Modelling the cost-effectiveness of pharmacotherapy compared with cognitive-behavioural therapy and combination therapy for the treatment of moderate to severe depression in the UK.

BACKGROUND: The National Institute of Health and Care Excellence (NICE) in England and Wales recommends the combination of pharmacotherapy and psychotherapy for the treatment of moderate to severe depression. However, the cost-effectiveness analysis on which these recommendations are based has not included psychotherapy as monotherapy as a potential option. For this reason, we aimed to update, augment and refine the existing economic evaluation. METHOD: We constructed a decision analytic model with a 27-month time horizon. We compared pharmacotherapy with cognitive-behavioural therapy (CBT) and combination treatment for moderate to severe depression in secondary care from a healthcare service perspective. We reviewed the literature to identify relevant evidence and, where possible, synthesized evidence from clinical trials in a meta-analysis to inform model parameters. RESULTS: The model suggested that CBT as monotherapy was most likely to be the most cost-effective treatment option above a threshold of £ 22,000 per quality-adjusted life year (QALY). It dominated combination treatment and had an incremental cost-effectiveness ratio of £ 20,039 per QALY compared with pharmacotherapy. There was significant decision uncertainty in the probabilistic and deterministic sensitivity analyses. CONCLUSIONS: Contrary to previous NICE guidance, the results indicated that even for those patients for whom pharmacotherapy is acceptable, CBT as monotherapy may be a cost-effective treatment option. However, this conclusion was based on a limited evidence base, particularly for combination treatment. In addition, this evidence cannot easily be transferred to a primary care setting.

Anxious and non-anxious forms of major depression: familial, personality and symptom characteristics.

BACKGROUND: Earlier clinical studies have suggested consistent differences between anxious and non-anxious depression. The aim of this study was to compare parental pathology, personality and symptom characteristics in three groups of probands from the general population: depression with and without generalized anxiety disorder (GAD) and with other anxiety disorders. Because patients without GAD may have experienced anxious symptoms for up to 5 months, we also considered GAD with a duration of only 1 month to produce a group of depressions largely unaffected by anxiety. METHOD: Depressive and anxiety disorders were assessed in a 10-year prospective longitudinal community and family study using the DSM-IV/M-CIDI. Regression analyses were used to reveal associations between these variables and with personality using two durations of GAD: 6 months (GAD-6) and 1 month (GAD-1). RESULTS: Non-anxious depressives had fewer and less severe depressive symptoms, and higher odds for parents with depression alone, whereas those with anxious depression were associated with higher harm avoidance and had parents with a wider range of disorders, including mania. CONCLUSIONS: Anxious depression is a more severe form of depression than the non-anxious form; this is true even when the symptoms required for an anxiety diagnosis are ignored. Patients with non-anxious depression are different from those with anxious depression in terms of illness severity, family pathology and personality. The association between major depression and bipolar disorder is seen only in anxious forms of depression. Improved knowledge on different forms of depression may provide clues to their differential aetiology, and guide research into the types of treatment that are best suited to each form.

Proposed new diagnoses of anxious depression and bodily stress syndrome in ICD-11-PHC: an international focus group study.

BACKGROUND: The World Health Organization is revising the primary care classification of mental and behavioural disorders for the International Classification of Diseases (ICD-11-Primary Health Care (PHC)) aiming to reduce the disease burden associated with mental disorders among member countries. OBJECTIVE: To explore the opinions of primary care professionals on proposed new diagnostic entities in draft ICD-11-PHC, namely anxious depression and bodily stress syndrome (BSS). METHODS: Qualitative study with focus groups of primary health-care workers, using standard interview schedule after draft ICD-11-PHC criteria for each proposed entity was introduced to the participants. RESULTS: Nine focus groups with 4-15 participants each were held at seven locations: Austria, Brazil, Hong Kong, New Zealand, Pakistan, Tanzania and United Kingdom. There was overwhelming support for the inclusion of anxious depression, which was considered to be very common in primary care settings. However, there were concerns about the 2-week duration of symptoms being too short to make a reliable diagnosis. BSS was considered to be a better term than medically unexplained symptoms but there were disagreements about the diagnostic criteria in the number of symptoms required. CONCLUSION: Anxious depression is well received by primary care professionals, but BSS requires further modification. International field trials will be held to further test these new diagnoses in draft ICD-11-PHC.

The structure of depression, anxiety and somatic symptoms in primary care.

BACKGROUND: Observed co-morbidity among the mood and anxiety disorders has led to the development of increasingly sophisticated dimensional models to represent the common and unique features of these disorders. Patients often present to primary care settings with a complex mixture of anxiety, depression and somatic symptoms. However, relatively little is known about how somatic symptoms fit into existing dimensional models. METHOD: We examined the structure of 91 anxiety, depression and somatic symptoms in a sample of 5433 primary care patients drawn from 14 countries. One-, two- and three-factor lower-order models were considered; higher-order and hierarchical variants were studied for the best-fitting lower-order model. RESULTS: A hierarchical, bifactor model with all symptoms loading simultaneously on a general factor, along with one of three specific anxiety, depression and somatic factors, was the best-fitting model. The general factor accounted for the bulk of symptom variance and was associated with psychosocial dysfunction. Specific depression and somatic symptom factors accounted for meaningful incremental variance in diagnosis and dysfunction, whereas anxiety variance was associated primarily with the general factor. CONCLUSIONS: The results (a) are consistent with previous studies showing the presence and importance of a broad internalizing or distress factor linking diverse emotional disorders, and (b) extend the bounds of internalizing to include somatic complaints with non-physical etiologies.

Insecure attachment and frequent attendance in primary care: a longitudinal cohort study of medically unexplained symptom presentations in ten UK general practices.

BACKGROUND: In primary care frequent attenders with medically unexplained symptoms (MUS) pose a clinical and health resource challenge. We sought to understand these presentations in terms of the doctor-patient relationship, specifically to test the hypothesis that such patients have insecure emotional attachment. METHOD: We undertook a cohort follow-up study of 410 patients with MUS. Baseline questionnaires assessed adult attachment style, psychological distress, beliefs about the symptom, non-specific somatic symptoms, and physical function. A telephone interview following consultation assessed health worry, general practitioner (GP) management and satisfaction with consultation. The main outcome was annual GP consultation rate. RESULTS: Of consecutive attenders, 18% had an MUS. This group had a high mean consultation frequency of 5.24 [95% confidence interval (CI) 4.79-5.69] over the follow-up year. The prevalence of insecure attachment was 28 (95% CI 23-33) %. A significant association was found between insecure attachment style and frequent attendance, even after adjustment for sociodemographic characteristics, presence of chronic physical illness and baseline physical function [odds ratio (OR) 1.96 (95% CI 1.05-3.67)]. The association was particularly strong in those patients who believed that there was a physical cause for their initial MUS [OR 9.52 (95% CI 2.67-33.93)]. A possible model for the relationship between attachment style and frequent attendance is presented. CONCLUSIONS: Patients with MUS who attend frequently have insecure adult attachment styles, and their high consultation rate may therefore be conceptualized as pathological care-seeking behaviour linked to their insecure attachment. Understanding frequent attendance as pathological help seeking driven by difficulties in relating to caregiving figures may help doctors to manage their frequently attending patients in a different way.

Training teachers to teach mental health skills to staff in primary care settings in a vast, under-populated area.

Background The Arkhangelsk Oblast is an area the size of France with a sparsely distributed population. The existing primary care staff have had very little training in the management of mental health disorders, despite the frequency of these disorders in the population. They requested special teaching on depression, suicide, somatisation and alcohol problems. Methods An educational intervention was developed in partnership with mental health and primary care staff in Russia, to develop mental health skills using established, evidence-based methods. After a preliminary demonstration of teaching methods to be employed, a 5-day full-time teaching course was offered to trainers of general practitioners and feldshers. Results The findings are presented by providing details of improvements that occurred over a 3-month period in four areas, namely depression in primary care, somatic presentations of distress, dealing with suicidal patients, and alcohol problems. We present preliminary data on how the training has generalised since our visits to Archangelsk. Conclusions Teachers who are used to teaching by didactic lectures can be taught the value of short introductory talks that invite discussion, and mental health skills can be taught using role play. The content of such training should be driven by perceived local needs, and developed in conjunction with local leaders and teachers within primary care services. Further research will be needed to establish the impact on clinical outcomes.

Exploring the feasibility of a meta-structure for DSM-V and ICD-11: could it improve utility and validity?

BACKGROUND: The organization of mental disorders into 16 DSM-IV and 10 ICD-10 chapters is complex and based on clinical presentation. We explored the feasibility of a more parsimonious meta-structure based on both risk factors and clinical factors. METHOD: Most DSM-IV disorders were allocated to one of five clusters as a starting premise. Teams of experts then reviewed the literature to determine within-cluster similarities on 11 predetermined validating criteria. Disorders were included and excluded as determined by the available data. These data are intended to inform the grouping of disorders in the DSM-V and ICD-11 processes. RESULTS: The final clusters were neurocognitive (identified principally by neural substrate abnormalities), neurodevelopmental (identified principally by early and continuing cognitive deficits), psychosis (identified principally by clinical features and biomarkers for information processing deficits), emotional (identified principally by the temperamental antecedent of negative emotionality), and externalizing (identified principally by the temperamental antecedent of disinhibition). CONCLUSIONS: Large groups of disorders were found to share risk factors and also clinical picture. There could be advantages for clinical practice, public administration and research from the adoption of such an organizing principle.

Emotional disorders: cluster 4 of the proposed meta-structure for DSM-V and ICD-11.

BACKGROUND: The extant major psychiatric classifications DSM-IV, and ICD-10, are atheoretical and largely descriptive. Although this achieves good reliability, the validity of a medical diagnosis would be greatly enhanced by an understanding of risk factors and clinical manifestations. In an effort to group mental disorders on the basis of aetiology, five clusters have been proposed. This paper considers the validity of the fourth cluster, emotional disorders, within that proposal. METHOD: We reviewed the literature in relation to 11 validating criteria proposed by a Study Group of the DSM-V Task Force, as applied to the cluster of emotional disorders. RESULTS: An emotional cluster of disorders identified using the 11 validators is feasible. Negative affectivity is the defining feature of the emotional cluster. Although there are differences between disorders in the remaining validating criteria, there are similarities that support the feasibility of an emotional cluster. Strong intra-cluster co-morbidity may reflect the action of common risk factors and also shared higher-order symptom dimensions in these emotional disorders. CONCLUSION: Emotional disorders meet many of the salient criteria proposed by the Study Group of the DSM-V Task Force to suggest a classification cluster.

Where should bipolar disorder appear in the meta-structure?

BACKGROUND: The extant major psychiatric classifications, DSM-IV and ICD-10, are purportedly atheoretical and largely descriptive. Although this achieves good reliability, the validity of a medical diagnosis is greatly enhanced by an understanding of both risk factors and clinical history. In an effort to group mental disorders on the basis of risk factors and clinical manifestations, five clusters have been proposed. The purpose of this paper is to consider the position of bipolar disorder (BPD), which could be either with the psychoses, or with emotional disorders, or in a separate cluster. METHOD: We reviewed the literature on BPD, unipolar depression (UPD) and schizophrenia in relation to 11 validating criteria proposed by the DSM-V Task Force Study Group, and then summarized similarities and differences between BPD and schizophrenia on the one hand, and UPD on the other. RESULTS: There are differences, often substantial and never trivial, for 10 of the 11 validators between BPD and UPD. There are also important differences between BPD and schizophrenia. CONCLUSION: BPD has previously been classified together with UPD, but this is the least justifiable place for it. If it is to be recruited to a 'psychotic cluster', there are several important respects in which it differs from schizophrenia, so the cluster would have a division within it. The alternative would be to allow it to be in an intermediate position in a cluster of its own.

The impact of language skills on mental health in teenagers with hearing impairments.

OBJECTIVE: The aim of this study was to examine the relationship of language competence level and mental distress in teenagers with hearing impairments. METHOD: 43 pupils were given a battery of linguistic tests and the Strengths and Difficulties Questionnaire (SDQ), which was also completed by 40 parents. Comparisons were made between the group of 33 children in mainstream education and 10 who were in a segregated school for the deaf. RESULTS: The children had impaired language skills relative to published norms, especially marked in segregated schools. Parents rated children as having more distress than published norms. Those with superior level of spoken language had fewer peer relationship problems in mainstream education, but significantly more in segregated schools. The reverse was almost significant for those proficient in signed language. CONCLUSION: Peer relationship problems are associated with the language competence levels in the way that children at school communicate with one another.

Genetic and environmental influences on psychological distress in the population: General Health Questionnaire analyses in UK twins.

BACKGROUND: The General Health Questionnaire (GHQ) is the most popular screening instrument for detecting psychiatric disorders in community samples. Using longitudinal data of a large sample of UK twin pairs, we explored (i) heritabilities of the four scales and the total score; (ii) the genetic stability over time; and (iii) the existence of differential heritable influences at the high (ill) and low (healthy) tail of the distribution. METHOD: At baseline we assessed the GHQ in 627 MZ and 1323 DZ female pairs and at a second occasion (3.5 years later) for a small subsample (90 MZ and 270 DZ pairs). Liability threshold models and raw ordinal maximum likelihood were used to estimate twin correlations and to fit longitudinal genetic models. We estimated extreme group heritabilities of the GHQ distribution by using a model-fitting implementation of the DeFries-Fulker regression method for selected twin data. RESULTS: Heritabilities for Somatic Symptoms, Anxiety, Social Dysfunction, Depression and total score were 0.37, 0.40, 0.20, 0.42 and 0.44, respectively. The contribution of shared genetic factors to the correlations between time points is substantial for the total score (73%). Group heritabilities of 0.48 and 0.43 were estimated for the top and bottom 10% of the total GHQ score distribution, respectively. CONCLUSION: The overall heritability of the GHQ as a measure of psychosocial distress was substantial (44%), with all scales having significant additive genetic influences that persisted across time periods. Extreme group analyses suggest that the genetic control of resilience is as important as the genetic control of vulnerability.

Understanding cross-national differences in depression prevalence.

UNLABELLED: BACKGROUND. Previous epidemiological studies indicate large cross-national differences in prevalence of depression. METHODS: At 15 centres in 14 countries. 25,916 primary care patients were screened for common mental disorders. A stratified random sample of 5,447 primary care patients completed a baseline diagnostic assessment and 3,197 completed a 12-month follow-up assessment. Psychiatric symptoms and diagnoses were assessed using the Composite International Diagnostic Interview (CIDI). Interviewer-rated disability was assessed using the Social Disability Schedule (SDS). RESULTS: Prevalence of current major depression varied 15-fold across centres. When centres were divided into three groups according to prevalence rates, the symptom pattern or latent structure of depressive illness was generally similar at low-, medium-, and high-prevalence centres. Depression was universally associated with disability, but this association varied significantly (t = 3.51, P = 0.0005) across centres. At higher-prevalence centres, depression was associated with lower levels of impairment. At 1 year follow-up, higher prevalence centres had both significantly higher rates of depression onset (t = 3.11, P = 0.002) and higher rates of persistence among those depressed at baseline (t = 2 49, P = 0.013). CONCLUSIONS: Large cross-national variations in depression prevalence cannot be attributed to 'category fallacy' (cross-national differences in the nature or validity of depressive disorder). Use of identical measures and diagnostic criteria may actually identify different levels of depression severity in different countries or cultures. Cross-national differences in the onset and outcome of depression may reflect either true prevalence differences or differences in diagnostic threshold.

Stratum-specific likelihood ratios of the general health questionnaire in the community: help-seeking and physical co-morbidity affect the test characteristics.

BACKGROUND: In evidence-based medicine, stratum-specific likelihood ratios (SSLRs) are now being increasingly recognized as a more convenient and generalizable method to interpret diagnostic information than an optimal cut-off and its associated sensitivity and specificity. We previously examined the SSLRs of the General Health Questionnaire (GHQ) in primary care settings. The present paper aims to examine if these SSLRs are generalizable to the community settings. METHODS: The Composite International Diagnostic Interview (CIDI) and the GHQ were administered on a representative sample of the Australian population in the Australian National Survey of Mental Health and Well-Being. We first compared the SSLRs of GHQ in urban Australia with the estimates that we had previously obtained from the developed urban centres in the WHO Psychological Problems in General Health Care study. If the SSLRs in the community were found to differ significantly from those in the primary care, we sought for explanatory variables. RESULTS: The SSLRs in urban Australia and in the urban centres in the WHO study were significantly different for three out of the six strata. When we limited the sample to those with physical problems who visited a health professional, however, the SSLRs in the Australian study were strikingly close to those observed for primary care settings. CONCLUSIONS: Different sets of SSLRs apply to primary care and general population samples. For general population surveys in developed countries, the results of the Australian National Survey represent the currently available best estimates. For developing countries or rural areas, the results are less definitive and an investigator may wish to conduct a pilot study.

Solitaire and gemini metallocene porphyrazines.

We report the synthesis and physical characterization of a series of peripherally functionalized porphyrazines (pzs) of the forms H2[pz(A;B3)] and trans-H2[pz(A2);B2], where A is a dithiolene chelate of molybdocene or vanadocene and B is a solublizing group. The precursor pz's 8 and 9, of the form H2[pz(A;B3)], where A = (4-(butyloxycarbonyl)-S-benzyl)2 and B = di-tert-butylphenyl (8) or di-n-propyl (9), have been prepared, deprotected, and peripherally metalated with molybdocene and vanadocene to form 1(Mo(IV)) and 1(V(IV)), prepared from 8, and 2(Mo(IV)) from 9, respectively. Likewise, the protected trans-H2[pz(A2);B2)], where A = (S-benzyl)2 and B = 3,6-butyloxybenzene (12) or A = (S-benzyl)2 and B = (tert-butylphenyl)2 (13), have been prepared and peripherally metalated with molybdocene and vanadocene to give the trans dinuclear complexes, 3(Mo(IV),Mo(IV)), 3(V(IV),V(IV)) (from 12), and 4(V(IV),V(IV)) (from 13). A crystal structure of the trans vanadocene pz 4(V(IV),V(IV)) is presented; the distance between the two vanadium atoms is 14.5 A. The molybdocene-appended pz's are highly redox active and exhibit cyclic voltammograms that are more than just the sum of the metallocene and the parent pz's. Chemical oxidation with FcPF6 gives the Mo(V) species 1(Mo(V)), 2(Mo(V)), 3(Mo(V),Mo(IV)), and 3(Mo(V),Mo(V)). Their EPR spectra are indicative of extensive delocalization from the Mo(V) into the dithiolato-pz. The EPR spectrum of the mononuclear paramagnetic vanadocene pz, 1(V(IV)), shows an expected 8-line pattern for an S = 2 system with hyperfine coupling to a single 51V (I = 7/2) nucleus, but the dinuclear vanadocene pz's, 3(V(IV),V(IV)) and 4(V(IV),V(IV)), exhibit a striking 15-line pattern of the same breadth from the S = 1 state formed by exchange coupling between the S = 2 vanadium centers of a dinuclear complex. Thus, the porphyrazine macrocycle is capable of mediating magnetic exchange interactions between metal ions bound to the periphery, separated by 14.5 A.

Stratum-specific likelihood ratios of two versions of the general health questionnaire.

BACKGROUND: In other branches of epidemiology, stratum specific likelihood ratios (SSLRs) have been found to be preferable to fixed best threshold approaches to screening instruments. This paper presents SSLRs of GHQ-12 and GHQ-28 and compares the SSLR method with the traditional optimal threshold approach. METHODS: Random effects meta-analysis and meta-regression were used to obtain pooled estimates of SSLRs of the two questionnaires for the 15 centres participating in the WHO study of Psychological Problems in General Health Care. We illustrated the use of SSLRs by applying them to random samples of patients from centres with different backgrounds. RESULTS: For developed and urban centres, the estimates of SSLRs were homogeneous for 10 out of 12 strata of the GHQ-12 and GHQ-28. For other centres, the overall results, which were heterogeneous for six out of 12 strata, were deemed the currently available best estimates. When we applied these results to centres with different prevalences of mental disorders and backgrounds, the estimates matched the actually observed closely. These examples showed how the SSLR approach is more informative than the traditional threshold approach. CONCLUSIONS: Those working in developed urban settings can use the corresponding SSLRs with reasonable confidence. Those working in non-urban or developing areas may wish to use the overall results, while acknowledging that they must remain less certain until further research can explicate heterogeneity. These SSLRs have been incorporated into nomograms and spreadsheet programmes so that future researchers can swiftly derive the post-test probability for a patient or a group of patients from a pre-test probability and GHQ score.

A model complex of a possible intermediate in the mechanism of action of peptide deformylase: first example of an (N2S)zinc(II)-formate complex.

The synthesis and crystallographic characterization of a new (N2S)zinc-alkyl complex and (N2S)zinc-formate complex is described; the bonding mode of the formate complex has implications for the mechanism of action of the enzyme peptide deformylase.

The stability of the factor structure of the General Health Questionnaire.

BACKGROUND: Different versions of the General Health Questionnaire (GHQ), including the GHQ-12 and GHQ-28 have been subjected to factor analysis in a variety of countries. The World Health Organization study of psychological disorders in general health care offered the opportunity to investigate the factor structure of both GHQ versions in 15 different centres. METHODS: The factor structures of the GHQ-12 and GHQ-28 extracted by principal component analysis were compared in participating centres. The GHQ-12 was completed by 26,120 patients and 5,273 patients completed the GHQ-28. The factor structure of the GHQ-28 found in Manchester in this study was compared with that found in the earlier study in 1979. RESULTS: For the GHQ-12, substantial factor variation between centres was found. After rotation, two factors expressing depression and social dysfunction could be identified. For the GHQ-28, factor variance was less. In general, the original C (social dysfunction) and D (depression) scales of the GHQ-28 were more stable than the A (somatic symptoms) and B (anxiety) scales. Multiple cross-loadings occurred in both versions of the GHQ suggesting correlation of the extracted factors. In Manchester, the factor structure of the GHQ had changed since its development. Validity as a case detector was not affected by factor variance. CONCLUSIONS: These findings confirm that despite factor variation for the GHQ-12, two domains, depression and social dysfunction, appear across the 15 centres. In the scaled GHQ-28, two of the scales were remarkably robust between the centres. The cross-correlation between the other two subscales, probably reflects the strength of the relationship between anxiety and somatic symptoms existing in different locations.

Attachment style in patients with unexplained physical complaints.

BACKGROUND: Patients who present with physical symptoms that lack an organic explanation are common, difficult to help and poorly understood. Their medical help-seeking is a form of care-eliciting behaviour and, as such, may be understandable in terms of attachment style. Adult attachment style influences functioning in relationships, and may affect help-seeking behaviour from professional carers such as the family doctor. METHOD: A consecutive sample of 2,042 primary-care attenders completed questionnaires on: the reason for consultation, attribution of symptoms, psychiatric distress (GHQ), somatic distress (BSI), and self-reported adult attachment style (ASQ). Their doctors rated presentations into explained physical, unexplained physical, or psychological. RESULTS: There is a powerful relationship between type of presentation and adult attachment style. Both abnormal attachment and level of psychiatric distress increased significantly from the explained physical group, through the unexplained physical group to the group who presented psychologically. Logistic regression models determined three explanatory variables that made significant independent contributions to presentation type: psychiatric distress, attachment style and symptom attribution. CONCLUSION: Presentation to the doctor with unexplained physical symptoms is associated with both higher levels of psychiatric symptoms and abnormal attachment style when compared to presentations with organic physical symptoms. Patients who present overt psychological symptoms suffer more psychiatric distress and have more abnormal attachment than those presenting physical symptoms (either organically explained or unexplained). Models to explain these findings are discussed.