, McMahon RP, et al. No, it is not possible to be schizophrenic yet neuropsychologically normal. Neuropsychology 2005; 19 (6): 778–786.​
  4. Jones PB, Buckley PF. Introduction and Background. In: Jones PB, Buckley PF, eds. In Clinical Practice Series. Schizophrenia. © 2006 Elsevier Limited. 7.​
  5. National Institute for Health and Care Excellence (NICE). Psychosis and schizophrenia in adults: treatment and management. NICE clinical guideline 178. March 2014.​
  6. Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia, ‘just the facts’ 4. Clinical features and conceptualization. Schizophr Res 2009; 110 (1–3): 1–23.
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Relapse is common in schizophrenia​
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In schizophrenia, episodes of relapse (recurrence of psychosis) are common. A prospective, longitudinal, study examined the occurrence of relapse after response to a first episode of schizophrenia or schizoaffective disorder in 104 patients.1 The cumulative rate for first relapse was 81.9% by the end of the 5-year follow-up.1 Of the 63 patients recovering from the first relapse, the cumulative rate for a second relapse was 78.0% after 5 years.1 The cumulative rate for a third relapse after 4 years was 86.2% among 20 patients who had recovered from a second relapse.1

Relapse can have significant repercussions for patients with schizophrenia:​

  • rehospitalisation2
  • slow and incomplete recovery3
  • treatment-resistant illness3
  • persistent symptoms4
  • progressive cognitive decline5
  • increasing difficultly to regain previous level of functioning3
  • reduced quality of life.6

​Data from the European Schizophrenia Cohort study (EuroSc) reported that a higher level of quality of life predicted a lower rate of relapse at 24 months among patients with schizophrenia.7

  1. Robinson D, Woerner MG, Alvir JM, et al. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry 1999; 56: 241–247.​
  2. Csernansky JG, Schuchart EK. Relapse and rehospitalisation rates in patients with schizophrenia: effects of second generation antipsychotics. CNS Drugs 2002; 16 (7): 473–484.​
  3. Kane JM. Treatment strategies to prevent relapse and encourage remission. J Clin Psychiatry 2007; 68 (Suppl 14): 27–30.​
  4. Lewis DA, Lieberman JA. Catching up on schizophrenia: natural history and neurobiology. Neuron 2000; 28 (2): 325–344.​
  5. Levander S, Jensen J, Gråwe R, Tuninger E. Schizophrenia--progressive and massive decline in response readiness by episodes. Acta Psychiatr Scand 2001; 104 (Suppl 408): 65–74.​
  6. Briggs A, Wild D, Lees M, et al. Impact of schizophrenia and schizophrenia treatment-related adverse events on quality of life: direct utility elicitation. Health Qual Life Outcomes 2008; 6: 105.​
  7. Boyer L, Millier A, Perthame E, et al. Quality of life is predictive of relapse in schizophrenia. BMC Psychiatry 2013; 13: 15.​
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Multiple factors increase the risk of relapse​
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Relapses negatively affect the disease trajectory and outcome ​
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Brain imaging and relapse
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Days to remission after each relapse​
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Impact of Relapse on Patients ​ With Schizophrenia​
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Short- and Long-term Consequences of Relapse ​ Are Substantial to Patients​
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Relapse May Reduce Patient Response to Medication​
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Response was measured during 33 weeks of treatment​

Patients who relapsed following randomization to placebo were offered entry into an open-label extension phase​

The postrelapse treatment phase was 52 weeks​

Fourteen of 97 patients (14.4%) who had initially responded favorably to treatment were nonresponsive to treatment following relapse​

Among these 14, the mean change in PANSS scores following 32 weeks of medication was −18.2 prior to relapse and +7 following relapse​

Relapse was defined as: ​

  • Hospitalization for symptoms of schizophrenia​
  • ≥25% increase in PANSS total score for 2 consecutive assessments if PANSS total was >40 at randomization, or ≥10-point PANSS total score increase for those with ≤40 at randomization​
  • Deliberate self-harm, significant aggression; suicidality or homicidality​
  • Increase in individual PANSS items: ​P1, P2, P3, P6, P7, and G8 to ≥5 for those whose score was ≤3 at randomization, or to ≥6 if score was 4 at randomization​

Nonresponse was defined as failure to achieve a 20% improvement in PANSS after at least 8 weeks of treatment​

 

  1. Emsley R, Nuamah I, Hough D, Gopal S. Treatment response after relapse in a placebo-controlled maintenance trial in schizophrenia. Schizophr Res. 2012;138(1):29-34. ​
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Relapse Can Decrease Patient Functioning​
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Patients were randomly selected from current psychiatric caseloads drawn from urban and suburban areas of Leicester, England​

Patients were included as participants if they had received a diagnosis of schizophrenia according to DSM-IV criteria and had no other psychosis, were aged 18 to 64 years, and had given their informed consent​

Relapse was identified retrospectively in this study as the re-emergence or aggravation of psychotic symptoms for at least 7 days during the 6 months prior to the study​

In addition to instances of relapse identified by clinical staff, recorded changes in mental state were regarded as significant and amounting to relapse if there was a clearly documented assessment of a relapse. A change in management, as appropriate, might also have occurred, and not all relapses led to readmission. Relapse could thus be identified in cases of patients who had been admitted to a hospital in the past 6 months, who had consulted their psychiatrist and had had their medication changed for deterioration in their condition, or who had had an increase in intensive support at home from the community mental health team. A planned hospital admission was not classified as a relapse​

Data were collected using the PANSS, CGI, and GAF scales​

A total of 145 patients completed interviews: 77 with relapses and 68 with no relapses​

Patients who relapsed demonstrated a significantly lower GAF score (52.6 vs 57.8; P<0.05)​

Although higher scores on the PANSS and the CGI suggested worse symptoms for relapse compared with nonrelapse cases, the differences were not statistically significant​

 

  1. Almond S, Knapp M, Francois C, Toumi M, Brugha T. Relapse in schizophrenia: costs, clinical outcomes and quality of life. Br J Psychiatry. 2004;184:346-351.​
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Impact of Early Intervention ​ for Patients With Schizophrenia​
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Shorter Duration of Psychosis Led to Improved Outcomes in Patients With First-Episode Schizophrenia​
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Individuals with first-episode schizophrenia (N=101) were grouped according to the DUI1:​

  • Onset of illness <44 days prior to admission (n=29)​
  • Onset of illness between 44 days and 1 year prior to admission (n=44)​
  • Onset of illness >1 year prior to admission (n=28)

Patients with the shortest DUI (<44 days) demonstrated the lowest relapse rate (41.4%) during 1 year of follow-up, while patients with the longest DUI (>1 year) had the highest relapse rate (82.1%)1​

Data from 80 patients with schizophrenia were collected retrospectively from standardized clinical records routinely used in the community mental health center2​

The DUP was defined as the time interval between the onset of the first clearly psychotic symptoms and the first antipsychotic treatment2​

The course of illness was divided into 2 categories; namely, an “unfavorable” course (ie, “continuous” plus “episodic with intercritical residual symptoms” according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR]), and a “favorable” course (ie, “episodic without intercritical residual symptoms,” plus “single episodes in partial remission,” and “single episode in full remission”)2​

16 Patients were considered to have a favorable course of illness, and 64 were considered to have an unfavorable course​

A favorable course of illness occurred significantly more frequently among patients with a short DUP2​

Moreover, a short DUP was significantly associated with a “low” number of hospital admissions (85.7% of cases) compared to cases with a long DUP (62.1%) (P=0.047) ​

Additionally, the mean number of hospital admissions was significantly lower among patients with a short DUP (1.5±2.3) than among patients with a long DUP (3.2±2.5) (P<0.001)​

  1. Owens DC, Johnstone EC, Miller P, Macmillan JF, Crow TJ. Duration of untreated illness and outcome in schizophrenia: test of predictions in relation to relapse risk. Br J Psychiatry. 2010;196(4):296-301.​
  2. Primavera D, Bandecchi C, Lepori T, Sanna L, Nicotra E, Carpiniello B. Does duration of untreated psychosis predict very long term outcome of schizophrenic disorders? Results of a retrospective study. Ann Gen Psychiatry. 2012;11(1):21.​
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Patients With First-Episode Schizophrenia Are​ at an Increased Risk of Nonadherence​
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The authors examined the risk of rehospitalization and drug discontinuation in a nationwide cohort of 2588 consecutive patients hospitalized in Finland with a first-time diagnosis of schizophrenia between 2000 and 2007. Date of prescription purchase, the Anatomical Therapeutic Chemical code of the drug, and the purchased amount stated as the number of defined daily doses were obtained from the prescription database of the Social Insurance Institution. Of 2588 patients with a first hospitalization, 1507 (58.2%) used an antipsychotic medication during the first 30 days after discharge, and 1182 (45.7% of the total) continued the initial antipsychotic medication for 30 days or longer1 ​

Another study examined relapse after response to a first episode of schizophrenia or schizoaffective disorder. Patients (N=104) were assessed on measures of psychopathologic variables, cognition, social functioning, and biological variables and were treated according to a standardized algorithm. The following rating scale criteria were used to define a relapse: at least “moderately ill” on the Clinical Global Impression (CGI) Severity of Illness Scale, “much worse” or “very much worse” on the CGI Improvement Scale, and at least “moderate” on 1 or more of the Schedule for Affective Disorders and Schizophrenia Change Version With Psychosis and Disorganization items listed above; moreover, these criteria had to be sustained for a minimum of 1 week2​

  1. Robinson D, Woerner MG, Alvir JM, et al. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry. 1999;56(3):241-247.​
  2. Tiihonen J, Haukka J, Taylor M, Haddad PM, Patel MX, Korhonen P. A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am J Psychiatry. 2011;168(6):603-609.​
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Continuous Maintenance Treatment Led to Decreased Deterioration in Symptoms During the Second Year Following Diagnosis​
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This randomized controlled trial investigated the impact of continuous maintenance treatment vs targeted intermittent treatment in the second year following the diagnosis of schizophrenia. A total of 96 first-episode patients were enrolled from the German Research Network on Schizophrenia, and 44 were assigned to treatment. Participants assigned to the maintenance treatment arm in the second year of the trial demonstrated decreased risk of relapse and a higher survival rate from deterioration​

  1. Gaebel W, Riesbeck M, Wölwer W, et al; for the German Study Group on First-Episode Schizophrenia. Relapse prevention in first-episode schizophrenia—maintenance vs intermittent drug treatment with prodrome-based early intervention: results of a randomized controlled trial within the German Research Network on Schizophrenia. J Clin Psychiatry. 2011;72(2):205-218. ​
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Supportive Relationships Can Improve Long-term Adherence and Reduce Relapse Risk in Patients With Schizophrenia​
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Family Involvement and Better Patient Insight May Improve Patient Adherence​
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Participants were enrolled with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnosis of schizophrenia (n=84) or schizoaffective disorder (n=28) based on a Structured Clinical Interview (SCID)​

Assessment of medication adherence, clinical information, cognition related to illness, cognitions and attitudes toward medication, and perceptions of family and treating physician were conducted at admission, discharge, and following discharge at 3 and 6 months​

The Visual Analog Scale was used to assess adherence, which was rated by participants, relatives, and treating physicians ​

 

  1. Baloush-Kleinman V, Levine SZ, Roe D, Shnitt D, Weizman A, Poyurovsky M. Adherence to antipsychotic drug treatment in early-episode schizophrenia: a six-month naturalistic follow-up study. Schizophr Res. 2011;130(1-3):176-181. ​
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Instrumental Family Support* Predicts Higher Medication Usage in Patients With Schizophrenia​
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The major focus of this study was to test whether family support predicts medication usage among 30 Mexican-American individuals with schizophrenia​

The study design was prospective—family and psychiatric status predictors were assessed near the time of psychiatric hospital discharge, and medication usage was judged for a 9-month time frame following discharge​

The Camberwell Family Interview (CFI), a personal and semistructured interview that yields rich family caregiver narratives of their relationship with their ill relative, was used to assess family caregivers’ supportive behaviors and expressed emotion (EE)​

A separate team of bilingual coders who were blind to patients’ EE ratings were trained to code the family support variables based on the entire audio taped CFI material​

There are 2 family support variables in the present study:​

  • Instrumental support was operationalized as the total number of statements that illustrated family caregiver ‘‘task-oriented’’ assistance, such as completion of errands; eg, ‘‘I helped him fill out an employment application’’​
  • Emotional support was operationalized as the total number of statements that illustrated family caregiver demonstrations of reassurance, concern, and affection; eg, ‘‘I told her that I love her’’​

The 9-month period following psychiatric hospital discharge was the time frame for assessing medication usage. Those patients who took their medications at least 75% of the time without a 4-week or longer interval of discontinued use of medications were classified as ‘‘regular’’ medication users, while the rest were considered to be ‘‘irregular’’ medication users​

Higher levels of instrumental family support were associated with greater likelihood of medication usage​

A logistic regression analysis was conducted to assess if family factors, including the independent dimensions of EE and family support variables, would predict usage of psychiatric medications​

Only family instrumental support predicted medication usage significantly (odds ratio = 4.8)​

  1. Ramírez García JI, Chang CL, Young JS, López SR, Jenkins JH. Family support predicts psychiatric medication usage among Mexican American individuals with schizophrenia. Soc Psychiatry Psychiatr Epidemiol. 2006;41(8):624-631.​
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Family-Supervised Treatment Led to Significant Improvement in Symptoms and Functioning​
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Participants (N=110) with schizophrenia or schizoaffective disorders were enrolled in a study to evaluate the effectiveness of family-supervised treatment on improving treatment adherence and clinical outcomes. The STOPS intervention, which utilized a family member to supervise medication administration, was compared to treatment as usual (TAU) and followed up for 1 year​

STOPS was defined as supervised treatment in outpatients for schizophrenia ​

Participants in the STOPS group had better treatment adherence (primary outcome measure), 67.3%, vs 45.5% in TAU group (P<0.02)​

PANSS for schizophrenia and GAF scores were also significantly improved (data presented on slide)​

Analyses were carried out using repeated measures ANCOVA​

 

  1. Farooq S, Nazar Z, Irfan M, et al. Schizophrenia medication adherence in a resource-poor setting: randomised controlled trial of supervised treatment in out-patients for schizophrenia (STOPS). Br J Psychiatry. 2011;199(6):467-472. ​
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The Value of a Support System​
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In a post hoc analysis of data from the CATIE study, 50 patients were dichotomized into 2 groups:​

  • The first group had a family/significant other—available and mostly supportive—to work collaboratively to facilitate adherence with the treatment team (n=27)​
  • The second group either did not have family/significant other support because there was no one available, the patient-family unit was in a highly conflicted struggle, or the family would not/could not come in regularly for treatment visits (n=23)​

Outcome ratings were based on the author’s ratings of outcome as well as the outcome ratings in the CATIE database​

It was demonstrated that having a family available and supportive improves outcome ​

  • 24 of the 27 patients (89%) with supportive families improved​
  • 14 of the 23 patients (61%) of the patients with a nonavailable nonsupportive group showed no change or worsened​

Improved outcomes may be mediated by improving long-term adherence​

23 of the 27 patients (85%) with supportive families remained in treatment for the entire study​

10 of the 23 patients (43%) without a supportive family remained in treatment for the entire study

  1. Glick ID, Stekoll AH, Hays S. The role of the family and improvement in treatment maintenance, adherence, and outcome for schizophrenia. J Clin Psychopharmacol. 2011;31(1):82-85.​
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Involving Patients in Their Own Care Increases Knowledge About Their Disease​
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Prior to meeting with physicians, patients in the intervention group (n=49) were provided with a booklet containing information regarding treatment options and were asked to write down their previous medication experiences and current preferences ​

Compared to patients in the control group (n=58), patients in the intervention group demonstrated a significantly higher perceived involvement as rated by the COMRADE scale​

Patients in the intervention group had a better knowledge about their disease​

  • The intervention increased their uptake of psychoeducation​
  1. Hamann J, Langer B, Winkler V, et al. Shared decision making for in-patients with schizophrenia. Acta Psychiatr Scand. 2006;114(4):265-273. ​
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Simple Techniques Improve the Communication Between Patients and Clinicians​
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Prior to meeting with clinicians, patients with schizophrenia were asked questions regarding their current status and treatment and were shown video clips of an actor demonstrating how to discuss specific problems with a physician ​

  • The clips provided examples of how someone with schizophrenia can broach potentially sensitive issues with a therapist, such as confusion about prescribed drugs, side effects, poor adherence, use of alcohol with medication, barriers to more consistent treatment adherence, and family tensions

Compared to patients in the control group (n=26), patients in the intervention group (n=24) demonstrated longer visits, contributed more to the dialogue, asked more questions about treatment, and disclosed more lifestyle information. Clinicians asked more questions about treatment, were more patient-centric, and made more empathetic statements​

  1. Steinwachs DM, Roter DL, Skinner EA, et al. A web-based program to empower patients who have schizophrenia to discuss quality of care with mental health providers. Psychiatr Serv. 2011;62(11):1296-1302.
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A Strong Therapeutic Alliance and High Patient Insight Was Significantly Correlated With Adherence to Medication​
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38 Inpatients who met International Classification of Diseases, Tenth Revision (ICD-10) criteria for schizophrenia or schizoaffective disorder were recruited and independently interviewed just before discharge​

Various rating scales, including the self-reported 4-Point ordinal Alliance Scale (4PAS), the Scale to Assess Unawareness of Mental Disorder (SUMD), and the Medication Adherence Rating Scale (MARS), were used ​

Insight (SUMD subscore) was significantly correlated with the total MARS score (r=−0.664, P<0.0001)​

  • The SUMD is a 9-item semistructured questionnaire rated on a 5-point scale (1=aware to 5=unaware). This study calculated a subscore of the first 3 items (item 1: awareness of mental disorder; item 2: awareness of the consequences of mental disorder; item 3: awareness of the achieved effects of medication). The authors believed that this would explore the level of general awareness of the disorder, leaving out the other items that measured the awareness of the different symptoms of the illness​

Therapeutic alliance (4PAS score) was significantly correlated with the total MARS score (r=0.663, P<0.0001)​

  • The 4PAS is an 11-item questionnaire scored using a 4-point Likert scale ranging from 1 (ie, “strongly disagree”) to 4 (ie, “strongly agree”). Higher 4PAS score indicates better therapeutic alliance​

  1. Misdrahi D, Petit M, Blanc O, Bayle F, Llorca PM. The influence of therapeutic alliance and insight on medication adherence in schizophrenia. Nord J Psychiatry. 2012;66(1):49-54.​
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High Prevalence of Nonadherence to Medication Among Patients With Schizophrenia​
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Rates of Medication Nonadherence in Chronic Nonpsychiatric Conditions and Schizophrenia​
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This chart demonstrates the rates of medication nonadherence among patients treated for nonpsychiatric conditions​

  • These were chosen to demonstrate that nonadherence is common among diseases that are similar to schizophrenia in that they are chronic, commonly occur in adults, and require regular and persistent drug therapy​

The study sample included approximately 1.3 million individuals aged 18 years or older who had a diagnosis of gout, hypercholesterolemia, hypertension, hypothyroidism, osteoporosis, seizure disorders, or type 2 diabetes during the study period​

The study data came from the 2001-2004 MarketScan Research databases​

MPR was used to measure adherence​

  • The MPR was the days’ supply of the drug dispensed during the follow-up year divided by the number of days in the year​

  1. Briesacher BA, Andrade SE, Fouayzi H, Chan KA. Comparison of drug adherence rates among patients with seven different medical conditions. Pharmacotherapy. 2008;28(4):437-443.​
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Few Patients With Schizophrenia Take Their Medication as Prescribed​
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The authors used data from San Diego County Adult Mental Health Services to identify individuals who were diagnosed with schizophrenia by a specialty mental health provider and who were living in the community during fiscal years 1999 and 2000​

These data were merged with 3 years of data from Medi-Cal eligibility and claims (1998-2000) and identified fee-for-service beneficiaries continuously enrolled over the course of a year who filled at least 1 prescription for an antipsychotic medication​

  • This analysis was based on prescription fills for oral antipsychotic medications​

Adherence to prescribed regimens was determined by examining Medi-Cal claims by means of medication refill records. Adherence was measured by the annual cumulative possession ratio, which was computed for each person in each calendar year. The cumulative possession ratio was calculated by dividing the number of days medications were available for consumption by the number of days participants were eligible for Medi-Cal​

A person-year’s adherence was derived from the cumulative possession ratio using the following designations: nonadherent (ratio=0.00-0.49), partially adherent (ratio=0.50-0.79), adherent (ratio=0.80-1.10), and excess medication fillers (ratio >1.10)​

24% of patients were considered nonadherent, 16% were partially adherent, 19% were excess fillers, and 41% were adherent​

  1. Gilmer TP, Dolder CR, Lacro JP, et al. Adherence to treatment with antipsychotic medication and health care costs among Medicaid beneficiaries with schizophrenia. Am J Psychiatry. 2004;161(4):692-699.
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Clinicians Overestimated Patient Adherence to Medication​
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Study involved 25 adult outpatients diagnosed with schizophrenia (n=18) or schizoaffective disorder (n=7), documented by a checklist of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, taking a single oral antipsychotic medication​

The antipsychotic adherence of patients was monitored at 3 monthly assessments with the MEMS, a medication vial cap that electronically records the date and time of bottle opening​

Patients were determined to meet criteria for daily adherence, as assessed by the MEMS cap, if they opened their bottle the prescribed number of times per day, irrespective of the time of bottle opening​

A patient was deemed nonadherent if during any single month the MEMS recordings revealed that the bottle was opened <70% of the requisite prescribed occasions​

The Clinician Rating Scale is an ordinal scale of 1-7, with higher numbers equaling greater adherence. The authors chose a priori to employ a score of ≤4 at any 1 of the 3 monthly evaluations as the threshold for clinically meaningful nonadherence​

Twelve patients (48.0%) were nonadherent as determined by the MEMS cap, while no patients were deemed nonadherent by the Clinician Rating Scale (P<0.0001)

  1. Byerly M, Fisher R, Whatley K, et al. A comparison of electronic monitoring vs. clinician rating of antipsychotic adherence in outpatients with schizophrenia. Psychiatry Res. 2005;133(2-3):129-133.​
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Clinicians Overestimate Medication Usage in Their Patients With Schizophrenia​
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A consensus survey of 47 expert opinions on the pharmacologic treatment of psychotic disorders included the following questions1:​

  • Please indicate what proportion of patients with schizophrenia you believe to be adherent, partially adherent, and nonadherent, based on your reading of the treatment literature2​
  • What proportion of your patients with schizophrenia are adherent, partially adherent, and nonadherent?2​

Clinicians identified their own patients as being approximately >50% more adherent than patients described in the literature, with adherence defined as2:​

  • Adherent: only misses occasional doses (<20% of prescribed medication)​
  • Partially adherent: misses more than occasional doses (20% to 80% of medication)​
  • Nonadherent: misses >80% of medication
  1. Kane JM, Leucht S, Carpenter D, Docherty JP; Expert Consensus Panel for Optimizing Pharmacologic Treatment of Psychotic Disorders. The expert consensus guideline series. Optimizing pharmacologic treatment of psychotic disorders. Introduction: methods, commentary, and summary. J Clin Psychiatry. 2003;64(suppl 12):5-19. ​
  2. Kane JM, Leucht S, Carpenter D, Doherty JP; Expert Consensus Panel for Optimizing Pharmacologic Treatment of Psychotic Disorders. The expert consensus guideline series. Optimizing pharmacologic treatment of psychotic disorders. Expert survey results and guideline references. J Clin Psychiatry. 2003;64(suppl 12):52-94.​
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Risk Factors for Nonadherence ​ in Patients With Schizophrenia​
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Adherence Is a Multidimensional Phenomenon​
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Adherence is a multidimensional phenomenon determined by the interplay of 5 sets of factors termed ‘dimensions’ ​

Patient-related factors are just 1 determinant. Health system, social-economic, treatment-related, and disease-related factors also affect people’s behavior and capacity to adhere to their treatment​

  1. Adherence to long-term therapies: evidence for action. World Health Organization Web site. http://www.who.int/chp/knowledge/publications/adherence_full_report.pdf. Published 2003. Accessed March 6, 2013.​
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Specific Factors Influence Adherence​
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Adherence to therapy is related to many contributing factors in patients with schizophrenia. Some factors viewed as important are listed on this slide​

Patient factors such as poor insight into their illness and distress associated with side effects can affect adherence​

Complex treatment regimens and lack of efficacy also contribute to problems with adherence​

Environmental factors, such as lack of transportation to the clinic or pharmacy and stigma associated with taking medications, can negatively impact adherence​

Also important to maintaining adherence are social factors, such as the therapeutic alliance with health care providers and social support​

  1. Velligan DI, Weiden PJ, Sajatovic M, et al; Expert Consensus Panel on Adherence Problems in Serious and Persistent Mental Illness. The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness. J Clin Psychiatry. 2009;70(suppl 4):1-48.​
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Barriers to Medication Adherence in Patients With Schizophrenia​
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This study analyzed data collected during the Schizophrenia Guidelines Project, a multisite study of strategies to implement practice guidelines that was funded by the US Department of Veterans Affairs and conducted from March 1999 to October 2000​

Administrative data were used to identify patients with an International Classification of Diseases, Ninth Revision (ICD-9) code for schizophrenia (295.1-295.3, 295.6, and 295.9)​

A total of 153 patients were included in this analysis​

The most common patient-reported barriers were related to the stigma of taking medications, adverse drug reactions, forgetfulness, and lack of social support​

  1. Hudson TJ, Owen RR, Thrush CR, et al. A pilot study of barriers to medication adherence in schizophrenia. J Clin Psychiatry. 2004;65(2):211-216.​
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Predictors for Nonadherence in First-Episode Patients With Schizophrenia​
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Kamali et al assessed all patients from a Dublin catchment area who were admitted to the services and met the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R) criteria for schizophrenia or schizophreniform disorder, over a 4-year period​

This study population used first-episode patients, defined as the first presentation of a patient with acute psychotic symptoms to a psychiatric service​

Data relating to alcohol and drug misuse were derived from the Structured Clinical Interview for DSM Disorders interview​

Lack of judgment and insight was assessed using the Positive and Negative Syndrome Scale ​

After 6 months, adherence was assessed using the Compliance Interview—a validated, 6-item interview examining patients concordance with, and knowledge of, prescribed medications​

Nonadherence was defined as 0% to 74% adherence over the preceding 3 months​

20 of 60 patients were nonadherent with medication​

Logistic regression analysis showed that total positive symptom score (P<0.01), alcohol misuse (P=0.01), lack of insight (P=0.04), and drug misuse (P=0.04) predicted nonadherence at 6 months​

Grandiosity (P=0.04) is the individual positive symptom with the highest predictive power​

Reduced insight is a more significant predictor of nonadherence (P=0.03) in the subgroup of patients without drug misuse​

  1. Kamali M, Kelly BD, Clarke M, et al. A prospective evaluation of adherence to medication in first episode schizophrenia. Eur Psychiatry. 2006;21(1):29-33. ​
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Patients With Schizophrenia Are Commonly Unaware of Signs and Symptoms Associated With Their Disease​
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In a sample of 221 patients with schizophrenia, insight into various symptoms was measured using a shortened version of the Scale to assess Unawareness of Mental Disorder scale​

At least 1 of the following positive or negative symptoms had to be currently present to at least a mild degree to be included: delusions, hallucinations, disorganized speech, flat affect, poverty of speech, or passive, apathetic social withdrawal​

57.4% of patients with schizophrenia showed a moderate to severe lack of awareness of having a mental disorder​

  • 31.5% had severe unawareness of the social consequences of mental disorder​
  • 21.7% had severe unawareness of the efficacy of medication​

Patients were unaware of 28%-58% of individual symptoms​

 

  1. Amador XF, Flaum M, Andreasen NC, et al. Awareness of illness in schizophrenia and schizoaffective and mood disorders. Arch Gen Psychiatry. 1994;51(10):826-836. ​
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Poor Insight Was Associated With Nonadherence ​
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Data are from a cross-sectional, naturalistic, multicenter study conducted in 15 French public hospitals in a region of southeastern France during a 1-week period in 2008​

Patients were outpatients with a diagnosis of schizophrenia or schizoaffective disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria​

Insight was measured by the psychiatrist using the SUMD​

The following 3 global insight dimensions were used:​

  • Having a mental disorder​
  • Effects of medication​
  • Consequences of the mental disorder​
  • Each of these dimensions is rated on a 5-point rating scale: 0=not applicable, 1=aware, 3=somewhat aware/unaware, and 5=severely unaware. A score ≥3 was indicative of a poor individual level of insight​

Nonadherent patients presented a lower level of insight than adherent patients for the 3 dimensions of the SUMD (P<0.001) ​

  1. Dassa D, Boyer L, Benoit M, Bourcet S, Raymondet P, Bottai T. Factors associated with medication non-adherence in patients suffering from schizophrenia: a cross-sectional study in a universal coverage health-care system. Aust N Z J Psychiatry. 2010;44(10):921-928. ​
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Poor Insight Was Associated With Nonadherence​
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In a study of 58 patients with schizophrenia, 26 were considered to be adherent while 32 were considered to be nonadherent based on missed appointments and deliberate discontinuation of treatment​

Upon discharge, patients were assessed using the GAS, which includes 2 items rated using 4 degrees of severity:​

  • “Lack of feeling of illness” (the patient denies being ill either spontaneously or when interviewed)​
  • “Lack of insight into illness” (the patient fails to acknowledge his/her emotional state and the behavior assessed as pathologic by the physician and does not perceive the necessity of treatment)​

Nonadherent patients demonstrated significantly higher scores for both “lack of feeling of illness” and “lack of insight into illness”​

“Lack of feeling of illness” and lack of “insight into illness” can be regarded as risk factors for nonadherence

  1. Bartkó G, Herczeg I, Zádor G. Clinical symptomatology and drug compliance in schizophrenic patients. Acta Psychiatr Scand. 1988;77(1):74-76.​
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Poor Insight in Schizophrenia Is a Well-Established ​ Risk Factor for Relapse and Rehospitalization​
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Patients with first episodes of schizophreniform disorder, schizophrenia, schizoaffective disorder, delusional disorder, and psychosis not otherwise specified were recruited from July 1996 to September 1998 from consecutive admissions to day-patient and inpatient units in England​

Patients were interviewed with the BIS, an 8-item self-completed scale​

At final interviews, medical notes were scored independently of the rater to determine dates of relapse​

This was defined as an exacerbation of positive symptoms lasting at least 2 weeks, leading to a change in management​

Hospitalization data were obtained from the National Health Service hospitals in the catchment area​

Insight at baseline was significantly lower in those who relapsed (mean BIS = 8.8) than in those who did not (mean BIS = 10.3)​

Mean BIS was lower in those who were rehospitalized (mean = 8.1) than in those who were not (mean = 10.2)​

The hazard ratio for relapse, per unit increase in the insight score, was estimated to be 0.943​

The rate of relapse in patients with the best insight scores was 39% of the rate among patients with the worst insight scores​

Poor insight also predicted readmission (hazard ratio, 0.924)

  1. Drake RJ, Dunn G, Tarrier N, Bentall RP, Haddock G, Lewis SW. Insight as a predictor of the outcome of first-episode nonaffective psychosis in a prospective cohort study in England. J Clin Psychiatry. 2007;68(1):81-86.​
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Insight Varies Over Time​
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It has been proposed that several steps of insight have to be traversed before insight can be expected to predict treatment adherence​

For example, unawareness of symptoms might be more directly associated with neuropsychologic deficits, and the labeling of symptoms as mental illness might be associated with reasoning biases (eg, external attribution, jumping to conclusions), whereas not accepting the diagnosis of mental disorder or its implications might be closely linked to attitudes toward treatment​

This figure depicts a theoretical hierarchical course of insight components over time and the way in which they are likely to differ in origin and implications​

To complicate the matter of assessment further, it cannot necessarily be assumed that patients are being open about their level of insight. Clinical observations show that some patients tend to verbally express insight to be left alone by doctors or therapists. In these cases, we can hardly expect insight to produce the same changes in behavior as in a person with ‘‘real’’ insight​

  1. Lincoln TM, Lüllmann E, Rief W. Correlates and long-term consequences of poor insight in patients with schizophrenia. A systematic review. Schizophr Bull. 2007;33(6):1324-1342. ​
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Consequences of Nonadherence to ​ Antipsychotics in Patients With Schizophrenia​
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Poor Adherence Negatively Impacts Patient Outcomes​
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Nonadherent Patients With First-Episode Psychosis Were More Likely to Relapse​
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This is a prospective, randomized, flexible-dose, open-label study in patients experiencing their first episode of psychosis (meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria for brief psychotic disorder, schizophreniform disorder, schizophrenia, schizoaffective disorder or psychotic disorder not otherwise specified)​

At study intake, all but 3 of the patients were antipsychotic naive​

Dose ranges were 5-20 mg/day of olanzapine, 3-6 mg/day of risperidone, and 3-9 mg/day of haloperidol. At the discretion of the treating physician, the dose and type of antipsychotic medication could be changed, based on clinical efficacy and the profile of side effects during the follow-up period​

Adherence to antipsychotic drugs was assessed using information obtained from patients and close relatives by staff (including nurses, social workers, and psychiatrists involved in the clinical follow-up). For the present investigation, patients were consensually dichotomized into having good adherence (defined as patients regularly taking at least 90% of prescribed medication) or poor adherence during the observational period​

Relapse was defined among patients who achieved clinical improvement and stability (Clinical Global Impression [CGI] rating ≤4 and a decrease of at least 30% on Brief Psychiatric Rating Scale [BPRS] total score and all BPRS key symptom items, by being rated ≤3 for more than 4 consecutive weeks at some point during the first 6 months following program entry) and was defined as any of the following criteria occurring after clinical improvement: ​

  • A rating of ≥5 on any key BPRS symptom items for at least 1 week​
  • CGI rating of ≥6 and a change score of CGI of “much worse” or “very much worse” for at least 1 week​
  • Hospitalization for psychotic psychopathology​
  • Completed suicide​
  • The key BPRS symptoms were unusual thought content, hallucinations, suspiciousness, conceptual disorganization, and bizarre behavior​
  • Patients were considered to have relapsed if the relapse state lasted at least 1 week​

Of the 140 patients, 91 (65%) relapsed at least once over the 3-year period. The rates for the first relapse at 1 year and 2 years were 20.7% and 40.7%, respectively​

The median time to relapse was 843 days (95% confidence interval, 667-1019) (range, 48-1164)​

The time to relapse between adherent (mean=933 days) and nonadherent (mean=568 days) patients was significantly different

  1. Caseiro O, Perez-Iglesias R, Mata I, et al. Predicting relapse after a first episode of non-affective psychosis: a three-year follow-up study. J Psychiatr Res. 2012;46(8):1099-1105.​
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Nonadherence Predicts Relapse in Patients With Recent-Onset Schizophrenia​
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Patients with recent onset of schizophrenia (n=49) were assessed for medication adherence using patient self-report, clinician judgments, pill counts, and plasma levels​

Psychiatric symptoms were assessed every 2 weeks using the expanded Brief Psychiatric Rating Scale ​

All patients were provided atypical antipsychotic medications, regular psychiatrist visits, and individual case management​

Nonadherence robustly predicted a return of psychotic symptoms during the early phase of schizophrenia ​

  • Hazard ratios=3.7-28.5, depending on the severity of nonadherence​

Missing as little as 25% of the prescribed dosage over a period of ≥2 weeks significantly increased the risk of psychotic symptom return​

Nonadherent patients were defined as patients with <50% adherence of the prescribed medication dose for at least 2 weeks 

  1. Subotnik KL, Nuechterlein KH, Ventura J, et al. Risperidone nonadherence and return of positive symptoms in the early course of schizophrenia. Am J Psychiatry. 2011;168(3):286-292.
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Nonadherence Led to Worsened Symptoms and Decreased Functioning in Patients With Schizophrenia​
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Lindenmayer and colleagues analyzed data from a randomized, double-blind, 8-week, fixed-dose trial of an atypical antipsychotic to examine the impact of medication nonadherence on treatment outcomes. A total of 599 patients with schizophrenia were analyzed on various symptomatology and functioning scales. Nonadherence was defined as not taking medication as prescribed, based on daily pill counts​

Results demonstrated significantly less improvement in patients who were nonadherent to medication vs patients adherent to medication in this 8-week trial

  1. Lindenmayer JP, Liu-Seifert H, Kulkarni PM, et al. Medication nonadherence and treatment outcome in patients with schizophrenia or schizoaffective disorder with suboptimal prior response. J Clin Psychiatry. 2009;70(7):990-996.​
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Nonadherence to Antipsychotics and Relapse ​ Are Associated With a High Health Care Burden​
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In the Schizophrenia Outpatient Health Outcomes (SOHO) study, a 3-year, prospective, observational study of 10,972 outpatients with schizophrenia across 10 European countries, costs associated with relapse were analyzed. Data regarding inpatient days, day care center days, outpatient consultations, antipsychotic drugs, and concomitant medications were collected during routine clinician visits, and costs were estimated from several United Kingdom–based price indexes. Relapse was defined as a 3-point increase in the Clinical Global Impression (CGI) overall severity score or having a hospitalization1 ​

The US Schizophrenia Care and Assessment Program (US-SCAP) study, a prospective, observational, noninterventional study of schizophrenia in the United States conducted between 1997 and 2003, included community mental health centers, university health care systems, community and state hospitals, and the Department of Veterans Affairs (VA) Health Services. Total direct mental health costs and cost components of patients with and without relapse in the prior 6 months were compared over the following year by using the propensity score matching method. Relapse was defined as having any of the following: psychiatric hospitalization, use of emergency services, use of a crisis bed, or a suicide attempt. Total 1-year direct mental health costs included these cost components: costs of medications (antipsychotics and other psychotropics, such as mood stabilizers, anticholinergics, antidepressants, and antianxiety and sleep agents), psychiatric hospitalizations, day treatment, emergency services, psychosocial group therapy, medication management, individual therapy, and Assertive Community Treatment (ACT) case management. Costs of atypical antipsychotic medications were based on average wholesale prices discounted by 15%; costs of psychiatric hospitalization were based on per diem costs at each site; costs of mental health services, other than psychiatric hospitalizations, were based on their relative value units developed from resource utilization and cost data available from the management information systems at each site2​

A series of multivariate regressions were performed with statewide 2001–2003 California Medicaid (Medi-Cal) data to estimate the fraction of acute-care hospital admissions and hospital days for schizophrenia that were attributable to gaps in antipsychotic medication treatment. This fraction was then applied to national estimates of the number and costs of inpatient treatment episodes for patients with schizophrenia in the national Medicaid program. This analysis focused on prescriptions of oral antipsychotic medications (patients receiving long-acting medications were excluded). Medi-Cal recipients aged 18 to 64 years who had received at least 2 outpatient or 1 inpatient claim for schizophrenia were selected. Two federal surveys were used to estimate the total national distribution and costs of Medicaid-reimbursed acute care for hospital admissions for schizophrenia: (1) the 1997 Client/Patient Sample Survey (CPSS); (2) the 2002 Survey of Mental Health Organizations (SMHO), General Hospital Mental Health Services, and Managed Behavioral Health Organizations. According to the 1997 CPSS, there are an estimated 86,878 annual acute care hospital admissions and a total of 930,062 inpatient days provided to Medicaid-financed patients for the treatment of schizophrenia in the United States. The total cost of these inpatient admissions is approximately $806 million. This estimate is derived by applying the 2002 SMHO mean daily costs of inpatient treatment for each organization, adjusted for inflation, to the estimated number of inpatient days in that organization. Applying the adjusted attributable fraction of inpatient admissions due to gaps in antipsychotic treatment (12.3%) to the national estimate of admissions yields 10,686 annual acute care hospital admissions attributable to gaps in antipsychotic treatment. Applying the adjusted attributable fraction of inpatient days (13.1%) yields 121,838 inpatient days and an inpatient cost of approximately $106 million attributed to gaps in treatment3​

  1. Hong J, Windmeijer F, Novick D, Haro JM, Brown J. The cost of relapse in patients with schizophrenia in the European SOHO (Schizophrenia Outpatient Health Outcomes) study. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(5):835-841.​
  2. Ascher-Svanum H, Zhu B, Faries DE, et al. The cost of relapse and the predictors of relapse in the treatment of schizophrenia. BMC Psychiatry. 2010;10:2.​
  3. Marcus SC, Olfson M. Outpatient antipsychotic treatment and inpatient costs of schizophrenia. Schizophr Bull. 2008;34(1):173-180.​
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Hospitalization Costs due to Patient Nonadherence​
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Specific inputs from Gilmer et al1 and Svarstad et al2 - including nonadherence rate, rehospitalization rate, annual hospitalization costs associated with the use of antipsychotic drugs, and the daily hospital costs - were used to calculate total costs due to nonadherence in 2005. The daily hospital costs were extrapolated from National Inpatient Sample of Healthcare Cost and Utilization Project data in 20053

Studies demonstrated that costs related to nonadherence ranged from $13922 to $1826 million4 in 2005

  1. Gilmer TP, Dolder CR, Lacro JP, et al. Adherence to treatment with antipsychotic medication and health care costs among Medicaid beneficiaries with schizophrenia. Am J Psychiatry. 2004;161(4):692-699.​
  2. Svarstad BL, Shireman TI, Sweeney JK. Using drug claims data to assess the relationship of medication adherence with hospitalization and costs. Psychiatr Serv. 2001;52(6):805-811.​
  3. Sun SX, Liu GG, Christensen DB, Fu AZ. Review and analysis of hospitalization costs associated with antipsychotic nonadherence in the treatment of schizophrenia in the United States. Curr Med Res Opin. 2007;23(10):2305-2312.​
  4. Valenstein M, Copeland LA, Blow FC, et al. Pharmacy data identify poorly adherent patients with schizophrenia at increased risk for admission. Med Care. 2002;40(8):630-639.​
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Nonadherent Patients Were More Likely to Be Hospitalized​
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The authors used data from San Diego County Adult Mental Health Services to identify individuals who were diagnosed with schizophrenia by a specialty mental health provider who were living in the community during fiscal years 1999 and 2000​

These data were merged with 3 years of data from Medi-Cal eligibility and claims (1998-2000) and identified fee-for-service beneficiaries continuously enrolled over the course of a year who filled at least 1 prescription for an antipsychotic medication​

  • This analysis was based on prescription fills for oral antipsychotic medications​

Adherence to prescribed regimens was determined by examining Medi-Cal claims by means of medication refill records. Adherence was measured by the annual cumulative possession ratio, which was computed for each person in each calendar year. The cumulative possession ratio was calculated by dividing the number of days medications were available for consumption by the number of days participants were eligible for Medi-Cal​

A person-year’s adherence was derived from the cumulative possession ratio using the following designations: nonadherent (ratio=0.00-0.49), partially adherent (ratio=0.50-0.79), adherent (ratio=0.80-1.10), and excess medication fillers (ratio >1.10)​

24% of patients were considered nonadherent, 16% were partially adherent, 19% were excess fillers, and 41% were adherent​

Psychiatric hospitalization was strongly related to the degree of adherence​

  • Nonadherent patients were 2.5 times more likely to be hospitalized than those who were adherent​
  • Partially adherent or excess fillers were 80% more likely to be hospitalized than those who were adherent
  1. Gilmer TP, Dolder CR, Lacro JP, et al. Adherence to treatment with antipsychotic medication and health care costs among Medicaid beneficiaries with schizophrenia. Am J Psychiatry. 2004;161(4):692-699.​
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Partial Adherence and Nonadherence Led to Increased Hospitalization​
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Data from the United States Schizophrenia Care and Assessment Program (US-SCAP), a 1997‑2003 study of schizophrenia, schizoaffective disorder, and schizophreniform disorder, were analyzed​

  • Of 2327 US-SCAP participants, 2010 (86.4%) had health care resource utilization for 1 year after study enrollment and comprised the analytic sample​

Antipsychotic medication use and adherence levels were derived from prescription information in patients' medical records​

MPR with any antipsychotic in the 6 months prior to enrollment was used to categorize patients as: adherent (MPR ≥80%, n=1758), partially adherent (MPR ≥60% to <80%, n=36), or nonadherent (MPR <60%, n=216)​

Mental health resource utilization during the 1 year following study enrollment was systematically abstracted from medical records​

During the 1 year following enrollment, adherent patients in the 6 months prior to enrollment were significantly less likely to have a psychiatric hospitalization (17.1%) compared with partially adherent (30.6%) and nonadherent patients (29.6%) (P<0.05)​

Adherent participants also had about half as many inpatient admissions (0.28 vs 0.64 and 0.55 [P<0.05 adherent vs partially and vs nonadherent]), and fewer total days hospitalized (8.8 vs 32.0 and 17.6 days [P<0.05 adherent vs partially adherent and vs nonadherent])​

  1. Ascher-Svanum H, Zhu B, Faries DE, Furiak NM, Montgomery W. Medication adherence levels and differential use of mental-health services in the treatment of schizophrenia. BMC Res Notes. 2009;2:6. ​
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Nonadherent Patients Were More Likely to Be Hospitalized​
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A 20% random sample of 1999-2001 California Medicaid data was used to evaluate the association between partial adherence and hospitalization​

To be included, patients with schizophrenia (defined by an International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code of 295.xx) had to have at least 2 dispensing events for antipsychotic medications during a 6-month enrollment period (July 1 to December 31, 1999). Qualifying prescription claims were claims for all approved oral antipsychotic medications, including newer antipsychotics available before January 1, 2000​

Each patient was assigned an index date, defined as the date of the patient’s first prescription during the enrollment period. Because it is possible that patients with new diagnoses would have significantly different adherence issues while being stabilized with medication therapy, the goal was to study patients who were already receiving antipsychotics. Therefore, patients were also required to have at least 1 prescription in the 6 months prior to their index date​

Four measures of adherence were evaluated: gaps in medication therapy, medication consistency, medication persistence, and an MPR​

For this study, medication gap was defined as the longest period during which no medication appeared to be available. Contiguous periods in which no medication appeared to be available were based on dispensing date and recorded days’ supply for each antipsychotic prescription. Four categories based on each patient’s maximum gap in therapy were defined: 0 days, 1 to 10 days, 11 to 30 days, and more than 30 days. The mean number of gaps per patient and the mean gap duration (across all therapy gaps) were also calculated​

A marker was created to indicate whether a patient had at least 1 “mental health hospitalization” during the 1-year, postindex observation period. Mental health hospitalizations were identified by using “mental health” ICD-9-CM diagnosis codes in the first (primary) diagnosis field​

A total of 4325 patients met the selection criteria​

Patients who were less than 70% adherent by the MPR had higher rates of hospitalization than those who were at least 70% adherent (22.3% vs 13.8%, respectively, P<0.001)​

  1. Weiden PJ, Kozma C, Grogg A, Locklear J. Partial compliance and risk of rehospitalization among California Medicaid patients with schizophrenia. Psychiatr Serv. 2004;55(8):886-891.​
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