Pre-onset sub-threshold psychotic symptoms and cortical organization in the first episode of psychosis.

Individuals with sub-threshold psychotic symptoms (STPS) are considered at clinical high risk for psychosis (CHR). Imaging studies comparing CHR and patients shortly after a first episode of psychosis (FEP) support progressive cortical thinning by illness stage. However, at least 30% of FEP patients deny pre-onset STPS, suggesting no history of CHR. This calls into question the generalizability of previous imaging findings. To better understand the physiology of early psychosis symptomology, we investigated the relationship between pre-onset STPS and cortical thickness (CT) among FEP patients, examining regional CT and structural covariance (SC). Patients (N = 93) were recruited from PEPP-Montreal, a FEP clinic at the Douglas Mental Health University Institute. The Circumstances of Onset and Relapse Schedule was administered to retrospectively identify patients who recalled at least one of nine expert-selected STPS prior to their FEP (STPS+, N = 67) and to identify those who did not (STPS-, N = 26). Age and sex-matched healthy controls (HC) were recruited (N = 84) for comparison. Participants were scanned between one and three times over the course of two years. CT values of 320 scans (143 HC, 123 STPS+, 54 STPS-) that passed quality control were extracted for group analysis. Linear mixed effects models accounting for effects of age, sex, education, and mean thickness were applied for vertex-wise, group comparisons of cortical thickness and SC. Multiple comparison corrections were applied with Random Field Theory (p-cluster = 0.001). Compared to controls, only STPS- patients exhibited significantly reduced CT in a cluster of the right ventral lateral prefrontal cortex. The vertex with the highest t-statistic within this cluster was employed as a seed in the subsequent SC analysis. After RFT-correction, STPS+ patients exhibited significantly stronger SC between the seed and right pars orbitalis compared to STPS- patients, and HC exhibited significantly stronger SC between the seed and right middle temporal gyrus compared to STPS- patients. Our results revealed patterns of SC that differentiated patient subgroups and patterns of cortical thinning unique to STPS- patients. Our study demonstrates that the early course of sub-threshold psychotic symptoms holds significance in predicting patterns of CT during FEP.

Linking persistent negative symptoms to amygdala-hippocampus structure in first-episode psychosis.

Early persistent negative symptoms (PNS) following a first episode of psychosis (FEP) are linked to poor functional outcome. Reports of reduced amygdalar and hippocampal volumes in early psychosis have not accounted for heterogeneity of symptoms. Age is also seldom considered in this population, a factor that has the potential to uncover symptom-specific maturational biomarkers pertaining to volume and shape changes within the hippocampus and amygdala. T1-weighted volumes were acquired for early (N=21), secondary (N=30), non-(N=44) PNS patients with a FEP, and controls (N=44). Amygdalar-hippocampal volumes and surface area (SA) metrics were extracted with the Multiple Automatically Generated Templates (MAGeT)-Brain algorithm. Linear mixed models were applied to test for a main effect of group and age × group interactions. Early PNS patients had significantly reduced left amygdalar and right hippocampal volumes, as well as similarly lateralized negative age × group interactions compared to secondary PNS patients (P<0.017, corrected). Morphometry revealed decreased SA in early PNS compared with other patient groups in left central amygdala, and in a posterior region when compared with controls. Early and secondary PNS patients had significantly decreased SA as a function of age compared with patients without such symptoms within the right hippocampal tail (P<0.05, corrected). Significant amygdalar-hippocampal changes with age are linked to PNS after a FEP, with converging results from volumetric and morphometric analyses. Differential age trajectories suggest an aberrant maturational process within FEP patients presenting with PNS, which could represent dynamic endophenotypes setting these patients apart from their non-symptomatic peers. Studies are encouraged to parse apart such symptom constructs when examining neuroanatomical changes emerging after a FEP.

Interplay of hippocampal volume and hypothalamus-pituitary-adrenal axis function as markers of stress vulnerability in men at ultra-high risk for psychosis.

BACKGROUND: Altered hypothalamus-pituitary-adrenal (HPA) axis function and reduced hippocampal volume (HV) are established correlates of stress vulnerability. We have previously shown an attenuated cortisol awakening response (CAR) and associations with HV specifically in male first-episode psychosis patients. Findings in individuals at ultra-high risk (UHR) for psychosis regarding these neurobiological markers are inconsistent, and assessment of their interplay, accounting for sex differences, could explain incongruent results. METHOD: Study participants were 42 antipsychotic-naive UHR subjects (24 men) and 46 healthy community controls (23 men). Saliva samples for the assessment of CAR were collected at 0, 30 and 60 min after awakening. HV was determined from high-resolution structural magnetic resonance imaging scans using a semi-automatic segmentation protocol. RESULTS: Cortisol measures and HV were not significantly different between UHR subjects and controls in total, but repeated-measures multivariate regression analyses revealed reduced cortisol levels 60 min after awakening and smaller left HV in male UHR individuals. In UHR participants only, smaller left and right HV was significantly correlated with a smaller total CAR (ρ = 0.42, p = 0.036 and ρ = 0.44, p = 0.029, respectively), corresponding to 18% and 19% of shared variance (medium effect size). CONCLUSIONS: Our findings suggest that HV reduction in individuals at UHR for psychosis is specific to men and linked to reduced post-awakening cortisol concentrations. Abnormalities in the neuroendocrine circuitry modulating stress vulnerability specifically in male UHR subjects might explain increased psychosis risk and disadvantageous illness outcomes in men compared to women.

Transforming youth mental health: a Canadian perspective.

In most mental illnesses, onset occurs before the age of 25 and the earliest stages are critical. The youth bear a large share of the burden of disease associated with mental illnesses. Yet, Canadian youths with mental health difficulties face delayed detection; long waiting lists; inaccessible, unengaging services; abrupt transitions between services; and, especially in remoter regions, even a complete lack of services. Responding to this crisis, the Canadian Institutes of Health Research announced a 5-year grant that was awarded to ACCESS, a pan-Canadian network of youths, families, clinicians, researchers, policymakers, community organisations and Indigenous communities. Using strategies developed collaboratively by all stakeholders, ACCESS will execute a youth mental healthcare transformation via early detection, rapid access and appropriate, high-quality care. The project includes an innovative, mixed-methods service research component. Similar in many respects to other national youth mental health initiatives, ACCESS also exhibits important differences of scale, scope and approach.

The pathways to mental health care of first-episode psychosis patients: a systematic review.

BACKGROUND: Although there is agreement on the association between delay in treatment of psychosis and outcome, less is known regarding the pathways to care of patients suffering from a first psychotic episode. Pathways are complex, involve a diverse range of contacts, and are likely to influence delay in treatment. We conducted a systematic review on the nature and determinants of the pathway to care of patients experiencing a first psychotic episode.MethodWe searched four databases (Medline, HealthStar, EMBASE, PsycINFO) to identify articles published between 1985 and 2009. We manually searched reference lists and relevant journals and used forward citation searching to identify additional articles. Studies were included if they used an observational design to assess the pathways to care of patients with first-episode psychosis (FEP). RESULTS: Included studies (n=30) explored the first contact in the pathway and/or the referral source that led to treatment. In 13 of 21 studies, the first contact for the largest proportion of patients was a physician. However, in nine of 22 studies, the referral source for the greatest proportion of patients was emergency services. We did not find consistent results across the studies that explored the sex, socio-economic, and/or ethnic determinants of the pathway, or the impact of the pathway to care on treatment delay. CONCLUSIONS: Additional research is needed to understand the help-seeking behavior of patients experiencing a first-episode of psychosis, service response to such contacts, and the determinants of the pathways to mental health care, to inform the provision of mental health services.

Signs and symptoms in the pre-psychotic phase: description and implications for diagnostic trajectories.

BACKGROUND: Few studies have examined the underlying factor structure of signs and symptoms occurring before the first psychotic episode. Our objective was to determine whether factors derived from early signs and symptoms are differentially associated with non-affective versus affective psychosis. METHOD: A principal components factor analysis was performed on early signs and symptoms reported by 128 individuals with first-episode psychosis. Factor scores were examined for their associations with duration of untreated illness, drug abuse prior to onset of psychosis, and diagnosis (schizophrenia versus affective psychosis). RESULTS: Of the 27 early signs and symptoms reported by patients, depression and anxiety were the most frequent. Five factors were identified based on these early signs and symptoms: depression, disorganization/mania, positive symptoms, negative symptoms and social withdrawal. Longer duration of untreated illness was associated with higher levels of depression and social withdrawal. Individuals with a history of drug abuse prior to the onset of psychosis scored higher on pre-psychotic depression and negative symptoms. The two mood-related factors, depression and disorganization/mania, distinguished the eventual first-episode diagnosis of affective psychosis from schizophrenia. Individuals with affective psychosis were also more likely to have a 'mood-related' sign and symptom as their first psychiatric change than individuals later diagnosed with schizophrenia. CONCLUSIONS: Factors derived from early signs and symptoms reported by a full diagnostic spectrum sample of psychosis can have implications for future diagnostic trajectories. The findings are a step forward in the process of understanding and characterizing clinically important phenomena to be observed prior to the onset of psychosis.

Premorbid adjustment in first episode schizophrenia and schizoaffective disorders: a comparison of social and academic domains.

OBJECTIVE: Recent evidence suggests that premorbid adjustment in schizophrenia and related disorders can be separated into social and academic domains. In this paper, we examine the correlates of and prognostic significance of social and academic premorbid adjustment in a sample of 113 patients. METHOD: Premorbid adjustment, symptoms and cognitive functioning were assessed at presentation for treatment and symptoms were re-assessed after a year of treatment. RESULTS: Females and those with a diagnosis of schizoaffective disorder were found to have better premorbid adjustment in the academic domain, but not in the social domain. Neurocognitive functioning was more consistently related to academic than social adjustment. Better social and academic premorbid adjustment was correlated with lower negative symptoms after 1 year of treatment, but neither was a significant predictor of positive symptoms. CONCLUSION: Social and academic premorbid adjustments show different relations to gender, specific diagnosis and neurocognitive functioning in schizophrenia and related disorders.

Understanding delay in treatment for first-episode psychosis.

BACKGROUND: A lengthy delay often occurs between the onset of symptoms of psychotic disorders and initiation of adequate treatment. In this paper we examine the extent to which this represents a delay in individuals contacting health professionals or a delay in receiving treatment once such contact is made. METHOD: Pathways to care were examined in 110 patients of the Prevention and Early Intervention Program for Psychosis in London, Canada. Data were collected using structured interviews with patients, family members, consultation with clinicians and review of case records. RESULTS: Family physicians and hospital emergency rooms were prominent components of pathways to care. Both delay to contact with a helping professional and delay from such contact to initiation of adequate treatment appear to be about equally important for the sample as a whole, but some individuals appear to be at risk for particularly lengthy delay in the second component. Individuals with younger age of onset, or who had initial contact with professional helpers before the onset of psychosis and were being seen on an ongoing basis at the time of onset of psychosis, had longer delays from first service contact after onset to initiation of adequate treatment. The greater delay to treatment for those being seen at the onset of psychosis does not appear to reflect differences in age, gender, symptoms, drug use or willingness to take medication. CONCLUSIONS: Interventions to reduce treatment delay should increase the public's awareness of the symptoms of psychotic illness and the need to seek treatment, but of equal importance is the education of service providers to recognize such illness and the potential benefits of earlier intervention.

Determinants of quality of life in first-episode psychosis.

OBJECTIVE: To assess patient and/or illness characteristics associated with aspects of quality of life (QOL) in first-episode psychosis (FEP). METHOD: Patient characteristics, symptom ratings and Wisconsin QOL scale (client version) were assessed. Data were analysed with correlation coefficients and a hierarchical regression analysis. RESULTS: Patients presented with varying levels of QOL on different domains. The level of 'general satisfaction' was related to age of onset and social premorbid adjustment; 'weighted index of QOL' to social premorbid adjustment and inversely to educational premorbid adjustment; 'social relations' inversely to duration of untreated psychosis (DUP), length of prodrome and negative symptoms; 'psychological well-being' inversely to depression and educational premorbid adjustment; 'activities of daily living' to social premorbid adjustment and inversely to negative symptoms; and 'outlook on symptoms' to level of depression. CONCLUSION: Domains of self-rated QOL in FEP patients are differentially associated with malleable and non-malleable aspects of patient and illness characteristics.

Symptoms, cognition, treatment adherence and functional outcome in first-episode psychosis.

BACKGROUND: The differential strength of correlation between symptoms, cognition and other patient characteristics with community functioning in first-episode psychosis has not been fully investigated. METHOD: In a sample of 66 first-episode psychosis patients demographic variables, ratings of pre-morbid adjustment, positive and negative symptoms, duration of untreated psychosis (DUP) and assessment of cognitive functions at baseline, and symptoms, cognitive functions and adherence to medication 1 year, were correlated with scores on social relations and activities of daily living (ADL) (outcome) at 1 year. Hierarchical regression analysis was used to confirm the independent contribution of baseline and concurrent variables to functional outcome at 1 year. RESULTS: Scores on functioning related to social relations and ADL were both significantly correlated with pre-morbid adjustment, all dimensions of residual positive and negative symptoms and adherence to medication at 1 year. Scores on social relations were also modestly correlated with DUP and several cognitive measures at baseline and 1 year (verbal IQ, attention, visual memory, word fluency and working memory). Hierarchical regression confirmed independent contribution of pre-morbid adjustment, total residual symptoms and adherence to medication at 1 year for both dimensions of outcome, and psychomotor poverty and working memory for social relations. CONCLUSIONS: In addition to pre-morbid adjustment potentially malleable variables such as level of residual (but not acute) symptoms, adherence to medication and cognitive deficits are likely to influence outcome on aspects of community functioning in individuals treated for first episode of psychosis.

Cognitive functioning in stabilized first-episode psychosis patients.

This paper describes the cognitive functioning of a community cohort of individuals presenting with a first episode of a schizophrenia spectrum psychosis. Data were obtained for 107 patients (mean age 25 years) following stabilization of acute psychotic symptoms, mostly with the use of novel antipsychotics, on measures of intellectual, memory, attentional and executive functioning using a standardized battery of cognitive measures, including WAIS III and WMS III. While patients generally performed in the average range across the majority of measures, deficits (Z-scores >1.0 S.D.) were observed on measures of speed of information processing (PASAT, WAIS III) and executive functions (Stroop Test and Trails B), with the greatest deficits observed on tests of processing speed (PASAT). Discrepancy scores between the NART and the WAIS suggest subtle but statistically significant declines in full scale and performance IQ following onset of psychosis. Differences in cognitive functioning between diagnostic groups were not supported. Comparison of the highest and lowest functioning patients with respect to the cognitive measures also did not support any demographic or clinical differences between these two subgroups. Our results suggest a relatively benign cognitive profile in first-episode schizophrenia spectrum psychosis, regardless of diagnosis, when most potential incidence cases in the community are included. The most severe deficits reported were on measures of speeded information processing, and level of performance did not distinguish between patients demographically or clinically.

Duration of untreated psychosis and cognitive functioning in first-episode patients.

BACKGROUND: The "toxicity" model of duration of untreated psychosis (DUP) suggests that longer DUP will be associated with poorer performance on cognitive tests in first-episode patients. AIMS: To test this hypothesis on a sample of 113 patients in a community-based early intervention programme for psychosis. METHOD: Information was collected concerning a number of possible predictors of cognitive functioning including DUP. These were examined for their relation to performance on an extensive battery of cognitive tests administered shortly after the patients' admission to the programme. RESULTS: Although several variables such as gender, premorbid adjustment, education and handedness predicted cognitive functioning, no relation was found between DUP and performance on any component of the test battery. CONCLUSIONS: Findings do not provide support for a toxic effect of DUP on cognitive functioning. Other mechanisms through which DUP might affect outcome such as psychological engulfment, social support and adherence to medication are discussed.

Impact of phase-specific treatment of first episode of psychosis on Wisconsin Quality of Life Index (client version).

OBJECTIVE: The objective of this study was to assess the impact of a phase-specific community-focused treatment program on different dimensions of self-reported quality of life in a representative sample of first episode psychosis patients. METHOD: Data were collected on patients presenting with a first episode of psychosis on the Wisconsin Quality of Life Index (client version), positive and negative symptoms, and demographic and clinical variables at baseline following clinical stabilization and at 1 year. RESULTS: Complete data on a representative sample of 41 patients showed a significant improvement in most dimensions of the WQOL at 1 year; these changes were generally independent of changes in symptoms and there were no significant differences in the magnitude of improvement in QOL between those with DUP < or >6 months. CONCLUSION: Patients with a first episode of predominantly schizophrenia spectrum psychosis show a highly significant improvement in subjectively assessed quality of life following a year of phase-specific comprehensive treatment.

Family history of schizophrenia and the relationship of stress to symptoms: preliminary findings.

OBJECTIVE: It has been hypothesized that patients with a diagnosis of schizophrenia who have a positive family history for schizophrenia will show greater reactivity of their symptoms to increasing levels of stress or negative affect than will patients without such a family history. In the past this hypothesis has only been tested through manipulations of negative affect in laboratory settings. In this paper we test this hypothesis using longitudinal clinical data. METHOD: Data were derived from an earlier longitudinal study using monthly assessments of daily stressors (Hassles Scale) and symptom measures (the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms). We compared longitudinal stress to symptom relations in 12 patients with schizophrenia for whom a positive family history of schizophrenia could be identified with 12 matched schizophrenic patients without any known family history of psychiatric illness. RESULTS: There was evidence that patients with a family history of schizophrenia demonstrated a stronger relation between stress and total score on the Scale for the Assessment of Positive Symptoms. This difference appears to have primarily reflected a greater reactivity to stress of reality distortion symptoms in the positive family history group. The two groups did not differ in apparent reactivity to stress of the disorganization and psychomotor poverty dimensions of symptomatology. CONCLUSIONS: The results of this study provide support from a naturalistic, longitudinal clinical study for the hypothesis that reactivity to stress of some symptoms of schizophrenia may vary as a function of family history of the disorder.

A comparison of long-term outcome in first-episode schizophrenia following treatment with risperidone or a typical antipsychotic.

BACKGROUND: Most reports assessing the efficacy and tolerability of risperidone have involved patients previously treated with typical antipsychotics. Such patients are more likely to have a greater resistance or intolerance to treatment, thus restricting our interpretation of the impact a new treatment might have on the course of schizophrenia and possibly biasing the results. The present study examines the relative effectiveness of risperidone and typical antipsychotics in patients being treated for their first episode of schizophrenia. METHOD: From a cohort of 126 patients, 2 groups of 19 first-episode DSM-III-R/DSM-IV schizophrenia patients matched for age, gender, length of illness, and length of treatment and treated with either a typical antipsychotic or risperidone for a minimum of 1 year were compared on a number of outcome dimensions during their course of treatment and at follow-up. Treatment allocation was not random, and patients were judged to be compliant with medication. Patients treated with typical antipsychotics were followed up for a statistically nonsignificantly longer time (mean = 2.7 vs. 1.9 years). RESULTS: Six patients (31.6%) from the typical antipsychotic group were admitted to the hospital within the first year following the index admission compared with 1 patient (5.3%) in the risperidone group (admitted at month 14). Patients in the risperidone group showed a statistically significantly lower length of first hospitalization (p < .01), utilization of inpatient beds during the course of treatment (p < .001), and use of anticholinergic medication (p < .05). There were no statistically significant differences in symptom levels, either during the course of treatment or at follow-up; in the use of antidepressant, antianxiety, or mood-stabilizing drugs; or in changes in living circumstances or employment. CONCLUSION: These findings confirm at least equal long-term efficacy of typical antipsychotics and risperidone, but a possible advantage for risperidone in decreased service utilization and decreased use of anticholinergic drugs.

Duration of untreated psychosis: a critical examination of the concept and its importance.

BACKGROUND: The concept of duration of untreated psychosis (DUP) has recently attracted much interest because of its possible relationship to treatment outcome and implications for preventive efforts with reference to psychotic disorders, especially schizophrenia. In this paper we review critically the literature concerning the concept and its importance. METHODS: Articles concerned with measuring DUP and those that have been suggested to provide indirect or direct evidence of the effect of DUP on treatment outcome are reviewed. RESULTS: Evidence thus far suggests that DUP may be related to ease of reducing psychotic symptoms once treatment begins for first episode patients, but there is no evidence of a relationship to likelihood of relapse. There has been little investigation of the relationship of DUP to other long-term outcomes such as negative symptoms and cognitive functioning neither have the possible confounds of DUP been widely investigated or controlled. CONCLUSIONS: It is important that there should be more thorough investigations of DUP, its correlates, and the extent to which it does mediate any advantages of earlier intervention.

Does sex influence the relation between symptoms and neurocognitive functions in schizophrenia?

OBJECTIVE: A secondary analysis of our data to investigate if sex influences the specificity of the relationship between each of the 3 clinical syndromes (i.e., reality distortion, disorganization and psychomotor poverty) in schizophrenia and the neurocognitive functions that are thought to represent regional brain functions. PATIENTS AND DESIGN: Fifty-seven male and 30 female patients with a DSM-III-R diagnosis of schizophrenia were rated on the Scale for Assessment of Negative Symptoms and the Scale for Assessment of Positive Symptoms to derive scores for psychomotor poverty, disorganization, and reality distortion syndromes. All subjects completed a battery of neuropsychological tests purported to assess functioning of left temporal, right temporal, left basal frontal, right basal frontal, and dorsolateral prefrontal cortex. RESULTS: Correlation coefficients between syndrome scores and neuropsychological measures showed only word fluency (left frontal functioning) to have a statistically significant association with psychomotor poverty in women (p < 0.01). This relation was specific to psychomotor poverty syndrome. No relations between neurocognitive measures and symptoms were seen in men. CONCLUSIONS: The lack of specific relations between symptom dimensions in schizophrenia may be influenced by the fact that the neuronal circuitry associated with particular symptom dimensions may differ in men and women.

The relationship of symptoms and level of functioning in schizophrenia to general wellbeing and the Quality of Life Scale.

OBJECTIVE: Reports suggesting that quality of life in schizophrenia is more highly related to negative rather than positive symptoms are largely based on use of the Quality of Life Scale which was devised to assess deficit symptoms and does not include an assessment of subjective general wellbeing. In the current paper we examined symptoms, level of community functioning as well as living circumstances as correlates of Quality of Life Scale scores and scores on the General Well-Being Scale. METHOD: One hundred and twenty-eight patients completed the General Well-Being Scale and were rated on the Quality of Life Scale as well as scales assessing positive and negative symptoms. RESULTS: While negative symptoms, level of functioning and positive symptoms all were related to the scores on the Quality of Life Scale, General Well-Being Scale scores were primarily related to positive symptoms, particularly reality distortion. CONCLUSION: The results highlight the importance of recognizing the complex nature of the concept of quality of life. They demonstrate that varying indices of quality of life are likely to have different predictors.

Predictors of service use and social conditions in patients with psychotic disorders.

OBJECTIVE: To determine independent predictors of outcome on 3 separate dimensions--namely, relapse and service use, employment, and living conditions--in patients with psychotic disorders. METHOD: One hundred and thirty-four patients, most with a diagnosis of schizophrenia or schizoaffective disorder (94%), were treated and followed up in a comprehensive treatment program with inpatient and community treatment components. Complete data on several predictor and outcome variables were available on 93 patients. Relationships between predictor variables and each dimension of outcome were analyzed using Spearman correlation and multiple regression analysis. RESULTS: Results showed that the use of inpatient resources (days in hospital) during the follow-up period was predicted by days in hospital prior to entry into the program, as was employment status. Although substance abuse was related to employment status, it did not have any predictive value. Better living conditions were predicted by being female and having a later age of onset. CONCLUSIONS: Use of inpatient resources and social dimensions of outcome in schizophrenia may be predicted by different patient- or illness-related variables. These relationships are likely to be modified by the nature and content of treatment received.

Exploring the longitudinal course of psychotic illness: a case-study approach.

OBJECTIVE: Thirty-three patients with a diagnosis of a psychotic disorder (schizophrenia, bipolar disorder, atypical psychosis) according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) were studied to qualitatively assess the longitudinal course of the disorder using a case-study approach. METHODS: Weekly fluctuations in patient symptomatology and overall social and personal functioning using the Global Assessment Scale were assessed following index hospitalization. Patients were followed for 1 year. RESULTS: The emergent courses showed no relationship to diagnosis but followed 3 general trends: 1) positive incline; 2) fluctuating; and 3) stable. Individual representations of each course were examined closely, and biological and psychosocial factors associated with each were evaluated. CONCLUSIONS: The results supported the longitudinal patterns and individual interactions of Strauss's Interactive Developmental Model. The clinical course of psychotic disorders may be represented by 3 patterns. Key factors in the interaction between patient and environment that generate important changes in the evolution of each illness were illustrated.