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Gene expression profiles of head and neck carcinomas from Sudanese and Norwegian patients reveal common biological pathways regardless of race and lifestyle.

PURPOSE: To explore possible range of gene expression profiles in head and neck squamous cell carcinomas (HNSCC) and pairwised normal controls from Sudanese (n = 72) and Norwegian (n = 45) patients using a 15K cDNA microarray and to correlate the findings with clinicopathologic variables. EXPERIMENTAL DESIGN: Samples from Sudan were grouped according to anatomic location/patients' habit of toombak (snuff) use, and 37 pools of 2 to 11 tumors matched to 37 pools of their normal controls from the same patients, respectively, were prepared. For Norway, eight pools of 3 to 11 tumors matched to eight pools of their normal controls from the same patients, respectively, were prepared according to anatomic location. Pools (n = 45) were hybridized to microarrays. For controls, 33 of the pools were hybridized against Human Reference RNA. Scanned array images were recorded, and data analysis was done in groups. For verification, results for selected genes were analyzed using quantitative real-time PCR/immunohistochemistry. RESULTS: We identified 136 genes from Sudan and 154 from Norway as differentially expressed between tumors and controls. Changes of the genes found were confirmed in >70% of the pools by hybridization against Reference RNA. Seventy-three genes and three main pathways (signal transduction, cell communication, and ligand-receptor interaction) were of relevance to the HNSCCs from both countries. Hierarchical clustering of the 73 genes identified subclasses of mixed tumors from the two populations, two independent subgroups for Norwegian tumors by their anatomic sites, and five subgroups for Sudanese tumors by their toombak habits. Quantitative real-time PCR/immunohistochemistry validated the microarray-based data. CONCLUSIONS: Differences in gene expression between tumor and nontumor tissues were identified in HNSCCs. Analysis of the two population groups revealed a common set of 73 genes within three main biological pathways. This indicates that the development of HNSCCs is mediated by similar biological pathways regardless of differences related to race, ethnicity, lifestyle, and/or exposure to environmental carcinogens. Of particular interest, however, was the valuable association of gene expression signature found with toombak use and anatomic site of the tumors.

Aged↗

In vitro drug response and molecular markers associated with drug resistance in malignant gliomas.

PURPOSE: Drug resistance in malignant gliomas contributes to poor clinical outcomes. We determined the in vitro drug response profiles for 478 biopsy specimens from patients with the following malignant glial histologies: astrocytoma (n = 71), anaplastic astrocytoma (n = 39), glioblastoma multiforme (n = 259), oligodendroglioma (n = 40), and glioma (n = 69). EXPERIMENTAL DESIGN: Samples were tested for drug resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), cisplatin, dacarbazine, paclitaxel, vincristine, and irinotecan. Biomarkers associated with drug resistance were detected by immunohistochemistry, including multidrug resistance gene-1, glutathione S-transferase pi (GSTP1), O(6)-methylguanine-DNA methyltransferase (MGMT), and mutant p53. RESULTS: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance. CONCLUSIONS: Assessment of in vitro drug response and profiles of relevant tumor-associated biomarkers may assist the clinician in stratifying patient treatment regimens.

ATP Binding Cassette Transporter, Subfamily B↗

Combination analysis of hypermethylated Wnt-antagonist family genes as a novel epigenetic biomarker panel for bladder cancer detection.

PURPOSE: Aberrant promoter hypermethylation of Wnt-antagonist genes contributes to the pathogenesis of several cancers. We hypothesized that combined methylation analysis of Wnt-antagonist genes could improve their use as a panel of biomarkers for diagnosing and staging of bladder cancers. EXPERIMENTAL DESIGN: Samples (54 total) of bladder tumor and corresponding normal bladder mucosa were analyzed for the methylation and expression levels of six Wnt-antagonist genes (sFRP-1, sFRP-2, sFRP-4, and sFRP-5, Wif-1, and Dkk-3). To increase the sensitivity/specificity of bladder tumor detection, the methylation score (M score), a new method for multigene methylation analysis, was developed. The M score of each sample was calculated as the sum of the corresponding log hazard ratio coefficients derived from multivariate logistic regression analysis of the methylation status for each Wnt-antagonist gene. Receiver operator characteristic (ROC) curve analysis was used to determine the optimal sensitivity/specificity of the M score. Urine DNA from 24 matched patients with bladder tumor and 20 cancer-free volunteers was also used to investigate the methylation status of Wnt-antagonist genes. RESULTS: The methylation levels of Wnt-antagonists were significantly higher and mRNA levels were significantly lower in bladder tumor than in bladder mucosa. Each methylation level was inversely correlated with the corresponding mRNA level. In multivariate regression analysis, the methylation levels of sFRP-2 and Dkk-3 were significant independent predictors of bladder tumor (P < 0.05 and P < 0.01, respectively), whereas with sFRP-1, sFRP-5, and Wif-1 there was a trend towards significance as independent predictors. The M score of Wnt-antagonist genes was significantly higher in bladder tumor than in bladder mucosa (P < 0.05). Overall, the M score had a sensitivity of 77.2% and a specificity of 66.7% as a diagnostic biomarker (areas under the curve, 0.763). The M score could distinguish superficial from invasive bladder tumors with a sensitivity of 72.2% and a specificity of 61.1% as a staging biomarker (areas under the curve, 0.671). In patients with bladder tumor, 80.6% of the methylation-specific PCR results had identical methylation in samples of tumor- and urine-derived DNA. Most urine DNA in normal controls showed no aberrant methylation of the Wnt-antagonist genes. CONCLUSIONS: Hypermethylation of Wnt-antagonist genes plays an important role in the pathogenesis of bladder tumor and can be detected using cellular DNA extracted from urine samples. This is the first report demonstrating that M score analysis of Wnt-antagonist genes could serve as an excellent epigenetic biomarker panel for bladder tumors.

Adaptor Proteins, Signal Transducing↗

Increased expression of Wiskott-Aldrich syndrome protein family verprolin-homologous protein 2 correlated with poor prognosis of hepatocellular carcinoma.

PURPOSE: Because of its role in cell migration, the Wiskott-Aldrich syndrome protein family verprolin-homologous protein (WAVE) 2 has been implicated in cancer metastasis. Evidence to support such a role of WAVE2 in human cancer, however, is lacking. We thus examined the expression of WAVE2 in hepatocellular carcinoma (HCC) tissues to test whether the levels of WAVE2 expression correlated to the progression of HCC. EXPERIMENTAL DESIGN: Samples of 112 HCC patients were determined immunohistochemically for WAVE2 expression and the correlation of WAVE2 levels with prognosis was analyzed. Among the 112 cases, 31 paired HCC and paracarcinomatous liver tissue specimens were analyzed for WAVE2 levels by reverse transcription-PCR and Western blotting, respectively. RESULTS: Among 112 cases of HCCs, the immunohistochemistry data indicated significant increase of WAVE2 expression levels in 71 cases. Importantly, the increased WAVE2 expression correlated with the multiple tumor nodules (P = 0.008), the absence of capsular formation (P = 0.035), Edmondson-Steiner grade (P = 0.009), vein invasion (P = 0.023), and a shortened median survival time (326 versus 512 days; P = 0.003). Multivariable Cox regression analysis revealed the WAVE2 expression level was an independent factor for prognosis. The immunohistochemistry data were further confirmed by results of reverse transcription-PCR and Western analysis of 31 HCC cases, in which the WAVE2 mRNA and protein in HCC tissues were significantly elevated when compared with paracarcinomatous liver tissue (P < 0.001). CONCLUSIONS: WAVE2 expression is elevated in HCC tissues, which correlates with a poor prognosis, suggesting WAVE2 as a candidate prognostic marker of HCC.

Adolescent↗

A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer.

PURPOSE: Patients with advanced cancer received temsirolimus (Torisel, CCI-779), a novel inhibitor of mammalian target of rapamycin, i.v. once daily for 5 days every 2 weeks to determine the maximum tolerated dose, toxicity profile, pharmacokinetics, and preliminary antitumor efficacy. EXPERIMENTAL DESIGN: Doses were escalated in successive cohorts of patients using a conventional phase I clinical trial design. Samples of whole blood and plasma were collected to determine the pharmacokinetics of temsirolimus and sirolimus, its principal metabolite. RESULTS: Sixty-three patients were treated with temsirolimus (0.75-24 mg/m(2)/d). The most common drug-related toxicities were asthenia, mucositis, nausea, and cutaneous toxicity. The maximum tolerated dose was 15 mg/m(2)/d for patients with extensive prior treatment because, in the 19 mg/m(2)/d cohort, two patients had dose-limiting toxicities (one with grade 3 vomiting, diarrhea, and asthenia and one with elevated transaminases) and three patients required dose reductions. For minimally pretreated patients, in the 24 mg/m(2)/d cohort, one patient developed a dose-limiting toxicity of grade 3 stomatitis and two patients required dose reductions, establishing 19 mg/m(2)/d as the maximum acceptable dose. Immunologic studies did not show any consistent trend toward immunosuppression. Temsirolimus exposure increased with dose in a less than proportional manner. Terminal half-life was 13 to 25 hours. Sirolimus-to-temsirolimus exposure ratios were 0.6 to 1.8. A patient with non-small cell lung cancer achieved a confirmed partial response, which lasted for 12.7 months. Three patients had unconfirmed partial responses; two patients had stable disease for >/=24 weeks. CONCLUSION: Temsirolimus was generally well tolerated on this intermittent schedule. Encouraging preliminary antitumor activity was observed.

Adult↗

Wnt antagonist family genes as biomarkers for diagnosis, staging, and prognosis of renal cell carcinoma using tumor and serum DNA.

PURPOSE: We hypothesized that combined methylation analysis of Wnt antagonist genes could serve as a panel of biomarkers for diagnosis, staging, and prognosis in renal cell carcinoma (RCC). EXPERIMENTAL DESIGN: Samples (n = 62) of RCC and corresponding normal renal tissue (NRT) were analyzed using methylation-specific PCR for methylation of six Wnt antagonist genes (sFRP-1, sFRP-2, sFRP-4, sFRP-5, Wif-1, and Dkk-3). To increase the sensitivity/specificity of RCC detection, the methylation score (M score) for multigene methylation analysis was developed. Receiver operator characteristic curve analysis was used to determine the optimal sensitivity/specificity of the M score. In addition, the M score was compared with the clinicopathologic outcome. Thirty-three serum DNA samples were also used to investigate the methylation status of Wnt antagonist genes. RESULTS: The methylation levels of all Wnt antagonists were significantly higher in RCC than in NRT. In multivariate regression analysis, the methylation level of sFRP-1 was a significant independent predictor of RCC, whereas for sFRP-2 and sFRP-4 there was a trend toward significance as independent predictors. The M score of Wnt antagonist genes was significantly higher in RCC than in NRT. Overall, the M score had a sensitivity of 79.0% and a specificity of 75.8% (area under the curve, 0.808) as a diagnostic biomarker. In addition, the M score could significantly distinguish grade, pT category, M category, and overall survival of RCC patients. The M score was independent of age and gender in predicting overall survival by the Cox proportional hazards model. In RCC patients, 72.7% of the methylation-specific PCR results had identical methylation in samples of tumor and serum DNA. No serum DNA in normal controls showed aberrant methylation of the Wnt antagonist genes. In addition, the methylation status of Wnt antagonist genes in serum DNA was significantly correlated with tumor grade and stage. CONCLUSIONS: This is the first report showing that M score analysis of Wnt antagonist genes can serve as an excellent epigenetic biomarker panel for detection, staging, and prognosis of RCC using serum DNA.

Adaptor Proteins, Signal Transducing↗

Combination of linkage evidence in complex inheritance.

The central problem of complex inheritance is to combine evidence from data that typically differ in markers, phenotypes, ascertainment, and other factors, without sacrificing the reliability that lods have given to linkage mapping for major loci. Here we evaluate 5 possible solutions on 200 replicates simulated in Genetic Analysis Workshop 10. Two methods differ from less efficient ones by distinguishing the tails of a normal distribution. Maximum likelihood scores (currently implemented only for the BETA model) and the approach of Self and Liang perform about as well as pooling samples, which is not feasible with heterogeneous data. With moderately heterogeneous data the Self and Liang method appears to be more efficient than maximum likelihood scores. Although improvements are being made in sample design and statistical analysis, the problem of combining linkage evidence from multiple data sets appears to have been solved. Allelic association presents different problems not yet addressed.

Alleles↗

PCR diagnosis of HPV in cervical biopsies of CIN and invasive neoplasia formerly diagnosed as HPV negative.

OBJECTIVE: To evaluate whether the polymerase chain reaction (PCR) enhances the diagnosis of human papillomavirus (HPV) in biopsies of the uterine cervix with cervical intraepithelial neoplasia (CIN) or invasive neoplasia. STUDY DESIGN: Samples of 71 paraffin-embedded cervical tissue blocks from patients seen in the period 1997-1998 were analyzed. Samples were selected according to age (18-60 years old) and an active sexual life and divided in to 3 groups: test (samples with CIN or invasive neoplasia and a negative HPV diagnosis), positive controls (samples with CIN or invasive neoplasia and a positive HPV diagnosis) and negative controls (samples without CIN or invasive neoplasia and a negative HPV diagnosis). Samples were subjected to DNA extraction and PCR for HPV detection. RESULTS: PCR analysis matched the colposcopic and cytopathologic diagnoses in the positive and negative controls. However, 77% of samples in test group were HPV positive. CONCLUSION: CIN, an invasive neoplasm, is associated with the presence of HPV. Colposcopy and cytopathology are efficient but not sufficient to identify HPV. Thus, despite the high cost, PCR can be used as an additional examination, in women with cervical lesions.

Adolescent↗

Effect of cellularity on the sensitivity of detecting squamous lesions in liquid-based cervical cytology.

OBJECTIVE: To evaluate the effect of cellularity on the sensitivity of both screening and diagnosis in a liquid-based cervical sample. STUDY DESIGN: SurePath samples (TriPath Imaging Inc., Burlington, North Carolina, U.S.A.) with known diagnoses were selected, including 18 negative, 16 low grade squamous intraepithelial lesion (LSIL) and 12 high grade squamous intraepithelial lesion (HSIL) cases. Through a serial dilution technique, samples of varying cellularity were prepared. The 275 slides were assigned random numbers and were routinely screened by 1 of 2 senior cytotechnologists, blinded to the reference diagnosis. Specimens with a screening diagnosis of atypical squamous cells of undetermined significance (ASCUS) or higher were reviewed by two pathologists, resulting in a final consensus diagnosis. Using a grid counting system, cellularity was determined for each slide. RESULTS: There was a clear demarcation in sensitivity between specimens with a cellularity of < 5,000 or > or = 5,000 squamous cells. This applied to both the sensitivity for screening and to the final consensus diagnosis. For cases with a reference diagnosis of LSIL+, at a cytotechnologist screening level of ASCUS or greater, sensitivity increased from 72.8% (< 5,000 cells) to 98.1% (> or = 5,000 cells) and for a reference diagnosis of HSIL from 85.7% to 100%, respectively. Similarly, for the consensus diagnosis, sensitivity rose from 78.5% (< 5,000 cells) to 96.6% (> or = 5,000 cells) for LSIL+ and from 82.9% to 100%, respectively, for HSIL. These differences were statistically significant (P < .001). CONCLUSION: A minimum cellularity of 5,000 squamous cells is recommended for SurePath liquid-based cervical preparations.

Carcinoma↗

Iron deficiency and smoking. Comparative criteria for buccal mucosa keratinization in menstruating and postmenopausal women.

OBJECTIVE: To compare the degree of keratinization of buccal mucosa between nonsmoking menstruating and postmenopausal women without oral complaints whose iron status was established. STUDY DESIGN: Samples collected from 26 nonsmoking, regularly menstruating women (mean age, 26 years) and 18 nonsmoking, postmenopausal women without oral complaints (mean age, 57 years) were stained according to the method of Papanicolaou. Keratinization was evaluated by the karyopyknotic index (KI). Iron status was assessed with blood ferritin levels. RESULTS: Mean ferritin values of menstruating and postmenopausal women were statistically significantly different (mean ferritin value = 28.97 micrograms/L and 103.69 micrograms/L, respectively). The difference in the degree of keratinization of buccal mucosa between menstruating women (mean KI = 16.03%) and postmenopausal women (mean KI = 13.16) was statistically nonsignificant. CONCLUSION: Our results indicate that the degree of keratinization of buccal mucosa does not show any alteration after menopause.

Adult↗

Detection of the HTLV-I gene on cytologic smear slides.

OBJECTIVE: To apply the polymerase chain reaction (PCR) for detection of the HTLV-I gene from cytologic smear slides. STUDY DESIGN: Samples were from seven cases of serum anti-ATL antibody (ATLA)-positive T-cell lymphoma and three from ATLA-negative T-cell lymphoma. Six of the seven ATLA-positive cases were confirmed to be ATLL by Southern blotting. From the seventh case a fresh sample for blotting could not obtained. DNA was extracted from the cytologic smear slides of all 10 cases; they had been stained with Papanicolaou or May-Giemsa stain, digested with proteinase K and precipitated with phenol and ethanol. The target sequence in the pX region of the HTLV-I gene was amplified by PCR. RESULTS: All seven ATLA-positive cases, including one that had not yet been confirmed by Southern blotting, showed a single band, as predicted, while the three ATLA-negative cases showed no band. CONCLUSION: If cytologic smear slides are available but a fresh sample is not, the PCR method should provide evidence that the virus is present since in our study sufficient DNA templates were successfully extracted from the stained cytologic smear slides for detection of the virus.

Biopsy, Needle↗

Diagnostic efficacy of endometrial cytology with the Abradul cell sampler supplemented by laser scanning confocal microscopy.

OBJECTIVE: To study the diagnostic efficacy of endometrial cytology with the Abradul cell sampler and the effect of supplementing it, in cases with overly thick smears, with laser scanning confocal microscopy. STUDY DESIGN: Sampling was performed in 1,684 women. All patients underwent subsequent histology. In eight cases with overly thick smears the original smears were restained to allow confocal microscopy. RESULTS: Efficacy was high, with 1,593 good samples. Thirty-one endometrial carcinomas were signed out as cytologically positive and 10 as atypia. In addition, 10 squamous cell carcinomas of the cervix and 1 ovarian carcinoma were diagnosed with this method. Only one case (endocervical adenocarcinoma) was not detected in the sample. In the eight cases in which confocal microscopy was performed, the images were high quality, allowing a correct diagnosis. In addition, the transition from hyperplasia to carcinoma could be visualized in the cytologic smear. CONCLUSION: Endometrial cytology in an outpatient setting is highly effective, and confocal microscopy in selected cases is not only helpful but also highly instructive.

Disposable Equipment↗

Apo(a) isoforms predict risk for coronary heart disease. A study in six populations.

Elevated concentrations of lipoprotein(a) (Lp[a]) in plasma are associated with premature coronary heart disease (CHD). Lp(a) levels are largely determined by alleles at the hypervariable apolipoprotein(a) (apo[a]) gene locus, but other genetic and environmental factors as well as diseases also affect plasma Lp(a) concentrations. It is therefore unclear whether Lp(a) is a primary genetic risk factor or whether Lp(a) levels are elevated secondary to disease in CHD patients. We have analyzed apo(a) phenotypes that represent a stable genetic trait in subjects with CHD and control subjects from different populations representing a variety of ethnic groups (Tyrol, Germany, Wales, Israel, Singapore Chinese, and Singapore Indian). Despite differences in sampling design and disease definition in this multipopulation case-control study, those apo(a) isoforms associated with high Lp(a) plasma concentrations (B, S1, and S2) were more frequent in the CHD patients in each ethnic group. These differences were significant in three of the studied populations and highly significant (p < 0.001) in the pooled (total) group. Lp(a) concentrations were also measured in all groups except Germans and were found to be consistently higher in cases than in control subjects in each ethnic group. For all but one population (Israeli) the differences were significant. The effects of the apo(a) size polymorphism on Lp(a) levels were similar in CHD patients and control subjects from different populations. The data demonstrate that alleles at the apo(a) locus determine the risk for CHD through their effects on Lp(a) concentrations across multiple populations with large differences in CHD frequency and risk factor profiles.

Adult↗

Comparison of use of medications after acute myocardial infarction in the Veterans Health Administration and Medicare.

BACKGROUND: There is concern that care provided in the Veterans Health Administration (VA) may be of poorer quality than non-VA health care. We compared use of medications after acute myocardial infarction in the VA with that in non-VA healthcare settings under fee-for-service (FFS) Medicare financing. METHODS AND RESULTS: We used clinical data from 2486 VA and 29 249 FFS men >65 years old discharged with a confirmed diagnosis of acute myocardial infarction from 81 VA hospitals and 1530 non-VA hospitals. We reported odds ratios (ORs) for use of thrombolytics, beta-blockers, ACE inhibitors, or aspirin among ideal candidates adjusted for age, sample design (hospital academic affiliation, availability of cardiac procedures, and volume), and within-hospital clustering. Ideal VA candidates were more likely to undergo thrombolytic therapy at arrival (OR [VA relative to Medicare] 1.40 [1.05, 1.74]) or to receive ACE inhibitors (OR 1.67 [1.12, 2.45]) or aspirin (OR 2.32 [1.81, 3.01]) at discharge and equally likely to receive beta-blockers (OR 1.09 [1.03, 1.40]) at discharge. CONCLUSIONS: Ideal candidates in VA were at least as likely as those in FFS to receive medical therapies of known benefit for acute myocardial infarction.

Adrenergic beta-Antagonists↗

Estimating the genetic contribution to schizophrenia.

The authors discuss the limitations of the concept of heritability in schizophrenia and, using reported incidence figures, assess two alternatives--the multifactorial and single major locus (SML) models. Both models predict genetic heterogeneity in schizophrenia. For some parameter values, the SML model indicates that homozygotes are rare but at very high risk. According to the multifactorial model, 9.1% of the schizophrenic population has a genetic risk of 99% or more. The authors conclude that neither model adequately accounts for the data but that predictions from both can be used to design sampling procedures which will increase the probability of selecting for study individuals whose illness is highly genetically determined.

Diseases in Twins↗

Treatment and adequacy of treatment of mental disorders among respondents to the Mexico National Comorbidity Survey.

OBJECTIVE: This study described the rate and adequacy of mental health service use among participants in the Mexico National Comorbidity Survey and the correlates of any 12-month treatment and of adequate treatment. METHOD: The authors conducted face-to-face household surveys of a probability sample of individuals ages 18 to 65 years in the noninstitutionalized population living in urban areas of Mexico from 2001 to 2002. The use of mental health services and 12-month DSM-IV disorders was assessed with the World Mental Health version of the World Health Organization Composite International Diagnostic Interview. The rates and correlates of any service use and the adequacy of treatment were identified in logistic regression analyses, taking into account the complex sample design and weighting process. RESULTS: The data reported here were based on 2,362 interviews. Fewer than one in five respondents with any psychiatric disorder during the last 12 months used any service during the prior year. The rates of service use by those with mood disorders were somewhat higher. About one in every two respondents who used services received minimally adequate care. CONCLUSIONS: The authors found large unmet needs for mental health services among those with psychiatric disorders. Those with mental illness and those who deliver or seek to improve mental health care in Mexico face enormous challenges.

Adolescent↗

Perceived stigma as a predictor of treatment discontinuation in young and older outpatients with depression.

OBJECTIVE: The authors' goal was to examine the extent to which perceived stigma affected treatment discontinuation in young and older adults with major depression. METHOD: A two-stage sampling design identified 92 new admissions of outpatients with major depression. Perceived stigma was assessed at admission. Discontinuation of treatment was recorded at 3-month follow-up. RESULTS: Although younger patients reported perceiving more stigma than older patients, stigma predicted treatment discontinuation only among the older patients. CONCLUSIONS: Patients' perceptions of stigma at the start of treatment influence their subsequent treatment behavior. Stigma is an appropriate target for intervention aimed at improving treatment adherence and outcomes.

Adolescent↗

Stigma as a barrier to recovery: Perceived stigma and patient-rated severity of illness as predictors of antidepressant drug adherence.

OBJECTIVE: Major depression is undertreated despite the availability of effective treatments. Psychological barriers to treatment, such as perceived stigma and minimization of the need for care, may be important obstacles to adherence to the pharmacologic treatment of major depression. The authors examined the impact of barriers that were present at the initiation of antidepressant drug therapy on medication adherence in a mixed-age sample of outpatients with major depression. METHODS: A two-stage sampling design was used to identify adults with a diagnosis of major depressive disorder, as determined by the Structured Clinical Interview for Diagnosis, who sought mental health treatment at outpatient clinics. Additional instruments were administered to 134 newly admitted adults who had been taking a prescribed antidepressant medication for at least a week to assess perceived stigma, self-rated severity of illness, and views about treatment. The patients were reinterviewed three months later and were classified as adherent or nonadherent on the basis of self-reported estimates of the number and frequency of missed doses. RESULTS: Medication adherence was associated with lower perceived stigma, higher self-rated severity of illness, age over 60 years, and absence of personality pathology. No other characteristics of treatment or illness were significantly related to medication adherence. CONCLUSIONS: Perceived stigma associated with mental illness and individuals' views about the illness play an important role in adherence to treatment for depression. Clinicians' attention to psychological barriers early in treatment may improve medication adherence and ultimately affect the course of illness.

Adaptation, Psychological↗