Neuroleptic dysphoria: revisiting the concept 50 years later.

OBJECTIVE: To review the concept of neuroleptic dysphoria, its historical development and the current state of the art. METHOD: This paper is based on extensive but selective literature review and also draws on our extensive clinical and research experiences. RESULTS: Although the construct of neuroleptic dysphoria was recognized shortly following the introduction of the first antipsychotic, chlorpromazine, it took several years for the concept to receive adequate research and clinical attention. Without having direct evidence to link neuroleptic dysphoria to dopamine, it was generally understood that dopamine played a significant role in its genesis. In recent neuroimaging studies and dopamine depletion strategies, the role of dopamine in the genesis of neuroleptic dysphoria has been directly confirmed. CONCLUSION: Neuroleptic dysphoria is a valid construct, which has significant implications for treatment and outcome. It is now clear that it relates to dopamine activities in the nigrostriatal complex. Recent research has also raised the issue of whether neuroleptic dysphoria is a variant of extrapyramidal symptoms. Meanwhile, the role of dopamine in both the genesis of neuroleptic dysphoria and addictive behaviour has raised the issue of both conditions being different facets of the schizophrenic disease process. The recent interface of addiction and psychiatry research may have opened a new science: the science of subjective tolerability disorders.

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.

Intervention research in psychosis: issues related to the assessment of quality of life.

Quality of life has emerged as the ideal of modern medicine viewed from a biopsychosocial perspective. The concept has been increasingly used as an important attribute in patient care and clinical studies as well as the basis in many health economic evaluations. Although the concept has been extensively applied in a number of other medical fields such as oncology, cardiovascular, and arthritis, it is only recently that quality of life has received serious attention in the study of severe psychiatric disorders. For the concept to be meaningfully applied in the study of these disorders, several basic and methodological issues have to be adequately resolved. Five such issues are identified: definition of quality of life, the subjective/objective dichotomy, significant determinants of quality of life, how quality of life is measured, and the role of quality of life in clinical management and health economics. Unless these issues are adequately clarified and resolved, the recent heightened interest in the concept of quality of life may fade away, and that would be a missed opportunity in the mental health field.

Assessing health utilities in schizophrenia. A feasibility study.

BACKGROUND: Utility, a concept derived from economics, is the desirability or preference that individuals exhibit for a certain health state. Utility measurement could be viewed as an alternative means of appraising the quality of life of individuals affected by a chronic illness such as schizophrenia. Traditional techniques of utility measurement involve 2 steps: (i) identifying the different health states experienced by individuals during the course of an illness; and (ii) assigning them numerical values known as utilities. AIM: The study examined the feasibility issues and psychometric aspects of obtaining accurate health state descriptions and their utilities from symptomatically stable patients with schizophrenia. METHODS: The study used a cross-sectional, case-controlled design, with a study group consisting of 120 clinically stabilised patients with schizophrenia and a control group of 32 treated and recovered patients with major depression. Patients were asked to provide detailed descriptions of 3 distinct health states associated with their illness: current state, worst state experienced since the onset of illness and a perfect state desired in the future. Further, patients were asked to assign utilities to these health states with the aid of a purpose-built evaluation protocol comprising Magnitude Estimation (ME), Rating Scale (RS), Standard Gamble (SG), Time Trade-Off (TTO) and Willingness-to-Pay (WTP) techniques. The battery was repeated after a 1-week interval. Independent raters assessed symptom severity, insight and quality of life, and nurse-clinicians involved in their care were asked to provide the utility ratings of their clients' mental health state. Patients' opinions about the acceptability of utility measurement techniques, and the respondent burden were also ascertained. RESULTS: Compared with control patients with treated depression, patients with schizophrenia were able to distinguish and describe the specified health states with an equal degree of ease and accuracy. RS, TTO and WTP techniques emerged as the favoured methods of utility evaluation. The test-retest reliability of utility ratings (r = 0.87 to 0.97; p < 0.001) was high, and concurrent validity with the quality of life measures was acceptable. Reliability and validity of patients' appraisals were unaffected by symptoms severity and insight. The accuracy of nurse-clinicians' appraisals were dependent on their close familiarity with the patients and their illness. CONCLUSION: Clinically stabilised patients with schizophrenia can provide accurate health state descriptions and assign them utilities with a fair degree of reliability and validity. Utility evaluations based on patients' self-appraisals can be seen as potential tools in outcome studies and clinical trials involving patients with schizophrenia, but the methodology requires further refinement to accommodate the limitations imposed by the patients' disturbed mental status.

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.

The influence of neurocognitive deficits and symptoms on quality of life in schizophrenia.

The purpose of the present study was to examine the relationship between neurocognitive deficits and self-reported quality of life in order to examine whether neurocognitive impairment interferes with any aspects of quality of life for patients with schizophrenia. Forty-two outpatients with stable chronic schizophrenia were assessed for neurocognitive deficits using a computerized test battery, and all patients completed a version of the Sickness Impact Profile (SIP) to assess their quality of life across a variety of domains. The neurocognitive assessment tests revealed significant deficits compared with normal control subjects, particularly with respect to impaired iconic memory and frontal functioning. Patients reported that their quality of life was compromised. Despite the substantiation of marked neurocognitive deficits and reduced quality of life, correlations between neurocognitive deficits and quality of life were largely nonsignificant or very weak. Symptom expression, however, particularly with regard to general psychopathology on the Positive and Negative Syndrome Scale (PANSS), was significantly associated with quality of life. These results suggest that neurocognitive deficits in schizophrenia, while often profound, appear to have little direct impact on the patient's perceived quality of life.

Quality of life measurement during antipsychotic drug therapy of schizophrenia.

The strategy for measuring quality of life and the choice of a rating scale should follow a rational scheme aimed at capturing the key components of quality of life of a specified clinical population. This is achieved through defining the purpose of the study, identifying the clinical population and its needs, developing a situation-specific quality of life model, and choosing a battery of psychometrically sound and user-friendly rating scales based on the model. Patients' self-reports and subjective feelings should be central to quality of life measurement, which should also monitor symptom severity, drug side effects, and psychosocial adjustment. This article describes the application of these principles in the context of antipsychotic drug therapy of schizophrenia and identifies potential problems that may arise from the conceptual, psychometric, clinical, and other feasibility issues. The highly subjective nature of the disorder, together with the poor insight, lack of motivation, and neurocognitive deficits of those who are afflicted, poses special difficulties for obtaining and interpreting patients' quality of life appraisals in schizophrenia.

Neurocognitive deficits and neurological signs in schizophrenia.

OBJECTIVE: This is a comprehensive study designed to examine the association between specific clusters of neurological abnormalities and several clinically relevant aspects of schizophrenia such as positive and negative symptoms, neurocognitive deficits and psychosocial performance. METHODS: Thirty-seven clinically stable schizophrenic (DSM-III-R) patients maintained on antipsychotic medication were comprehensively examined and Convit's Quantified Neurologic Scale (QNS) was completed. In addition, patients' psychopathology was rated on the Positive and Negative Syndromes Scale (PANSS); psychosocial performance was rated on the Global Scale of Adaptive Functioning (GAF) and the Social Performance Schedule (SPS); and neurocognitive deficits were measured with a computer-assisted neurocognitive test battery, COGLAB. The association between these factors was determined using Pearson's correlation coefficients. RESULTS: Frontal and soft neurological scores on the QNS correlated significantly with negative syndrome scores (r = 0.45-0.51, p < 0.05) and general psychopathology scores (r = 0.46-0.49, p < 0.02) on PANSS; poor psychosocial performance on GAF (r = 0.43-0.56, p < 0.02) and SPS (r = 0.37-0.54, p < 0.007); and performance on the span of apprehension (r = 0.48-0.67, p < 0.0001), backward masking (r = 0.34-0.54, p < 0.01) and Wisconsin card sorting (r = 0.48-0.67, p < 0.001) tasks. CONCLUSION: Frontal and soft neurological signs in schizophrenic patients are associated with prominent negative symptoms, relatively poor psychosocial performance and significantly more cognitive impairment. Past research has associated soft neurological signs, cognitive impairment and structural brain abnormalities with poor outcome and prognosis in patients with schizophrenia.

A conceptual model of quality of life in schizophrenia: description and preliminary clinical validation.

The utility of quality of life (QOL) as an evaluative tool in clinical psychiatric research and drug trials could be enhanced by developing appropriate conceptual models of QOL, specific for psychiatric disorders. In our proposed model, QOL of individuals maintained on antipsychotic drug therapy for schizophrenia, is viewed as the subject's perception of the outcome of an interaction between severity of psychotic symptoms, side-effects including subjective responses to antipsychotic drugs, and the level of psychosocial performance. In order to test the validity of the model in clinical setting, we selected a sample of 62 schizophrenic patients clinically stabilized on antipsychotic drug therapy, and measured their subjective QOL and other potentially relevant clinical and psychosocial factors. Standardized scales including the positive and negative syndromes scale (PANSS), abnormal involuntary movements scale (AIMS), Hillside Akathisia scale (HAI), and the social performance schedule (SPS) were used for this purpose. Results of a multiple regression analysis using subjective quality of life as the outcome variable, indicated that severity of schizophrenic symptoms (partial R2 = 0.32, p < 0.0001) and subjective distress caused by akathisia (partial R2 = 0.11, p < 0.01) and neuroleptic dysphoria (partial R2 = 0.06, p < 0.05), accounted for nearly half of the variance, while the contribution from the psychosocial indicators was negligible. These results broadly endorse key aspects of the proposed model, and suggest further studies in this direction. These results experiences during antipsychotic therapy can enhance patients' QOL. This conceptual model has been developed with particular focus on the impact of antipsychotic medications on the QOL of persons with schizophrenia. As such, it is more applicable to clinical trials of new antipsychotic medications but may not be broad enough to be applicable for other social or vocational interventions.

Neurocognitive correlates of positive and negative syndromes in schizophrenia.

OBJECTIVE: To identify the neurocognitive correlates of positive and negative schizophrenic syndromes using a battery of information-processing measures as the principal method of evaluation. METHOD: Fifty-two treated, symptomatically stable, schizophrenic (DSM-III-R) patients and 24 age-matched, healthy volunteers were administered a computerized cognitive test battery (COGLAB). The battery included measures of preattentional, attentional, conceptual, and psychomotor performance. The patients' psychopathology was rated with the positive and negative syndromes scale (PANSS), which derived scores for positive symptoms, negative symptoms, general psychopathology, and insight. RESULTS: Compared with controls, schizophrenic patients, as a group, showed significant deficits on all of the neurocognitive tasks. Impaired performance on the backward masking, span of apprehension, and Wisconsin card sorting tasks correlated significantly with negative symptoms (r = 0.27-0.40), general psychopathology (r = 0.29-0.42) and impaired insight (r = 0.34-0.52), but no clear association was found between positive symptom scores and neurocognitive deficits. CONCLUSIONS: Schizophrenic patients with predominantly negative symptoms and impaired insight seem to exhibit more severe neurocognitive deficits, which lends support to the evolving concept of schizophrenia subtypes and their distinctive neurobiological mechanisms.

Measuring quality of life in patients with schizophrenia.

Schizophrenia is a chronic disabling illness that affects about 1% of the population. It is a heterogenous disorder with variable aetiological, prognostic and treatment response patterns. Its course is generally long term, with acute psychotic exacerbations that may require hospitalisation. The cornerstone of clinical management is the use of antipsychotic (neuroleptic) medications. Although these are effective, they can cause adverse effects that may impact negatively on the functional status of the individual. Early studies of quality of life in schizophrenia were mainly concerned with the development of techniques to identify patients' needs in the community. Difficulties encountered in these studies included: lack of agreement on definition of quality of life; lack of appropriate integrative conceptual models; concerns about reliability of patients' self-reports about their quality of life; and the lack of standardised quality-of-life measures appropriate for schizophrenia. A number of disease-specific or generic scales have subsequently been used for measurement of quality of life in schizophrenia. The list of disease-specific scales is extensive; unfortunately, many of them were used only in a single study or their psychometric properties were not specified. Generic scales can be applied across various types and severity of illness, as well as in different health interventions across demographic and cultural groups. Medication costs in schizophrenia represent only a small fraction of the total cost of the illness. However, pharmacoeconomic studies have attracted much interest as a result of the high cost of newly introduced medications and of concern about the limitations of antipsychotic medications, particularly their adverse effects, as exemplified by the reintroduction of clozapine for the treatment of refractory schizophrenia. Few studies have combined quality-of-life measures with cost analysis in schizophrenia; a number of these have methodological shortcomings. Many studies are retrospective in nature, and in most the number and length of hospitalisations has been used as the parameter for cost analysis, which can introduce bias depending on the varying approaches to hospitalisation. We conclude that the following factors are important in choosing or developing a quality-of-life measure for schizophrenia: quality of life is a multidimensional concept that has to be reflected in its measurement; the scale has to be appropriate for the purpose as well as the population studied; measurement has to include patients' self-reports about their quality of life; measures should include only items that are relevant and expected to change; single-item global measures are useful only when combined with multidimensional measures; in developing new scales, psychometric properties have to be established as well as being field-tested.

Assessment of the patient's subjective experience in acute neuroleptic treatment: implications for compliance and outcome.

The concept of subjective response to neuroleptics in schizophrenia was reviewed with particular focus on scales for its measurement. The significance of recognizing such a phenomenon early on in the course of treatment has been illustrated by research data linking it to compliance, clinical improvement, quality of life, suicidal behaviour and comorbid drug abuse. Negative subjective response to neuroleptics has been identified as a strong predictor of compliance and outcome. Awareness of this subjective response in the management of the acute phase of the illness would require the physician to develop specific or additional approaches to the management of such dysphoric patients on neuroleptics at the time of discharge.

Patients' subjective experiences on antipsychotic medications: implications for outcome and quality of life.

The phenomenon of subjective response to antipsychotic medications in schizophrenia was reviewed, focusing on validity, measurement, implications for clinical outcome and quality of life. Recommendations were made on improvements in research approaches to important factors that may contribute to the genesis of this phenomenon. Clinicians should pay attention to the subjective complaints of their patients about medications and not ignore them as unreliable. Researchers should not dismiss research into subjective experiences as non-scientific, because it provides valuable information on recognizing psychopathology and for improving the management of patients.