A. George Awad

The Burden of Schizophrenia on Caregivers: A Review

Schizophrenia is a disabling, chronic psychiatric disorder that poses numerous challenges in its management and consequences. It extols a significant cost to the patient in terms of personal suffering, on the caregiver as a result of the shift of burden of care from hospital to families, and on society at large in terms of significant direct and indirect costs that include frequent hospitalizations and the need for long-term psychosocial and economic support, as well as life-time lost productivity.‘Burden of care’ is a complex construct that challenges simple definition, and is frequently criticized for being broad and generally negative. Frequently, burden of care is more defined by its impacts and consequences on caregivers. In addition to the emotional, psychological, physical and economic impact, the concept of ‘burden of care’ involves subtle but distressing notions such as shame, embarrassment, feelings of guilt and self-blame.The early conceptualization of ‘burden of care’ into two distinct components (objective and subjective) has guided research efforts until the present time. Objective burden of care is meant to indicate its effects on the household such as taking care of daily tasks, whereas subjective burden indicates the extent to which the caregivers perceive the burden of care. Research contributions in later years (1980s to the present) have added more depth to understanding of the construct of burden of care by exploring important determinants and factors that likely contribute or mediate the caregiver’s perception of burden of care. Several studies examined the role of gender, and reported that relatives of male patients with schizophrenia frequently experience more social dysfunction and disabilities than those of female patients. Similarly, a number of other studies documented the contribution of ethnicity and cultural issues to subjective burden of care. Although there is no complete agreement on whether a specific cluster of psychotic symptoms has the most impact on a caregiver’s burden of care, there is agreement that the severity of symptoms increases it.An extensive literature concerning family interventions in schizophrenia has demonstrated the positive impact of various family interventions in improving family environment, reducing relapse and easing the burden of care. Although the evidence of such positive impact of family interventions in schizophrenia is well documented, such interventions are neither widely used nor appropriately integrated in care plans, and are frequently underfunded.Although the cost of caregiving is considered to be significant, there are no reliable estimates of the costs associated with such care. The majority of available literature categorized the cost of burden of care among the indirect costs of schizophrenia in general. In recent years, attempts to compare the costs of caregiving in several countries have been reported in the evolving literature on this topic. ‘Burden of care’ as a complex construct certainly requires the development of appropriate methodology for its costing.In achieving a balance between the patients’ and caregivers’ perspectives, caregivers have to be included in the care plan and adequate information and support extended to the family and caregivers. Access to better treatment for patients, including medications, psychosocial interventions and rehabilitation services, are important basic elements in easing the burden on caregivers. Other measures such as availability of crisis management, provision of legally mandated community treatment to avert hospitalization, and well informed and balanced advocacy are also important.Although research efforts have been expanded in the last 3 decades, an urgent need exists for enhancing such efforts, particularly in the development and evaluation of effective family interventions strategies. There is also a need for continued improvement in the delivery of psychiatric services to the severely psychiatrically ill and their families. As there is a lack of reliable cost information about the family burden of care specific to schizophrenia, there is an urgent need to develop reliable approaches that can generate data that can inform in policy making and organization of services.

Measuring Quality of Life in Patients with Schizophrenia

In 1997, we published a review in Pharmaco Economics about quality of life (QOL) measurement in patients with schizophrenia. The objective of this article is to provide an update, as well as to revisit the development of the construct of QOL and its measurement as applied to schizophrenia. Since our previous article, there has been significant growth in the number of publications about QOL in schizophrenia. Unfortunately, alongside this significant increase in research interest, a number of concerns have also risen about the limitations and lack of impact the concept of QOL has on clinical care and health-policy decision making. A number of concerns previously outlined (such as lack of consensus on a uniform definition of QOL) continue to be an issue. However, we believe that a uniform definition may not be possible, and instead, it may be preferable to have several definitions, which may enrich the concept and broaden its usefulness.Some of the scales we reviewed in 1997 continue to be in use, while others are now rarely or never used. New scales with better psychometrics have been introduced, but most are without theoretical or conceptual foundation. On the other hand, the field of scaling in general has been changing over the past few years and is moving towards a new approach for scale development, based on item response theory, item banks and computer adaptive testing. Unfortunately, this has not extended to QOL in schizophrenia. There continues to be a dearth of theoretical and conceptual models for QOL in schizophrenia, which seems to create the perception that the construct lacks a good theoretical and scientific foundation.One of the major gaps identified in this review is the recognized lack of impact of QOL measurements on clinical management or policy decision making. The majority of publications continue to focus on measurement rather than what to do with the data. The lack of strategies to integrate QOL data in clinical care, as well as the failure to contribute to policy decisions, particularly in cost analysis or resource allocations, has created the perception that the construct of QOL in schizophrenia is not that useful. It is evident that, for QOL in schizophrenia to regain its promise, researchers must take the ultimate next step beyond measurement: to develop credible strategies for integrating QOL data in clinical practice. Additionally, more focused research is needed to demonstrate the role of QOL, not only as an outcome in itself but also as a contributor to other outcomes, such as adherence to medications, more satisfaction, less resource utilization and so on.Since self-appraisal of QOL does not happen in a vacuum but relates to the total human experience in all its biological, psychosocial and environmental aspects, particular attention must also be focused on important neurobiological dimensions such as affect and cognition. Both are significantly affected by the illness itself and its treatment.

Cannabis induced dopamine release: an in-vivo SPECT study

In a research study aimed at examining the alterations in dopaminergic function in schizophrenia, the authors identified a surreptitious case scenario which provided new insights into the subjective and neurochemical effects of cannabis. A 38-year-old drug-free schizophrenic patient took part in a single photon emission computerized tomographic (SPECT) study of the brain, and smoked cannabis secretively during a pause in the course of an imaging session. Cannabis had an immediate calming effect, followed by a worsening of psychotic symptoms a few hours later. A comparison of the two sets of images, obtained before and immediately after smoking cannabis, indicated a 20% decrease in the striatal dopamine D2 receptor binding ratio, suggestive of increased synaptic dopaminergic activity. This observation offers a plausible biological explanation for the psychotogenic effects of cannabis in vulnerable individuals, and also raises speculations about an interaction between cannabinoid and dopaminergic systems in the brain reward pathways.

Neurocognitive subtypes of chronic schizophrenia

Performance on four key neurocognitive tasks was used to search for subtypes in 104 DSM-IIIR schizophrenic patients. The tasks were the Wisconsin Card Sorting Test to index executive prefrontal cerebral function, intrusion errors from the California Verbal Learning Test to tap hippocampal-diencephalic mnestic function, bilateral hand performance on the Purdue Pegboard to index fine motor-basal ganglial function, and a pro-rated IQ from the Wechsler Adult Intelligence Scale-Revised to measure general cognitive-cerebral function. Neurocognitive data were analyzed using hierarchical and disjoint clustering procedures with Euclidean distance. A five cluster solution was considered optimal. Cluster 1 (n = 24) comprised patients with selective executive-prefrontal dysfunction; cluster 2 (n = 16) suggested normative function; cluster 3 (n = 20) involved patients with executive-motor/cortico-basal ganglial deficit; cluster 4 (n = 25) suggested dementia/multi-focal disturbance; and cluster 5 (n = 19) consisted of patients with selective motor-basal ganglial deficit. The subtypes differed significantly in age, duration of illness, and extent of hospitalization. Suggestive trends in sex composition and anti-Parkinsonian medication patterns were noted. Neurocognitive tasks combined with cluster analysis have promise in reducing and clarifying the heterogeneity of schizophrenia.

Impact of Atypical Antipsychotics on Quality of Life in Patients with Schizophrenia

Schizophrenia is a long-term disabling illness that affects approximately 1% of the population. Its course is generally chronic with acute psychotic exacerbations that may require frequent hospitalisations. The clinical picture includes a range of symptoms such as delusions, hallucinations, agitation, suspiciousness, hostility, conceptual disorganisation, blunted affect, emotional and social withdrawal, lack of spontaneity, poverty of speech and a wide range of neurocognitive deficits. Over the past 50 years, antipsychotic medications have emerged as the cornerstone of management in concert with other important interventions, such as psychosocial and economic support and rehabilitation efforts. However, the unrivalled role of conventional antipsychotic medications has been continuously challenged by the wide range of adverse effects of these medications and their lack of usefulness in the treatment of neurocognitive deficits as well as deficit and negative symptoms. In addition, the lack of subjective tolerability of these agents and their negative impact on quality of life have complicated management for a large number of patients. Over the last 15 years, several new atypical antipsychotic medications have been introduced, including amisulpride, remoxipride, risperidone, sertindole, olanzapine, zotepine, quetiapine, ziprasidone and aripiprazole. In general, the new antipsychotics have shown themselves to be at least comparable in efficacy to conventional antipsychotics but with superior subjective tolerability and a more favourable adverse effect profile.The majority of quality of life studies involving new antipsychotic agents have evaluated the benefits of risperidone, olanzapine and clozapine; only a few studies have examined the effects of other new antipsychotics. While most of these studies have methodological and design limitations, the weight of evidence from them nevertheless points to a trend towards a more positive impact on quality of life with atypical agents.A number of recommendations can be made. First, more independent well designed and controlled studies are urgently needed to evaluate the effects of antipsychotic therapy on quality of life in patients with schizophrenia. New comparative studies should explore not only the differences between new and old antipsychotics but also identify any potential differences between individual new agents. The role of cost-effectiveness studies such as cost utility approaches in schizophrenia needs to be revisited, notwithstanding the fact that these types of studies have been reported to be feasible in schizophrenia. Finally, quality-of-life-based pharmacoeconomic studies of antipsychotic agents should not concentrate solely on cost reduction or containment, as it is likely that in order to maximise the benefits of new antipsychotic medications, greater expenditure on rehabilitation programmes and other support services will be necessary in the short-term at least.

Subjective Effects of AMPT-induced Dopamine Depletion in Schizophrenia: Correlation between Dysphoric Responses and Striatal D2 Binding Ratios on SPECT Imaging

Approximately one third of schizophrenic patients treated with neuroleptic drugs experience unpleasant subjective responses, that are collectively known as neuroleptic dysphoria. Experimental research in animals indicates that drug induced dopaminergic blockade in mesolimbic circuits, especially the nucleus accumbens, leads to impaired pleasure responsivity and dysphoria. The present study tested this putative mechanism in drug-free schizophrenic patients (n = 12), through inducing dysphoric responses with alphamethyl paratyrosine (AMPT) and simultaneously quantifying their baseline striatal dopmine (D2) function with 123IBZM-SPECT imaging. Results showed a wide variability in the occurrence and severity of dysphoric responses, clearly distinguishing a dysphoric group from non-dysphoric responders. Severity of dysphoric responses, measured by standardized rating scales, correlated inversely with changes in D2 receptor binding ratios (r = +0.82, p < .01). These results support the notion that striatal dopaminergic activity is not uniformly elevated in all schizophrenic patients, and the sub-group of individuals with lower baseline dopamine function are at an increased risk for dysphoric responses during antipsychotic therapy with dopaminergic blocking drugs.

New Antipsychotics, Compliance, Quality of Life, and Subjective Tolerability—Are Patients Better Off?

Objectives: This overview reviews the impact of second-generation antipsychotics on less frequently researched outcomes such as medication-adherence behaviour, quality of life, and subjective tolerability in patients with schizophrenia. Methods: We selectively reviewed recent literature and considered our own research and experiences in the field. Results: Most published studies about second-generation antipsychotics have dealt with issues related to efficacy and safety. So far, not many studies have focused on effectiveness in terms of such important outcomes as medication-adherence behaviour, quality of life, subjective tolerability, and overall satisfaction with treatment. Although most studies are inconclusive and their results are inconsistent—which has to do with several design and methodological limitations—there seems, on balance, to be a trend indicating superiority of second-generation, compared with first-generation, antipsychotics in improving medication-adherence behaviour and quality of life. The trend toward more favourable subjective tolerability and less frequent neuroleptic dysphoria seems to be relatively stronger. Conclusions: At present, the state of the art can only indicate a more favourable trend for second-generation antipsychotics in regard to improving medication adherence behaviour, quality of life, and subjective tolerability. It is surprising that such important outcomes, which are likely the defining factors in the superiority of second-generation antipsychotics, have not received adequate research attention. Well-designed, controlled, and adequately powered studies are urgently needed before any firm conclusions can be reached.

Quality of life and new antipsychotics in schizophrenia. Are patients better off

The recent introduction of several antipsychotic medications has raised expectations for better pharmacological management of schizophrenia. Although conventional and new neuroleptics (Risperidone, Olanzapine, Seroquel and soon to be released Ziprasidone) are generally comparable in terms of efficacy; the new antipsychotic medications possess a better side-effects profile and are overall, much better tolerated. The reintroduction of Clozapine as an effective antipsychotic for treatment refractoriness has also improved management for a segment of the schizophrenic population who failed to respond adequately to other antipsychotic medications. Such increased benefits from new antipsychotic medications come with a higher acquisition cost that has somewhat strained the historically low psychiatric budgets. The question then was whether the expected benefits of the new antipsychotics can offset the high cost of these medications in the long-term. In that context, quality of life assessment has provided a tool for the comparative analysis of new and conventional antipsychotic medications, particularly regarding their impact on functional status and satisfaction. In a recently concluded study, we demonstrated that the new antipsychotic medications are subjectively much better tolerated and have a more favourable impact on quality of life compared with conventional neuroleptics. The ultimate question is whether such favourable benefits can translate in the future into better compliance with medications and improved long-term outcomes.

Methodological Issues in Negative Symptom Trials

Individuals from academia, the pharmaceutical industry, and the US Food and Drug Administration used a workshop format to discuss important methodological issues in the design of trials of pharmacological agents for improving negative symptoms in schizophrenia. The issues addressed included the need for a coprimary functional measure for registration trials; the characteristics of individuals who should enter negative symptom trials; the optimal duration for a proof-of-concept or registration trial; the optimal design of a study of a broad-spectrum agent that treats both positive and negative symptoms or a co-medication that is added to an antipsychotic; the relative strengths and weaknesses of available instruments for measuring negative symptoms; the definition of clinically meaningful improvement for these trials; and whether drugs can be approved for a subdomain of negative symptoms.

Subjective and behavioural consequences of striatal dopamine depletion in schizophrenia — Findings from an in vivo SPECT study

Dysphoria is an integral part of the symptomatology of a variety of clinical states, though there is little empirical data available on the qualitative and quantitative aspects of this phenomenon. The purpose of the study was to administer alphamethyl paratyrosine (AMPT), a catecholamine depleting agent as a chemical probe to induce dysphoria, and document the ensuing changes in mental status. AMPT (4-5 g/day) was administered to a group of medication-free schizophrenic patients (n=13) over a 48 hour period, and changes in their mental status were monitored at 12 hour intervals with the Profile of Mood States (POMS), Addiction Research Center Inventory (ARCI), Drug Attitude Inventory (DAI) and other standardized rating scales. All of the subjects experienced dysphoric responses of variable severity. The profile of changes included blunted pleasure responsivity, clouded thinking, loss of motivation and lowered vigilance. Subtle subjective changes were experienced soon after the first dose of AMPT and the dysphoria steadily worsened, resulting in social withdrawal and personal distress. Subjective responses were the earliest to manifest, followed by akathisia, akinesia and rigidity. We conclude that AMPT induced dopamine depletion is a safe, rapid, reliable and reversible method of studying dysphoric states in humans. The technique is helpful in examining the phenomenology of dysphoria, the temporal relationship between subjective and behavioural consequences of dopamine depletion, and the role of dopamine in mediating subtle aspects of pleasure responsivity, which is in turn crucial to the understanding of treatment non-adherence in schizophrenia and the origins of comorbid substance abuse.