Cognition, functioning and quality of life in schizophrenia treatment: results of a one-year randomized controlled trial of olanzapine and quetiapine.

BACKGROUND: Cognitive deficits are recognized as a critical determinant of functional outcomes in schizophrenia; and second generation antipsychotic drugs have been touted for their potential to enhance cognitive functioning and community tenure. OBJECTIVES: The study examined the relative merits of olanzapine and quetiapine in improving cognitive deficits and enhancing psychosocial functioning in a sample of community dwelling adults previously treated with first generation antipsychotic drugs for schizophrenia. METHODS: In a prospective, rater-blinded study, 86 participants were randomized to receive either olanzapine or quetiapine, and assessed at baseline and after 3, 6, 9 and 12 months. Outcome measures included, besides symptoms and side effects rating scales, the subjective scale to investigate cognition in schizophrenia (SSTICS), a computer-assisted cognitive test battery (COGLAB), the sickness impact profile (SIP), the global assessment of functioning (GAF) scale, and the drug attitude inventory (DAI). RESULTS: Both olanzapine and quetiapine were equally effective in improving symptom severity and decreasing the neurological side effects. Quetiapine was significantly better tolerated (p=0.002), improved self-rated cognitive dysfunction (p=0.002) and subjects' performance on selected neurocognitive tasks (p=0.01). Olanzapine use was associated with greater symptom stability, fewer drop outs (p=0.01) and frequent metabolic aberrations (p=0.001). The accrued benefits of drug therapy, however, were not reflected as significant gains in daily functioning and quality of life. CONCLUSIONS: Quetiapine is noted to have specific cognition enhancing properties in schizophrenia that warrants further exploration. The observed clinical and cognitive benefits associated with quetiapine may likely be attributable to its loose binding to, and fast dissociation from the dopamine receptors. Olanzapine has proved to be a reliable antipsychotic drug with a greater liability to cause metabolic abnormalities.

Dysglycemia in a community sample of people treated for schizophrenia: the Diabetes in Schizophrenia in Central-South Ontario (DiSCO) study.

OBJECTIVE: Despite increasing recognition of schizophrenia as a risk factor for diabetes, the prevalence and correlates of dysglycemia in people with schizophrenia have not been adequately studied. Discerning the modifiable risk factors is crucial for developing diabetes prevention strategies in schizophrenia. METHODS: Socio-demographic, clinical and recent laboratory data were compiled from the case records and supplemental sources of 1123 people treated for schizophrenia who were living across five different communities in the region. RESULTS: Screening rates for fasting plasma glucose (FPG) varied between 63-100% across the five communities, while other metabolic indices were monitored less frequently. 39 subjects (3.5%) in the sample had an existing diagnosis of type 2 diabetes. Among the others, 845 (78%) had FPG measured in the preceding 6 months, with the following results: FPG < or = 5.6 mmol/l in 474 (56%), 5.6-6.9 mmol/l in 268 (31%), and > or = 7 mmol/l in 103 (12.2%) subjects. Dysglycemia (FPG > or = 5.6 mmol/l) was significantly associated with older age (odds ratio [OR] 1.031), longer duration of schizophrenia (OR 1.062), self reported family history of diabetes (OR 8.87), body mass index (OR 1.081), excess weight (OR 1.014) and independent living status (OR 1.779), while European ethnicity (OR 0.706) and regular physical activity (OR 0.958) lowered the risk. No statistically significant correlations were noted with gender, level of education or functioning, or the type of antipsychotic drug prescribed. CONCLUSIONS: There was a two-fold increase in the prevalence of dysglycemia, while there was a substantial under-recognition of and intervention for, diabetes and pre-diabetes in this sample of people treated for schizophrenia.

Symptoms and cognition as predictors of community functioning: a prospective analysis.

OBJECTIVE: It has been suggested that level of cognitive functioning as assessed by formal neurocognitive tests may be as important as, or even more important than, symptoms in predicting level of community functioning for patients with schizophrenia. The results of past prospective studies, when carefully examined, do not consistently support this hypothesis. In the current study, the authors used symptom and neurocognitive data to predict subsequent level of functioning in the community. METHOD: Neurocognitive and symptom data collected as part of an earlier study were used to predict the community functioning of 50 patients with a diagnosis of 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 performance. RESULTS: Symptoms were more predictive of community functioning than were neurocognitive measures. Disorganization symptoms were generally more predictive of community functioning than was either psychomotor poverty or reality distortion. CONCLUSIONS: The results of this study and of previous longitudinal studies suggest the importance of using symptom levels after optimal treatment, rather than symptoms during acute episodes, as predictors of community functioning. They also indicate the need to evaluate the effects of treatment on disorganization as a separable dimension of symptoms.

Subjective effects of AMPT-induced dopamine depletion in schizophrenia: correlation between dysphoric responses and striatal D(2) 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 (D(2)) function with (123)IBZM-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 D(2) 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.

Cost-utility analysis in schizophrenia.

Estimation of quality of life is important to the study of the pharmacoeconomics of schizophrenia. The subject has gained popularity among policymakers, clinicians, and patients and their families, since the advent of new antipsychotic medications that are more expensive than older drugs yet have been shown to cause fewer side effects. Quantifying quality of life has been difficult, since studies often inconsistently define the concept or use rating scales that are inappropriate for the patient population. Utility analysis is a procedure that calculates subjects' preferences regarding living with various health states, given such options as trading more years of life at a lowered health state for dying sooner but having a strong health state during the last years of life. The feasibility of performing utility analysis among patients with schizophrenia was recently examined in a study carried out by the authors. This article reflects initial observations from that study of utility analysis and includes a discussion of problems still facing the study of quality of life and utility analysis.

Neuroleptic dysphoria: towards a new synthesis.

RATIONALE: Neuroleptic dysphoria (ND) is a subtle and under-recognized side effect of antipsychotic drugs. It is an all-inclusive descriptive phrase that encompasses a variety of unpleasant subjective changes in arousal, mood, thinking and motivation induced by neuroleptic drugs. Understanding this phenomenon has wide ranging clinical and research implications. OBJECTIVE: The present review examined the themes identified in the original studies from the neuroleptic era in the light of recent findings from neuroimaging research, cumulative experience with second generation antipsychotic drugs, and new concepts such as pleasure responsivity, hedonic regulation and subjective tolerability. METHODS: Empirical studies on neuroleptic drugs involving clinical populations treated for schizophrenia, Tourette's disorder and stuttering, studies performed on normal healthy volunteers and selected experimental studies in animals, are reviewed. RESULTS: Dysphoric responses occur early during treatment and typically manifest as a dislike towards medication (drug aversiveness). Dysphoria persisting over time, may lead to adverse clinical consequences such as treatment non-adherence, substance abuse, poor clinical outcome, increased suicidality and compromised quality of life. Interference with the physiological processes of hedonic capacity by the neuroleptics due to their dopaminergic blocking action in the prefrontal cortex and the shell of nucleus accumbens is the putative mediating mechanism underlying the occurrence of dysphoric responses. Second generation antipsychotic drugs with an atypical receptor blocking profile are less likely to elicit dysphoric responses. CONCLUSION: Viewing neuroleptic dysphoria within a broader spectrum of disorders of subjective tolerability and exploring its neurobiological mechanisms is relevant to addressing the nuances of antipsychotic therapy, and could help unravel the questions surrounding the pathophysiology of depression, substance abuse and other dysphoric clinical states.

Comparative evaluation of conventional and novel antipsychotic drugs with reference to their subjective tolerability, side-effect profile and impact on quality of life.

This study compared the effectiveness of conventional and novel antipsychotic drugs from a patient's perspective. Five comparable groups of schizophrenic patients (n=230) clinically stabilized on conventional antipsychotic drugs, risperidone, olanzepine, quetiapine or clozapine for a period of 6months or longer were cross-sectionally evaluated. Patients' clinical symptom profile, subjective responses and attitudes toward drugs, prevalence of dysphoria, akathisia, abnormal involuntary movements and Parkinsonian symptoms, and quality of life were ascertained using standardized rating scales. Between-group differences were examined with analysis of variance and chi-square tests. Patients receiving novel antipsychotic drugs experienced fewer side-effects, reported positive subjective responses and favourable attitudes toward their treatment, and revealed a lower prevalence of neuroleptic dysphoria. The differences were statistically significant (p<0.05) with the risperidone, olanzepine and quetiapine groups. Self-rated quality of life, measured with the sickness impact profile, was also significantly better among patients receiving novel antipsychotic drugs. These perceived benefits, however, were not reflected in the clinician rated (objective) measures of psychosocial functioning and quality of life. These findings substantiate the general notion that novel antipsychotic medications are uniformly better tolerated as indicated by the measures of subjective responses, side-effects and self rated quality of life.

Switching from conventional to novel antipsychotic drugs: results of a prospective naturalistic study.

OBJECTIVE: We examined the long-term consequences of switching patients from conventional to novel antipsychotic drugs, from a patient's perspective. METHODS: In a prospective, single-blinded, naturalistic study, a cohort of subjects (n=150) with schizophrenia or schizo-affective disorder (DSM-IV) were switched from conventional neuroleptic drugs to either risperidone (n=50), olanzepine (n=50) or quetiapine (n=50), and monitored for a period of 2 to 6 years. The ensuing natural history of transitions in treatments was charted, and the outcomes including symptoms, side effects, subjective tolerability of drugs and their impact on quality of life were documented with standardized rating scales. RESULTS: Majority (85%) of the subjects benefited from a switch to the novel antipsychotic drugs, though some preferred to return to their original neuroleptic (8%), and others eventually required clozapine (7%) therapy. Novel antipsychotic drugs were significantly tolerated better, and had a positive impact on treatment-adherence, psychosocial functioning and quality of life. Among the novel drugs, risperidone was significantly better in improving negative symptoms, while olanzepine was particularly well tolerated and effective against comorbid anxiety and depressive symptoms. Patients treated with quetiapine reported fewer side effects, and showed a significantly greater improvement in neurocognitive deficits. CONCLUSION: Novel antipsychotics emerged as the drug of choice in view of their overall effectiveness, though conventional neuroleptics and clozapine will continue to have a limited but distinct role in the management of schizophrenia. The challenge for clinicians lies in matching a patient's clinical and biochemical profile with that of a drug's pharmacological actions, in order to achieve optimum outcomes.

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.

An evaluation of a stress management program for individuals with schizophrenia.

Vulnerability-stress models suggest that training in specific stress management techniques should yield benefits to those suffering from schizophrenia and related disorders. In this paper, we describe an evaluation of the impact of adding a stress management program to other medical and psychosocial interventions for such patients. Outcomes were compared for 121 patients randomly assigned to receive either a 12-week stress management program with follow-up sessions or participation in a social activities group. The two treatment conditions did not differ in levels of symptoms, perceived stress or life skills immediately after completion of treatment or at 1-year follow-up. Patients who received the stress management program did have fewer hospital admissions in the year following treatment. This effect of stress management was most apparent for those who showed high levels of attendance for treatment sessions. It was concluded that training in stress management may provide patients with skills for coping with acute stressors and reduce the likelihood of subsequent acute exacerbation of symptoms with need for hospitalization.

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.

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.

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.

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.

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.

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.

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.

Psychiatric emergency rates during the Christmas season in the years 1991 to 1997.

We compared the number of psychiatric admissions from the emergency room during the Christmas season, defined as the rate for the month of December, with those in other months. The psychiatric emergency rates were recorded for each month over six consecutive years, 1991 to 1997. The average number of emergency patients in none of the 12 months differed significantly from any of the remaining months (ANOVA, p > .05). Our data and those of other authors do not support the clinical lore that Christmas season is associated with higher rate of psychiatric emergencies.

Brain imaging research on subjective responses to psychotropic drugs.

OBJECTIVE: Neuroimaging studies on subjective responses to psychotropic drugs in humans were reviewed to examine progress in the field and identify gaps in knowledge. METHOD: An exhaustive search of computerized databases identified two categories of in vivo imaging studies: i) correlates of negative(dysphoric) subjective responses to neuroleptic use in schizophrenia, and ii) research on positive (euphoric) subjective responses, mostly from substance abuse population. RESULTS: Research has been largely confined to neurochemical imaging of dopamine in the striatal complex, confirming earlier speculations that impaired or deficient dopaminergic function is associated with dysphoric responses, and enhanced activity is associated with euphoric or pleasurable responses. Cerebral blood flow, regional metabolic rate and glucose utilization studies provided preliminary clues to the putative neuroanatomical sites. CONCLUSION: Neuroimaging techniques added credibility to the study of subjective responses; however, further studies are required to identify the underlying anatomical and neurochemical interactions in order to enhance their applied value.

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.