Long-term Outcome Of Depression Research Articles

Distinct predictors of short- versus long-term depression outcomes following electroconvulsive therapy

Patients and clinicians considering electroconvulsive therapy (ECT) for treatment-resistant depression are faced with limited information about the likely long-term outcomes, and the individual characteristics that predict those outcomes. We aimed to identify sociodemographic and clinical predictors of acute ECT response and subsequent long-term depression severity. This prospective longitudinal study followed adult patients at a single academic ECT center. Among 114 participants, 105 completed an index ECT series and 70 were classified as acute ECT responders. Over a 2-year follow-up period, 82 subjects provided data on depression severity (Patient Health Questionnaire; PHQ-9). Better acute ECT response was predicted by less medication resistance, shorter index episode, and psychotic features (p < 0.05). PHQ-9 scores during the two-year follow-up period improved from baseline at all time points (p < 0.000001) but individual scores varied widely. Lower long-term PHQ-9 scores were predicted by better acute therapeutic response to ECT (p = 0.004) but not by ECT adverse effects (p > 0.05). Married status and greater baseline clinician-rated severity were not associated with acute ECT response but those variables did predict lower PHQ-9 scores longitudinally (p < 0.001), independent of other baseline features, initial ECT response, or intensity of ongoing treatment. These findings confirm previously identified predictors of short-term ECT response and demonstrate that distinct individual characteristics predict long-term depression outcomes. An individual's social context appears to strongly influence long-term but not short-term outcomes, suggesting a potential target for post-ECT therapeutic interventions.

Comparing the associations of three psychometric scales at baseline with long-term prognosis of depression over a 10-year period.

ObjectiveThe Depression and Somatic Symptoms Scale (DSSS), a free scale, includes depression (DS) and somatic (SS) subscales. This study aimed to compare the associations of the baseline DSSS, Hamilton Depression Rating Scale (HAMD) and Hospital Anxiety and Depression Scale (HADS) scores with the outcome of depression over a 10‐year follow‐up period.MethodsTwo hundred ninety outpatients with major depressive disorder (MDD) were enrolled and were followed‐up at the 6‐month, 2‐year, and 10‐year points. The three scales were administered at each follow‐up. Multiple linear regressions were used to compare the associations.ResultsIn a comparison of the HAMD, DS, and HADS‐depression, the HAMD and DS scores at baseline were most strongly associated with the HAMD score at two (6‐month and 2‐year) and one (10‐year) follow‐up points, respectively. In a comparison of the HAMD, DS, SS, HADS‐depression, and HADS‐anxiety, the SS and HAMD scores at baseline were most strongly associated with the HAMD score at two (6‐month and 10‐year) and one (2‐year) follow‐up points, respectively.ConclusionsThe DS, SS, and HAMD scores at baseline were significantly associated with the long‐term outcome of depression. Scales or subscales assessing somatic symptoms might be more strongly associated with the outcome of depression.

Does Symptom Linkage Density Predict Outcomes in Cognitive Therapy for Recurrent Depression?

Acute-phase cognitive therapy (CT) is an efficacious treatment for major depressive disorder (MDD), but how CT helps patients is incompletely understood. As a potential means to clarify CT mechanisms, we defined "symptom linkage density" (SLD) as a patient's mean time-lagged correlation among nine depressive symptoms across 13 weekly assessments. We hypothesized that patients with higher SLD during CT have better outcomes (treatment response, and fewer symptoms after response), and we explored whether SLD correlated with other possible CT processes (growth in social adjustment and CT skills). Data were drawn from two clinical trials of CT for adult outpatients with recurrent MDD (primary sample n = 475, replication sample n = 146). In both samples, patients and clinicians completed measures of depressive symptoms and social adjustment repeatedly during CT. In the primary sample, patients and cognitive therapists rated patients' CT skills. After CT, responders were assessed for 32 (primary sample) or 24 (replication sample) additional months to measure long-term depression outcomes. Higher SLD predicted increases in social adjustment (both samples) and CT skills (primary sample) during CT, CT response (both samples), and lower MDD severity for at least 2 years after CT response (both samples). Analyses controlled patient-level symptom means and variability to estimate SLD's incremental predictive validity. These novel findings from two independent samples with longitudinal follow-up require further replication and extension. SLD may reflect or facilitate generalization of CT skills, improvement in social functioning, or other processes responsible for CT's shorter and longer term benefits.

Precision medicine for long-term depression outcomes using the Personalized Advantage Index approach: cognitive therapy or interpersonal psychotherapy?

Psychotherapies for depression are equally effective on average, but individual responses vary widely. Outcomes can be improved by optimizing treatment selection using multivariate prediction models. A promising approach is the Personalized Advantage Index (PAI) that predicts the optimal treatment for a given individual and the magnitude of the advantage. The current study aimed to extend the PAI to long-term depression outcomes after acute-phase psychotherapy. Data come from a randomized trial comparing cognitive therapy (CT, n = 76) and interpersonal psychotherapy (IPT, n = 75) for major depressive disorder (MDD). Primary outcome was depression severity, as assessed by the BDI-II, during 17-month follow-up. First, predictors and moderators were selected from 38 pre-treatment variables using a two-step machine learning approach. Second, predictors and moderators were combined into a final model, from which PAI predictions were computed with cross-validation. Long-term PAI predictions were then compared to actual follow-up outcomes and post-treatment PAI predictions. One predictor (parental alcohol abuse) and two moderators (recent life events; childhood maltreatment) were identified. Individuals assigned to their PAI-indicated treatment had lower follow-up depression severity compared to those assigned to their PAI-non-indicated treatment. This difference was significant in two subsets of the overall sample: those whose PAI score was in the upper 60%, and those whose PAI indicated CT, irrespective of magnitude. Long-term predictions did not overlap substantially with predictions for acute benefit. If replicated, long-term PAI predictions could enhance precision medicine by selecting the optimal treatment for a given depressed individual over the long term.

Treating insomnia in depression: Insomnia related factors predict long-term depression trajectories.

Insomnia and major depressive disorders (MDD) often co-occur, and such comorbidity has been associated with poorer outcomes for both conditions. However, individual differences in depressive symptom trajectories during and after treatment are poorly understood in comorbid insomnia and depression. This study explored the heterogeneity in long-term depression change trajectories, and examined their correlates, particularly insomnia-related characteristics. Participants were 148 adults (age M ± SD = 46.6 ± 12.6, 73.0% female) with insomnia and MDD who received antidepressant pharmacotherapy, and were randomized to 7-session Cognitive Behavioral Therapy for Insomnia or control conditions over 16 weeks with 2-year follow-ups. Depression and insomnia severity were assessed at baseline, biweekly during treatment, and every 4 months thereafter. Sleep effort and beliefs about sleep were also assessed. Growth mixture modeling revealed three trajectories: (a) Partial-Responders (68.9%) had moderate symptom reduction during early treatment (p value < .001) and maintained mild depression during follow-ups. (b) Initial-Responders (17.6%) had marked symptom reduction during treatment (p values < .001) and low depression severity at posttreatment, but increased severity over follow-up (p value < .001). (c) Optimal-Responders (13.5%) achieved most gains during early treatment (p value < .001), continued to improve (p value < .01) and maintained minimal depression during follow-ups. The classes did not differ significantly on baseline measures or treatment received, but differed on insomnia-related measures after treatment began (p values < .05): Optimal-Responders consistently endorsed the lowest insomnia severity, sleep effort, and unhelpful beliefs about sleep. Three depression symptom trajectories were observed among patients with comorbid insomnia and MDD. These trajectories were associated with insomnia-related constructs after commencing treatment. Early changes in insomnia characteristics may predict long-term depression outcomes. (PsycINFO Database Record

Self-Rated Health and Long-Term Prognosis of Depression

Indicators of prognosis should be considered to fully inform clinical decision making in the treatment of depression. This study examines whether self-rated health predicts long-term depression outcomes in primary care. Our analysis was based on the first 5 years of a prospective 10-year cohort study underway since January 2005 conducted in 30 randomly selected Australian primary care practices. Participants were 789 adult patients with a history of depressive symptoms. Main outcome measures include risks, risk differences, and risk ratios of major depressive syndrome (MDS) on the Patient Health Questionnaire. Retention rates during the 5 years were 660 (84%), 586 (74%), 560 (71%), 533 (68%), and 517 (66%). At baseline, MDS was present in 27% (95% CI, 23%-30%). Cross-sectional analysis of baseline data showed participants reporting poor or fair self-rated health had greater odds of chronic illness, MDS, and lower socioeconomic status than those reporting good to excellent self-rated health. For participants rating their health as poor to fair compared with those rating it good to excellent, risk ratios of MDS were 2.10 (95% CI, 1.60-2.76), 2.38 (95% CI, 1.77-3.20), 2.22 (95% CI, 1.70-2.89), 1.73 (95% CI, 1.30-2.28), and 2.15 (95% CI, 1.59-2.90) at 1, 2, 3, 4, and 5 years, after accounting for missing data using multiple imputation. After adjusting for age, sex, multimorbidity, and depression status and severity, self-rated health remained a predictor of MDS up to 5 years. Self-rated health offers family physicians an efficient and simple way to identify patients at risk of poor long-term depression outcomes and to inform therapeutic decision making.

Early reduction in painful physical symptoms is associated with improvements in long-term depression outcomes in patients treated with duloxetine

BackgroundTo investigate the association of the change of painful physical symptoms (PPS) after 4 weeks, with the 6-month treatment outcomes of depressive symptoms in patients treated with duloxetine in clinical practice.MethodsMulticenter, prospective, 6-month, non-interventional study in adult outpatients with a depressive episode and starting treatment with duloxetine. Depression severity was assessed by the clinician (Inventory for Depressive Symptomatology [IDS-C]) and patient (Kurz-Skala Stimmung/Aktivierung [KUSTA]). Somatic symptoms and PPS were assessed using the patient-rated Somatic Symptom Inventory (SSI) and visual analog scales (VAS) for pain items. Association of change in PPS with outcomes of depressive symptoms was analyzed based on mean KUSTA scores (mean of items mood, activity, tension/relaxation, sleep) and achievement of a 50% reduction in the total IDS-C score after 6 months using linear and logistic regression models, respectively.ResultsOf the 4,517 patients enrolled (mean age: 52.2 years, 71.8% female), 3,320 patients (73.5%) completed the study. 80% of the patients had moderate to severe overall pain (VAS > 30 mm) at baseline. A 50% VAS overall pain reduction after 4 weeks was associated with a 13.32 points higher mean KUSTA score after 6 months, and a 50% pain reduction after 2 weeks with a 6.33 points improvement. No unexpected safety signals were detected in this naturalistic study.ConclusionPain reduction after 2 and 4 weeks can be used to estimate outcomes of long-term treatment with duloxetine. PPS associated with depression have a potential role in predicting remission of depressive symptoms in clinical practice.

The long-term trajectory of depression among Latinos in primary care and its relationship to depression care disparities

Objective Lower use of medication treatment, poorer doctor–patient communication (DPC) and depression stigma are key contributors to mental healthcare disparities among Latinos with depression. The current study investigated the relationship between these key variables and the long-term trajectory of depression in primary care among Latinos. Method Participants ( N=220) were Latinos presenting to primary care who screened positive for depression. A repeated measures design was used to assess participants at baseline and 6, 25 and 30 months. Repeated measures included depression (Patient Health Questionnaire-9), self-reported quality of DPC and stigma pertaining to antidepressants. Using growth curve modeling, participants' depressive symptom trajectories were examined for a 30-month period. Self-reported utilization of antidepressants, DPC and antidepressant stigma were examined as predictors of the depressive symptom trajectory. In addition, rates of depression improvement/remission and recurrence/relapse were examined. Results Improvement/remission was experienced by 69.4% of participants during a 30-month period. Among those who improved/remitted at 6 or 25 months, 63.4% maintained that improvement/remission by 30 months. The long-term trajectory of depressive symptoms demonstrated a significant positive association with antidepressant stigma and significant negative associations with use of antidepressant treatment and quality DPC. Conclusions While relapse/recurrence is common, most Latinos in this study experienced improvement in depression over 30 months. For many, there is a considerable time to reach improvement/remission. Also, these findings confirm the significance of antidepressant underutilization, DPC and stigma in the long-term outcome of depression among Latinos in primary care.

Clinical outcomes of an integrated treatment for depression and substance use disorders.

The authors compared longitudinal treatment outcomes for depressed substance-dependent veterans (N = 206) assigned to integrated cognitive-behavioral therapy plus standard pharmacotherapy (ICBT + P) or 12-step facilitation therapy plus standard pharmacotherapy (TSF + P). Drug and alcohol involvement and depressive symptomology were measured at intake and at 3-month intervals during treatment and up to 1 year posttreatment. Participants in both treatment conditions showed decreased depression and substance use from intake. ICBT + P participants maintained improvements in substance involvement over time, whereas TSF + P participants had more rapid increases in use in the months following treatment. Decreases in depressive symptoms were more pronounced for TSF + P than ICBT + P in the 6 months posttreatment. Within both treatment groups, higher attendance was associated with improved substance use and depression outcomes over time. Initial levels of depressive symptomology had a complex predictive relationship with long-term depression outcomes. Early treatment response predicted long-term substance use outcomes for a portion of the sample. Although both treatments were associated with improvements in substance use and depression, ICBT + P may lead to more stable substance use reductions compared with TSF + P.

Expressed emotion, perceived criticism and 10-year outcome of depression

Outcome studies of patients suffering from depression indicate a high relapse rate and a tendency towards chronicity. A family atmosphere characterised by expressed emotion (EE) and perceived criticism (PC) was reported to be a robust predictor of outcome in affective disorders. The aim of the study was to analyze the association between EE, PC and long-term outcome of depression. Fifty inpatients with major depression were followed up 1, 2 and 10 years after discharge from the hospital. After 10 years, 26 patients (56.5%) had at least one recurrence. Spousal EE, assessed with the Five-Minute Speech Sample (FMSS), and the Perceived Criticism Index (PCI) were not significant prognostic factors for depression outcome. The significance of EE and PC for the long-term course of depression has to be questioned. The findings indicate a need to examine factors that may partly mediate the effect of EE and PC on the outcome of depression.

Neuroendocrine and sleep regulation as predictors of illness course and therapy in depression

Background and Aims:In depression, changes in EEG sleep measures are well documented findings. However, the predictive value of these alterations for treatment and long-term course of depression still warrants clarification. Therefore, we examined whether the previous course of depression, treatment response during antidepressant therapy, and the long-term outcome in follow-up are associated with sleep regulation. Since the hypothalamic-pituitary-adrenocortical (HPA) system may play a crucial role in depression's neurobiology, we evaluated HPA system function as well.Methods:15 patients (4 men, 11 women; age 43–59) with depression were enrolled in the study. HPA system assessment using the combined DEX/CRH test and sleep EEG studies were conducted at baseline, after a 6 week antidepressant treatment period (trimipramine), and at follow-up, i.e., after 2-10 years.Results:The previous clinical course, i.e., the number of episodes until baseline, correlated significantly with EEG sleep measures i.e. sleep continuity values, slow wave sleep (SWS) and REM latency.During treatment sleep continuity values improved and the correlation with the previous long-term course disappeared. The correlation with SWS persisted. The only sleep EEG marker at baseline predictive for treatment response was REM latency.In the prospective long-term outcome SWS and REM density variables were related to the occurrence of recurrences. These sleep EEG markers correlated closely with HPA system regulation.Conclusions:The long-term outcome of depression is related to the sleep EEG pattern: SWS and REM density measures may reflect predictive markers for the long-term course. These markers are associated with HPA system regulation.

Dex/CRH-test response and sleep in depressed patients and healthy controls with and without vulnerability for affective disorders

Sleep electroencephalographic (EEG) abnormalities and increased hypothalamo–pituitary–adrenal (HPA) axis activity are the most prominent neurobiological findings in depression and were suggested as potential biomarker for depression. In particular, increased rapid eye movement sleep (REM) density, deficit in slow wave sleep and excessive stress hormone response are associated with an unfavorable long-term outcome of depression. Recent studies indicate that the sleep and endocrine parameters are related to each other. This study investigated the association of sleep structure including a quantitative EEG analysis with the results of the combined dexamethasone (Dex)/corticotropin-releasing hormone (CRH)-test in 14 patients with a severe major depression, 21 healthy probands with a positive family history of depression (HRPs) and 12 healthy control subjects without personal and family history for psychiatric disorders. As expected patients with depression showed an overactivity of the HPA axis, disturbed sleep continuity and prolonged latency until slow wave sleep in the first sleep cycle. Differences in microarchitecture of sleep were less prominent and restricted to a higher NonREM sigma power in the HRP group. Dexamethasone suppressed cortisol levels were positively associated with higher NonREM sigma power after merging the three groups. We also observed an inverse association between the ACTH response to the Dex/CRH-test and rapid eye movement sleep (REM) density in HRPs, with suggestive evidence also in patients, but not in controls. This contra-intuitive finding might be a result of the subject selection (unaffected HRPs, severely depressed patients) and the complementarity of the two markers. HRPs and patients with high disease vulnerability, indicated by an elevated REM density, seem to have a lower threshold until an actual disease process affecting the HPA axis translates into depression, and vice versa. To summarize, our findings provide further evidence that the HPA axis is involved in the sleep regulation in depression. These associations, however, are not unidimensional, but dependent on the kind of sleep parameters as well as on the selection of the subjects.

A System-Based Approach to Depression Management in Primary Care Using the Patient Health Questionnaire-9

Primary care physicians are more likely to see patients with depression than with any other disorder except hypertension, and its management poses a challenge to busy primary care practices. The Patient Health Questionnaire-9, a simple self-administered tool of proven validity and reliability, is a commonly used screening instrument for depression in primary care practice. This review article provides a system-based approach to depression management using the Patient Health Questionnaire-9 to guide clinicians in the identification and treatment of depression and its follow-up care.

Improving long-term outcome of depression in primary care: a review of RCTs with psychological and supportive interventions

Background and objectives: Depression is often a recurrent or persistent disorder. Since the majority of depressed patients are treated in primary care, it is clear that to improve long-term outcomes more effective treatments in this setting are needed. The goal of this study was to review the strategies used for improvement of routine treatment in terms of their effects on patient outcome. Methods: We conducted a systematic literature search to identify improvement strategies tested in randomized controlled trials in primary care, reporting at least six months effects on depression course and outcome. Results: Four strategies were identified: (1) training primary care physicians (PCPs) - this appears ineffective (2) supporting PCPs by other professionals - this produces better short term outcomes but does not prevent recurrence (3) organisational quality improvement - this shows improved outcomes at 6 months, and there is some evidence of longer term effectiveness; and (4) recurrence - and chronicity prevention strategies - these have not been shown to be effective. Conclusion: Since effects of the reviewed strategies generally do not seem to persist over time and no clear superiority over usual care has been demonstrated, we conclude that for improving long-term outcome of depression in primary care new directions or even a novel paradigm is needed.

Depression Outcomes and Quality of Postdischarge Care of Elders Hospitalized for Major Depression

Depression Outcomes and Quality of Postdischarge Care of Elders Hospitalized for Major Depression

Cognitive Impairment and Depression Outcomes in the IMPACT Study

It is unclear whether cognitive impairment affects acute and long-term treatment response in geriatric depression. In addition, little is known about the long-term outcome of depression among older individuals who experience cognitive decline during a course of treatment for depression. The authors examined both of these issues using data from the IMPACT trial. The sample consisted of 1,684 participants in the IMPACT study who had baseline and two-year follow-up data. Subjects were randomized to one year of active intervention with a depression care manager or usual care. After one year, all subjects had usual care for another year. Data were collected for two years. The authors used the Six-Item Cognitive Screener to examine acute and long-term effects on depression outcome of baseline cognitive impairment and of cognitive decline. Depression measures included the HSCL-20 and an estimation of depression-free days. Outcomes were determined using both linear regression and repeated-measures analyses. Depressed subjects in the active intervention group had better depression outcomes at one year regardless of baseline cognitive impairment. Cognitively impaired subjects within each treatment group had similar outcomes to subjects without cognitive impairment. Subjects who experienced decline in cognitive score over two years had worse 24-month depression outcomes compared with subjects whose cognitive score did not change. Cognitively impaired depressed patients can experience significant improvement in depression with appropriate acute and continuation-phase management. Older depressed adults experiencing ongoing cognitive decline may be at higher risk for poor depression outcomes and may require more careful clinical monitoring and management of both cognitive and affective symptoms.

The Importance of Longitudinal Studies in Family Medicine: Experiences of Two Practice-based Research Networks

For evidence-based decision making in family practice, it is essential to know the long-term (natural) course of common diseases and their outcomes under care and treatment. This article, based on a research methodology workshop, aims to raise awareness and interest in longitudinal research in practice-based research networks (PBRNs) among family physicians (FP) and researchers, and to elucidate a number of broad principles that apply to longitudinal research in such settings. A workshop discussion of PBRN experts, based on 2 examples of PBRN-based longitudinal studies, focusing on the general methodological principles was held in March 2005 in Colorado Springs, CO. The first study, conducted in a historic cohort, documented long-term outcome of depression in 386 patients in family practice. The second study analyzed consequences of age-associated peripheral neuropathy in a concurrent follow-up study design. It was possible to prospectively follow a cohort of 604 healthy subjects enrolled in the practices by research nurses. Discussion at the workshop was generated around the following methodological topics: study designs, recruitment, retention and tracking of participants, dealing with changes in diagnostic and treatment of standards over time, informed consent, data analysis, and funding issues. The workshop concluded that, although there are many obstacles to be overcome when conducting longitudinal studies in practice settings, the benefits for our discipline could be substantial. Concurrent and historic cohorts each have advantages and disadvantages. Although tracking patients (and physicians) over time is a challenge, periodic rewards enhance recruitment and retention. Informed consent is critical although ethical requirements may change. Use of standard well-defined definitions promotes consistency of data collection over time, as does training of FPs and staff. Data analysis has become both easier and more sophisticated, and statistical assistance is advised from the outset. Funding remains a challenge, but costs need not be prohibitive. Given its importance, PBRNs should be encouraged to develop methods of long-term data collection on cohorts of patients followed by primary care physicians.

Remission and recurrence of depression in the maintenance era: long-term outcome in a Cambridge cohort.

Long-term studies of severe depression have described high rates of non-recovery, recurrence, chronic incapacity and mortality. A more recent cohort was followed-up to ascertain whether the course had improved given developments in pharmacological and psychological treatments in the last 15 years. Subjects from a cohort of 70 mainly severe recurrent depressives originally recruited to a shorter follow-up study from 1990-1992 were followed-up after 8-11 years. Data included longitudinal information on course of depression and other psychiatric disorders, pharmacological and psychological treatment and social functioning during follow-up. Sixty-nine (99%) subjects were successfully followed-up, with 61 of 66 living subjects interviewed and detailed follow-up data obtained in total on 65. Sixty (92%) of 65 subjects recovered during follow-up, with two-thirds subsequently suffering a recurrence. Eleven (17%) suffered from an episode of chronic depression of at least 2 years duration during follow-up. Social function at follow-up was good and there were high levels of pharmacological and psychological treatment. Greater severity of illness was the most consistent predictor of poor outcome. Times to recovery and recurrence and recovery and recurrence rates were very similar to older studies. The long-term outcome of depression still shows high recurrence rates and does not appear to have changed in the last 20 years.

HIGHLIGHTS IN THIS ISSUE

This issue features groups of papers on genetics, long-term outcome of depression, fatigue syndromes and somatization, and the neuropsychology of schizophrenia, autism and obsessive–compulsive disorder.

Residual symptoms in depression: can treatment be symptom-specific?

Most patients with depression continue to have symptoms after treatment. It is well documented that these "residual" symptoms are common and are associated with increases in suboptimal long-term outcomes such as relapse and disability. While it is clear that residual symptoms, as a group, contribute to poor outcomes, individual residual symptoms have received relatively little attention. To some extent, this lack of attention reflects an uncertainty in the field about the relationship of the syndrome of depression to the symptoms by which the syndrome is defined. Recognizing that for clinicians and patients symptom relief is the goal of treatment, this article reviews the evidence that a symptomatic approach to individual residual symptoms is both feasible and useful. Evidence was gathered through a MEDLINE review of articles published in English from 1966 to 2002. Multiple keywords relating to symptoms, depression, and treatment were used. Many of the agents that psychiatrists use for augmentation of depression treatment, such as psychostimulants and alerting agents, atypical antipsychotics and mood stabilizers, and buspirone and benzodiazepines, have specific symptomatic effects, which raises the question of whether we are augmenting the core antidepressant effect or providing symptomatic relief. Fatigue, anxiety, sexual dysfunction, and sleep disturbances are all symptoms that are commonly leftover after treatment of depression. Some data indicate that treatment of these residual symptoms is efficacious and may affect the long-term outcome of depression. This discussion of the treatment of residual depressive symptoms raises a variety of research questions that should be addressed. Also implicit in this discussion are theoretical questions on the relationship between symptoms and syndrome.