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1.  Cognitive trio: relationship with major depression and clinical predictors in Han Chinese women 
Psychological Medicine  2013;43(11):2265-2275.
Previous studies support Beck's cognitive model of vulnerability to depression. However, the relationship between his cognitive triad and other clinical features and risk factors among those with major depression (MD) has rarely been systematically studied.
The three key cognitive symptoms of worthlessness, hopelessness and helplessness were assessed during their lifetime worst episode in 1970 Han Chinese women with recurrent MD. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression.
Compared to patients who did not endorse the cognitive trio, those who did had a greater number of DSM-IV A criteria, more individual depressive symptoms, an earlier age at onset, a greater number of episodes, and were more likely to meet diagnostic criteria for melancholia, postnatal depression, dysthymia and anxiety disorders. Hopelessness was highly related to all the suicidal symptomatology, with ORs ranging from 5.92 to 6.51. Neuroticism, stressful life events (SLEs) and a protective parental rearing style were associated with these cognitive symptoms.
During the worst episode of MD in Han Chinese women, the endorsement of the cognitive trio was associated with a worse course of depression and an increased risk of suicide. Individuals with high levels of neuroticism, many SLEs and high parental protectiveness were at increased risk for these cognitive depressive symptoms. As in Western populations, symptoms of the cognitive trio appear to play a central role in the psychopathology of MD in Chinese women.
PMCID: PMC3807662  PMID: 23425530
Cognitive trio; Han Chinese women; major depression; suicide; symptoms
2.  The structure of the symptoms of major depression: exploratory and confirmatory factor analysis in depressed Han Chinese women 
Psychological Medicine  2013;44(7):1391-1401.
The symptoms of major depression (MD) are clinically diverse. Do they form coherent factors that might clarify the underlying nature of this important psychiatric syndrome?
Symptoms at lifetime worst depressive episode were assessed at structured psychiatric interview in 6008 women of Han Chinese descent, age ⩾30 years with recurrent DSM-IV MD. Exploratory factor analysis (EFA) and confirmatoryfactor analysis (CFA) were performed in Mplus in random split-half samples.
The preliminary EFA results were consistently supported by the findings from CFA. Analyses of the nine DSM-IV MD symptomatic A criteria revealed two factors loading on: (i) general depressive symptoms; and (ii) guilt/suicidal ideation. Examining 14 disaggregated DSM-IV criteria revealed three factors reflecting: (i) weight/appetite disturbance; (ii) general depressive symptoms; and (iii) sleep disturbance. Using all symptoms (n = 27), we identified five factors that reflected: (i) weight/appetite symptoms; (ii) general retarded depressive symptoms; (iii) atypical vegetative symptoms; (iv) suicidality/hopelessness; and (v) symptoms of agitation and anxiety.
MD is a clinically complex syndrome with several underlying correlated symptom dimensions. In addition to a general depressive symptom factor, a complete picture must include factors reflecting typical/atypical vegetative symptoms, cognitive symptoms (hopelessness/suicidal ideation), and an agitated symptom factor characterized by anxiety, guilt, helplessness and irritability. Prior cross-cultural studies, factor analyses of MD in Western populations and empirical findings in this sample showing risk factor profiles similar to those seen in Western populations suggest that our results are likely to be broadly representative of the human depressive syndrome.
PMCID: PMC3967839  PMID: 23920138
Atypical symptoms; China; cognitive symptoms; depression; factor analysis
Depression and Anxiety  2011;29(1):10-15.
A number of clinical features potentially reflect an individual's familial vulnerability to major depression (MD), including early age at onset, recurrence, impairment, episode duration, and the number and pattern of depressive symptoms. However, these results are drawn from studies that have exclusively examined individuals from a European ethnic background. We investigated which clinical features of depressive illness index familial vulnerability in Han Chinese females with MD.
We used lifetime MD and associated clinical features assessed at personal interview in 1,970 Han Chinese women with DSM-IV MD between 30–60 years of age. Odds Ratios were calculated by logistic regression.
Individuals with a high familial risk for MD are characterized by severe episodes of MD without known precipitants (such as stress life events) and are less likely to feel irritable/angry or anxious/nervous.
The association between family history of MD and the lack of a precipitating stressor, traditionally a characteristic of endogenous or biological depression, may reflect the association seen in other samples between recurrent MD and a positive family history. The symptomatic associations we have seen may reflect a familial predisposition to other dimensions of psychopathology, such as externalizing disorders or anxiety states. Depression and Anxiety 0:1–6, 2011. © 2011 Wiley-Liss, Inc.
PMCID: PMC3429856  PMID: 22065525
major depression; family history; symptom; life events
4.  Concordance between Chart Review and Structured Interview Assessments of Schizophrenic Symptoms 
Comprehensive psychiatry  2011;53(3):275-279.
It is unclear whether direct structured interviews are able to capture the full range of psychopathology in schizophrenia, as is required in diagnostic assessments or clinical ratings. We examined agreement between symptom ratings derived from direct patient interviews and from review of casenotes.
The study sample comprised 1021 schizophrenic subjects collected as part of the Irish Case-Control Study of Schizophrenia (ICCSS). Diagnostic interviews utilized a modified version of the Structured Clinical Interview for DSM-III-R. Symptoms were rated by the interviewer. In addition, the Casenote Rating Scale was used to rate symptoms based on medical record information. For each negative and positive symptom, we calculated the Pearson correlation between the interview and the casenote rating. Using the mean of the interview and casenote rating for each symptom, exploratory factor analysis using Varimax rotation was performed.
Three factors were extracted in factor analysis: positive, negative, and Schneiderian symptoms. The highest correlations between interview and casenote ratings were for negative symptoms, in which all symptoms were significantly correlated. Positive and Schneiderian symptoms were significantly correlated with the exception of thought insertion, thought withdrawal, voices speaking in sentences, and somatic hallucinations. Significant correlations were generally moderate (0.2–0.55)
Most schizophrenic symptoms, especially negative symptoms, can be assessed by direct interviews as the sole source of information with moderate reliability. However, the presence of some Schneiderian and possibly less prevalent positive symptoms may be difficult to determine without a review of records, which may include longitudinal observations and information from multiple observers.
PMCID: PMC3752589  PMID: 21658694
schizophrenia; clinical features; structured interview; factor analysis
5.  Clinical predictors associated with full remission versus episode of major depressive disorder outpatients: the experience at a teaching hospital in Taiwan 
BMC Psychiatry  2014;14(1):273.
When depressed patients are in remission, the clinical characteristics indicate that they are able to participate in social activities more regularly, and their impairment in daily functioning is improved. The present study examines the clinical characteristics associated with one- and two month clinical response in outpatients with Major Depressive Disorder (MDD) in Taiwan.
A total of 160 outpatients were initially recruited from the medical centre in Taiwan. Of these participants, 151 MDD patients completed the baseline-assessment interview, 111 were interviewed and assessed again 4 weeks later, and 78 completed the final interview and assessment 8 weeks later. In the present study, asymptomatic was defined as scoring ≤ 7 on the Hamilton Depression Rating Scale (HAM-D); partially symptomatic was defined as scoring 8–14; fully symptomatic was defined as scoring ≥15. Finally, asymptomatic, partially symptomatic, and fully symptomatic were defined in patients with MDD respectively as in full remission, in persistent depressive symptom, and in episode.
Of the remaining 78 patients, a total of 21 (26.9%) were in full remission, 35 (44.9%) were in persistent depressive symptom, and 22 (28.2%) were in episode. Patients in full remission were older (p = 0.03), exhibited greater psychosocial functioning, (p < 0.001), held more-positive beliefs regarding antidepressant medication (p = 0.03), had higher self-efficacy (p = 0.001), and scored lower for neuroticism (p = 0.003), as compared to patients in episode. Younger patients were more prevalent in persistent depression. Repeated-measures ANOVA revealed that differences in four factors (psychosocial functioning, beliefs regarding antidepressant medication, self-efficacy in managing and preventing depression, and neuroticism) were significantly different between full remission and episode. Episode was significantly associated with psychosocial-functioning impairment (OR = 1.12, 95% CI: 1.00-1.26) and poorer self-efficacy (OR = 0.91, 95% CI: 0.82-1.00).
Our findings identify significant factors of full remission, persistent depressive symptom, and episode. We highlight the importance of enhancing patients’ psychosocial functioning and self-efficacy until achieving full remission. Suggestions are provided for clinical health-care management services in Taiwan.
PMCID: PMC4189597  PMID: 25248639
Episode; Major depressive disorder; Remission
6.  Repetitive Transcranial Magnetic Stimulation for the Treatment of Major Depressive Disorder 
Executive Summary
This review was conducted to assess the effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder (MDD).
The Technology
rTMS is a noninvasive way to stimulate nerve cells in areas of the brain. During rTMS, an electrical current passes through a wire coil placed over the scalp. The current induces a magnetic field that produces an electrical field in the brain that then causes nerve cells to depolarize, resulting in the stimulation or disruption of brain activity.
Researchers have investigated rTMS as an option to treat MDD, as an add-on to drug therapy, and, in particular, as an alternative to electroconvulsive therapy (ECT) for patients with treatment-resistant depression.
The advantages of rTMS over ECT for patients with severe refractory depression are that general anesthesia is not needed, it is an outpatient procedure, it requires less energy, the simulation is specific and targeted, and convulsion is not required. The advantages of rTMS as an add-on treatment to drug therapy may include hastening of the clinical response when used with antidepressant drugs.
Review Strategy
The Medical Advisory Secretariat used its standard search strategy to locate international health technology assessments and English-language journal articles published from January 1996 to March 2004.
Summary of Findings
Some early meta-analyses suggested rTMS might be effective for the treatment of MDD (for treatment-resistant MDD and as an add-on treatment to drug therapy for patients not specifically defined as treatment resistant). There were, however, several crucial methodological limitations in the included studies that were not critically assessed. These are discussed below.
Recent meta-analyses (including 2 international health technology assessments) have done evidence-based critical analyses of studies that have assessed rTMS for MDD. The 2 most recent health technology assessments (from the Oxford Cochrane Collaboration and the Norwegian Centre for Health Technology Assessment) concluded that there is no evidence that rTMS is effective for the treatment of MDD, either as compared with a placebo for patients with treatment-resistant or nontreatment-resistant MDD, or as an alternative to ECT for patients with treatment-resistant MDD. This mainly due to the poor quality of the studies.
The major methodological limitations were identified in older meta-analyses, recent health technology assessments, and the most recently published trials (Level 2–4 evidence) on the effectiveness of rTMS for MDD are discussed below.
Small sample size was a limitation acknowledged by many of the authors. There was also a lack of a priori sample size calculation or justification.
Biased randomization may have been a problem. Generally, the published reports lacked detailed information on the method of allocation concealment used. This is important because it is impossible to determine if there was a possible influence (direct or indirect) in the allocation of the patients to different treatment groups.
The trials were single blind, evaluated by external blinded assessors, rather than double blind. Double blinding is more robust, because neither the participants nor the investigators know which participants are receiving the active treatment and which are getting a placebo. Those administering rTMS, however, cannot be blinded to whether they are administering the active treatment or a placebo.
There was patient variability among the studies. In some studies, the authors said that patients were “medication resistant,” but the definitions of resistant, if provided, were inconsistent or unclear. For example, some described “medication resistant” as failing at least one trial of drugs during the current depressive episode. Furthermore, it was unclear if the term “medication resistant” referred to antidepressants only or to combinations of antidepressants and other drug augmentation strategies (such as neuroleptics, benzodiazepine, carbamazepine, and lithium). Also variable was the type of depression (i.e., unipolar and/or bipolar), if patients were inpatients or outpatients, if they had psychotic symptoms or no psychotic symptoms, and the chronicity of depression.
Dropouts or withdrawals were a concern. Some studies reported that patients dropped out, but provided no further details. Intent-to-treat analysis was not done in any of the trials. This is important, because ignoring patients who drop out of a trial can bias the results, usually in favour of the treatment. This is because patients who withdraw from trials are less likely to have had the treatment, more likely to have missed their interim checkups, and more likely to have experienced adverse effects when taking the treatment, compared with patients who do not withdraw. (1)
Measurement of treatment outcomes using scales or inventories makes interpreting results and drawing conclusions difficult. The most common scale, the Hamilton Depression Rating Scale (HDRS) is based on a semistructured interview. Some authors (2) reported that rating scales based on semistructured interviews are more susceptible to observation bias than are self-administered questionnaires such as the Beck Depression Inventory (BDI). Martin et al. (3) argued that the lack of consistency in effect as determined by the 2 scales (a positive result after 2 weeks of treatment as measured by the HDRS and a negative result for the BDI) makes definitive conclusions about the nature of the change in mood of patients impossible. It was suggested that because of difficulties interpreting results from psychometric scales, (4) and the subjective or unstable character of MDD, other, more objective, outcome measures such as readmission to hospital, time to hospital discharge, time to adjunctive treatment, and time off work should be used to assess rTMS for the treatment of depression.
A placebo effect could have influenced the results. Many studies reported response rates for patients who received placebo treatment. For example, Klein et al. (5) reported a control group response rate as high as 25%. Patients receiving placebo rTMS may receive a small dose of magnetic energy that may alter their depression.
Short-term studies were the most common. Patients received rTMS treatment for 1 to 2 weeks. Most studies followed-up patients for 2 to 4 weeks post-treatment. Dannon et al. (6) followed-up patients who responded to a course of ECT or rTMS for up to 6 months; however, the assessment procedure was not blinded, the medication regimen during follow-up was not controlled, and initial baseline data for the patient groups were not reported. The long-term effectiveness of rTMS for the treatment of depression is unknown, as is the long-term use, if any, of maintenance therapy. The cost-effectiveness of rTMS for the treatment of depression is also unknown. A lack of long-term studies makes cost-effectiveness analysis difficult.
The complexity of possible combinations for administering rTMS makes comparing like with like difficult. Wasserman and Lisanby (7) have said that the method for precisely targeting the stimulation in this area is unreliable. It is unknown if the left dorsolateral prefrontal cortex is the optimal location for treatment. Further, differences in rTMS administration include number of trains per session, duration of each train, and motor threshold.
Clinical versus statistical significance. Several meta-analyses and studies have found that the degree of therapeutic change associated with rTMS across studies is relatively modest; that is, results may be statistically, but not necessarily clinically, significant. (8-11). Conventionally, a 50% reduction in the HDRS scores is commonly accepted as a clinically important reduction in depression. Although some studies have observed a statistically significant reduction in the depression rating, many have not shows the clinically significant reduction of 50% on the HDRS. (11-13) Therefore, few patients in these studies would meet the standard criteria for response. (9)
Clinical/methodological diversity and statistical heterogeneity. In the Norwegian health technology assessment, Aarre et al. (14) said that a formal meta-analysis was not feasible because the designs of the studies varied too much, particularly in how rTMS was administered and in the characteristics of the patients. They noted that the quality of the study designs was poor. The 12 studies that comprised the assessment had small samples, and highly variable inclusion criteria and study designs. The patients’ previous histories, diagnoses, treatment histories, and treatment settings were often insufficiently characterized. Furthermore, many studies reported that patients had treatment-resistant MDD, yet did not listclear criteria for the designation. Without this information, Aarre and colleagues suggested that the interpretation of the results is difficult and the generalizability of results is questionable. They concluded that rTMS cannot be recommended as a standard treatment for depression: “More, larger and more carefully designed studies are needed to demonstrate convincingly a clinically relevant effect of rTMS.”
In the Cochrane Collaboration systematic review, Martin et al. (3;15) said that the complexity of possible combinations for administering rTMS makes comparison of like versus like difficult. A statistical test for heterogeneity (chi-square test) examines if the observed treatment effects are more different from each other than one would expect due to random error (or chance) alone. (16) However, this statistical test must be interpreted with caution because it has low power in the (common) situation of a meta-analysis when the trials have small sample sizes or are few. This means that while a statistically significant result may indicate a problem with heterogeneity, a nonsignificant result must not be taken as evidence of no heterogeneity.
Despite not finding statistically significant heterogeneity, Martin et al. reported that the overall mean baseline depression values for the severity of depression were higher in the treatment group than in the placebo group. (3;15) Although these differences were not significant at the level of each study, they may have introduced potential bias into the meta-analysis of pooled data by accentuating the tendency for regression to the mean of the more extreme values. Individual patient data from all the studies were not available; therefore, an appropriate adjustment according to baseline severity was not possible. Martin et al. concluded that the findings from the systematic review and meta-analysis provided insufficient evidence to suggest that rTMS is effective in the treatment of depression. Moreover, there were several confounding factors (e.g., definition of treatment resistance) in the studies, thus the authors concluded, “The rTMS technique needs more high quality trials to show its effectiveness for therapeutic use.”
Due to several serious methodological limitations in the studies that have examined the effectiveness of rTMS in patients with MDD, it is not possible to conclude that rTMS either is or is not effective as a treatment for MDD (in treatment-resistant depression or in nontreatment-resistant depression).
PMCID: PMC3387754  PMID: 23074457
7.  Spreading convulsions, spreading depolarization and epileptogenesis in human cerebral cortex 
Brain  2011;135(1):259-275.
Spreading depolarization of cells in cerebral grey matter is characterized by massive ion translocation, neuronal swelling and large changes in direct current-coupled voltage recording. The near-complete sustained depolarization above the inactivation threshold for action potential generating channels initiates spreading depression of brain activity. In contrast, epileptic seizures show modest ion translocation and sustained depolarization below the inactivation threshold for action potential generating channels. Such modest sustained depolarization allows synchronous, highly frequent neuronal firing; ictal epileptic field potentials being its electrocorticographic and epileptic seizure its clinical correlate. Nevertheless, Leão in 1944 and Van Harreveld and Stamm in 1953 described in animals that silencing of brain activity induced by spreading depolarization changed during minimal electrical stimulations. Eventually, epileptic field potentials were recorded during the period that had originally seen spreading depression of activity. Such spreading convulsions are characterized by epileptic field potentials on the final shoulder of the large slow potential change of spreading depolarization. We here report on such spreading convulsions in monopolar subdural recordings in 2 of 25 consecutive aneurismal subarachnoid haemorrhage patients in vivo and neocortical slices from 12 patients with intractable temporal lobe epilepsy in vitro. The in vitro results suggest that γ-aminobutyric acid-mediated inhibition protects from spreading convulsions. Moreover, we describe arterial pulse artefacts mimicking epileptic field potentials in three patients with subarachnoid haemorrhage that ride on the slow potential peak. Twenty-one of the 25 subarachnoid haemorrhage patients (84%) had 656 spreading depolarizations in contrast to only three patients (12%) with 55 ictal epileptic events isolated from spreading depolarizations. Spreading depolarization frequency and depression periods per 24 h recording episodes showed an early and a delayed peak on Day 7. Patients surviving subarachnoid haemorrhage with poor outcome at 6 months showed significantly higher total and peak numbers of spreading depolarizations and significantly longer total and peak depression periods during the electrocorticographic monitoring than patients with good outcome. In a semi-structured telephone interview 3 years after the initial haemorrhage, 44% of the subarachnoid haemorrhage survivors had developed late post-haemorrhagic seizures requiring anti-convulsant medication. In those patients, peak spreading depolarization number had been significantly higher [15.1 (11.4–30.8) versus 7.0 (0.8–11.2) events per day, P = 0.045]. In summary, monopolar recordings here provided unequivocal evidence of spreading convulsions in patients. Hence, practically all major pathological cortical network events in animals have now been observed in people. Early spreading depolarizations may indicate a risk for late post-haemorrhagic seizures.
PMCID: PMC3267981  PMID: 22120143
epilepsy; subarachnoid haemorrhage; spreading depression; spreading depolarization; delayed cerebral ischaemia
8.  Comparing Cognitive and Somatic Symptoms of Depression in Myocardial Infarction Patients and Depressed Patients in Primary and Mental Health Care 
PLoS ONE  2013;8(1):e53859.
Depression in myocardial infarction patients is often a first episode with a late age of onset. Two studies that compared depressed myocardial infarction patients to psychiatric patients found similar levels of somatic symptoms, and one study reported lower levels of cognitive/affective symptoms in myocardial infarction patients. We hypothesized that myocardial infarction patients with first depression onset at a late age would experience fewer cognitive/affective symptoms than depressed patients without cardiovascular disease. Combined data from two large multicenter depression studies resulted in a sample of 734 depressed individuals (194 myocardial infarction, 214 primary care, and 326 mental health care patients). A structured clinical interview provided information about depression diagnosis. Summed cognitive/affective and somatic symptom levels were compared between groups using analysis of covariance, with and without adjusting for the effects of recurrence and age of onset. Depressed myocardial infarction and primary care patients reported significantly lower cognitive/affective symptom levels than mental health care patients (F (2,682) = 6.043, p = 0.003). Additional analyses showed that the difference between myocardial infarction and mental health care patients disappeared after adjusting for age of onset but not recurrence of depression. These group differences were also supported by data-driven latent class analyses. There were no significant group differences in somatic symptom levels. Depression after myocardial infarction appears to have a different phenomenology than depression observed in mental health care. Future studies should investigate the etiological factors predictive of symptom dimensions in myocardial infarction and late-onset depression patients.
PMCID: PMC3544747  PMID: 23342019
9.  Core Verbal Autopsy Procedures with Comparative Validation Results from Two Countries 
PLoS Medicine  2006;3(8):e268.
Cause-specific mortality statistics remain scarce for the majority of low-income countries, where the highest disease burdens are experienced. Neither facility-based information systems nor vital registration provide adequate or representative data. The expansion of sample vital registration with verbal autopsy procedures represents the most promising interim solution for this problem. The development and validation of core verbal autopsy forms and suitable coding and tabulation procedures are an essential first step to extending the benefits of this method.
Methods and Findings
Core forms for peri- and neonatal, child, and adult deaths were developed and revised over 12 y through a project of the Tanzanian Ministry of Health and were applied to over 50,000 deaths. The contents of the core forms draw upon and are generally comparable with previously proposed verbal autopsy procedures. The core forms and coding procedures based on the International Statistical Classification of Diseases (ICD) were further adapted for use in China. These forms, the ICD tabulation list, the summary validation protocol, and the summary validation results from Tanzania and China are presented here.
The procedures are capable of providing reasonable mortality estimates as adjudged against stated performance criteria for several common causes of death in two countries with radically different cause structures of mortality. However, the specific causes for which the procedures perform well varied between the two settings because of differences in the underlying prevalence of the main causes of death. These differences serve to emphasize the need to undertake validation studies of verbal autopsy procedures when they are applied in new epidemiological settings.
A procedure for recording verbal autopsy information was tested in two countries and found to be capable of providing reasonable mortality data. The need to undertake validation studies was also demonstrated.
Editors' Summary
People living in developed countries take it for granted that when a loved one dies an accurate cause-of-death certificate will be issued. But for two-thirds of the deaths that occur worldwide, there are no certificates. Detailed information about what people die from is unavailable for more than 50% of countries, many of which have high death rates. This information is badly needed for public-health planning, for using scarce health resources wisely, and for monitoring the effect of new health initiatives. One way to improve knowledge about what people die from is a procedure called verbal autopsy (VA). Relatives or caregivers are interviewed about the symptoms experienced by the deceased before their death and the circumstances surrounding their death by trained personnel who use a standard form. Doctors then review the completed VA forms and assign a specific cause of death from a short version of the International Classifications of Diseases, or ICD, an internationally agreed on list of codes for hundreds of diseases.
Why Was This Study Done?
VA procedures are being developed in many countries, but each step in a VA can be affected by factors that vary from place to place, such as how long after the death the interview is done, the training that interviewers receive, how the questions are worded, and the locally common diseases, which tend to be recognized better than rare diseases. To ensure that the data collected are accurate and comparable between countries and also over time, VA procedures need to be standardized. In this study, the researchers describe their efforts to achieve this through the development and validation of core VA procedures.
What Did the Researchers Do and Find?
In 2001, the researchers refined the VA forms that were being used in Tanzania for deaths occurring around the time of birth and for deaths occurring in childhood and adulthood. They then translated the forms for use in China, adapting them slightly to allow for cultural differences in how symptoms are described. They also drew up a short list of ICD codes to use in tabulating and validating important causes of death. Then, for four years, they collected VA and medical record information for the same deceased individuals and measured how well the VA procedure agreed with the medical record information in both countries. They found that the procedure could be transferred between China and Tanzania but that it performed rather differently for different causes of death in the two countries. So, in both countries, the procedure accurately recorded tuberculosis, cerebrovascular diseases such as strokes, and transport accidents as causes of death. But some other causes of death were accurately recorded in one country only—generally the common diseases in that country—and many causes of death were inaccurately reported in both countries.
What Do These Findings Mean?
The researchers use their experience of developing VAs for use in Tanzania and China and the results of this study to make several recommendations about how to develop standardized VA procedures that will yield accurate cause of death. For example, they suggest that the VA form should contain a detailed core symptom duration checklist and only a short space for a narrative history (an open-ended description of the last illness provided by the relative or caregiver) because long narrative histories are hard to standardize. They discuss the need to adapt core VA forms when moving between countries to allow for linguistic differences and colloquial expression and also the need to consider cultural differences between countries—for example, how soon after bereavement a VA interview can occur. Most importantly, they strongly recommend that validation studies like theirs should be routinely done when VA procedures are applied in new countries or if the major cause of death in a country changes because of a new epidemic or health initiative. Provided this is done, write the researchers, although VA procedures can never be as accurate as proper medical certification at the time of death, they should provide important information about the causes of death for the many countries where this information would otherwise be completely missing.
Additional Information.
Please access these Web sites via the online version of this summary at
• World Health Organization information on mortality and on the International Classification of Diseases
• The United Nations' World Mortality Report 2005
• Information on the Tanzania Ministry of Health Adult Morbidity and Mortality Project, which used the VA procedures on which this study was based
• A description of a standard VA method for investigating deaths in infants and children from the World Health Organization
• The INDEPTH Network, an organization collecting health statistics from developing countries that provides standardized VA forms
• MEASURE Evaluation, a USAID-funded project that, in collaboration with the US Census Bureau and the University of Queensland (Australia), supports countries to implement core VA procedures and sample/sentinel vital registration methods
• The Health Metrics Network, a global collaboration focused on strengthening country health information systems to generate sound data for decision-making at country and global levels, is committed to improving sources of vital statistics and cause-of-death data
PMCID: PMC1502154  PMID: 16942391
10.  Elevated left mid-frontal cortical activity prospectively predicts conversion to bipolar I disorder 
Journal of abnormal psychology  2012;121(3):592-601.
Bipolar disorder is characterized by a hypersensitivity to reward-relevant cues and a propensity to experience an excessive increase in approach-related affect, which may be reflected in hypo/manic symptoms. The present study examined the relationship between relative left-frontal electroencephalographic (EEG) activity, a proposed neurophysiological index of approach-system sensitivity and approach/reward-related affect, and bipolar course and state-related variables. Fifty-eight individuals with cyclothymia or bipolar II disorder and 59 healthy control participants with no affective psychopathology completed resting EEG recordings. Alpha power was obtained and asymmetry indices computed for homologous electrodes. Bipolar spectrum participants were classified as being in a major/minor depressive episode, a hypomanic episode, or a euthymic/remitted state at EEG recording. Participants were then followed prospectively for an average 4.7 year follow-up period with diagnostic interview assessments every four-months. Sixteen bipolar spectrum participants converted to bipolar I disorder during follow-up. Consistent with hypotheses, elevated relative left-frontal EEG activity at baseline 1) prospectively predicted a greater likelihood of converting from cyclothymia or bipolar II disorder to bipolar I disorder over the 4.7 year follow-up period, 2) was associated with an earlier age-of-onset of first bipolar spectrum episode, and 3) was significantly elevated in bipolar spectrum individuals in a hypomanic episode at EEG recording. This is the first study to identify a neurophysiological marker that prospectively predicts conversion to bipolar I disorder. The fact that unipolar depression is characterized by decreased relative left-frontal EEG activity suggests that unipolar depression and vulnerability to hypo/mania may be characterized by different profiles of frontal EEG asymmetry.
PMCID: PMC3743092  PMID: 22775582
Bipolar Disorder; EEG; Reward; Biomarker; Hypo/mania
11.  Response to past depression treatments is not accurately recalled 
The Journal of clinical psychiatry  2012;73(12):1503-1508.
Assessing response to prior depression treatments is common in research and clinical practice, but few data are available regarding accuracy of recall. Data from a population-based survey were linked to electronic medical records to examine agreement between recalled treatment response and depression severity scores in medical records.
Electronic medical records from a large health system identified 1878 patients with two or more episodes for clinician-diagnosed depression between 2005 and 2009. 578 of those completed a survey including structured recall of response to each prior treatment – both global improvement during treatment and improvement specifically attributed to treatment. For 269 of these survey participants, at least one treatment episode could be unambiguously linked to both pre- and post-treatment PHQ9 depression scores in electronic medical records. Analyses examined agreement between patients recall of treatment response and improvement in PHQ9 scores from medical records.
Agreement with medical records was poor both for recall of overall improvement following treatment (kappa = 0.10, 95% CI 0.00–0.19) and for recall of improvement attributed to treatment (kappa=0.12, 95% CI 0.00–0.25). Agreement remained poor when the sample was limited to medication treatment episodes, episodes lasting 3 months or more, or episodes for which the participant was “very sure” of her/his ability to recall. Agreement reached a fair level only for episodes in the six months prior to the survey (kappa = 0.23 for overall improvement, kappa = 0.36 for improvement attributed to treatment).
Patients’ recall of response to past depression treatments agrees poorly with data from medical records. Interview assessment of prior treatment response may not be a useful tool for research or clinical practice.
PMCID: PMC3711230  PMID: 23290322
12.  Depression symptomatology and diagnosis: discordance between patients and physicians in primary care settings 
To examine the agreement between depression symptoms using an assessment tool (PHQ-9), and physician documentation of the same symptoms during a clinic visit, and then to examine how the presence of these symptoms affects depression diagnosis in primary care settings.
Interviewer administered surveys and medical record reviews. A total of 304 participants were recruited from 2321 participants screened for depression at two large urban primary care community settings.
Of the 2321 participants screened for depression 304 were positive for depression and of these 75.3% (n = 229) were significantly depressed (PHQ-9 score ≥ 10). Of these, 31.0% were diagnosed by a physician with a depressive disorder. A total of 57.6% (n = 175) of study participants had both significant depression symptoms and functional impairment. Of these 37.7% were diagnosed by physicians as depressed. Cohen's Kappa analysis, used to determine the agreement between depression symptoms elicited using the PHQ-9 and physician documentation of these symptoms showed only slight agreement (0.001–0.101) for all depression symptoms using standard agreement rating scales. Further analysis showed that only suicidal ideation and hypersomnia or insomnia were associated with an increased likelihood of physician depression diagnosis (OR 5.41 P sig < .01 and (OR 2.02 P sig < .05 respectively). Other depression symptoms and chronic medical conditions had no affect on physician depression diagnosis.
Two-thirds of individuals with depression are undiagnosed in primary care settings. While functional impairment increases the rate of physician diagnosis of depression, the agreement between a structured assessment and physician elicited and or documented symptoms during a clinical encounter is very low. Suicidality, hypersomnia and insomnia are associated with an increase in the rate of depression diagnosis even when physician and self report of the symptom differ. Interventions that emphasize the use of routine structured screening of primary care patients might also improve the rate of diagnosis of depression in these settings. Further studies are needed to explore depression symptom assessment during physician patient encounter in primary care settings.
PMCID: PMC2254627  PMID: 18173835
13.  Subthreshold Depressive Disorder in Adolescents: Predictors of Escalation to Full-Syndrome Depressive Disorders 
Subthreshold depressive disorder is one of the best established risk factors for the onset of full-syndrome depressive disorders. However, many youths with subthreshold depressive disorder do not develop full-syndrome depression. We examined predictors of escalation to full-syndrome depressive disorders in a community sample of 225 adolescents with subthreshold depressive disorder.
Criteria for subthreshold depressive disorder were an episode of depressed mood or loss of interest or pleasure lasting at least 1 week and at least two of the seven other DSM-IV-associated symptoms for major depression. Participants were assessed four times from mid-adolescence to age 30 years using semistructured diagnostic interviews.
The estimated risk for escalation to full-syndrome depressive disorders was 67%. Five variables accounted for unique variance in predicting escalation: severity of depressive symptoms, medical conditions/symptoms, history of suicidal ideation, history of anxiety disorder, and familial loading for depression. Adolescents with three or more risk factors had an estimated 90% chance of escalating to full-syndrome depressive disorder, compared with 47% of adolescents with fewer than three risk factors.
These data may be useful in identifying a subgroup of youths with subthreshold depressive disorder who are at especially high risk for escalating to full-syndrome depressive disorders.
PMCID: PMC2866498  PMID: 19465876
14.  Is postpartum depression a homogenous disorder: time of onset, severity, symptoms and hopelessness in relation to the course of depression 
Postpartum depression (PPD) is a common illness, but due to the underlying processes and the diversity of symptoms, some variability is exhibited. The risk of postpartum depression is great if the mother has previously suffered from depression, but there is some evidence that a certain subgroup of women only experience depression during the postpartum period.
The study group consisted of 104 mothers with postpartum major depression and a control group of 104 postpartum mothers without depression. The Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) was used for data collection. The severity of depression and other mental symptoms were assessed using several validated rating scales.
A history of past depression (82%), including depression during pregnancy (42%) and during the postpartum period (53%), was very common in those with current PPD. Eighteen per cent of mothers with current PPD had previously not had any depressive episodes and four per cent had experienced depression only during the postpartum period. Therefore, pure PPD was rare. The onset of PPD was usually (84%) within six weeks of childbirth. Obsessive-compulsive symptoms, phobic anxiety, paranoid ideation, depressed mood, diminished pleasure/interest, decreased energy, and psychomotor agitation/retardation were common with all kinds of depression histories. Pure PPD was the most similar to the first depressive episode. Nevertheless, the severity of depression, the level of hopelessness, somatisation, interpersonal sensitivity, anxiety, hostility, psychoticism, sleep disturbance, and suicidal ideation were lower, appetite changed less, and concentration was better than in other recurrent depressions.
According to this study, PPD is not a homogenous disorder. The time of onset, severity, symptoms, level of hopelessness, and the course of depression vary. Recurrent depression is common. All mothers must be screened during the sixth week postpartum at the latest. Screening alone is not effective; it is also important to give mothers information about PPD and to discuss the symptoms with them in order for them to recognise this disorder and possible new episodes in the future.
PMCID: PMC4279462  PMID: 25491477
Postpartum depression; Pregnancy; Delivery; Depression; Symptoms; Hopelessness; General population
15.  Intima-media thickness and age of first depressive episode 
Biological psychology  2008;80(3):361-364.
Late life depression, including patients with vascular depression, has been associated with higher levels of intima-media thickness (IMT). Although individuals with vascular depression tend to report a later onset of depression, the relationship of IMT and age of first depressive episode is uncertain in younger adults. We therefore investigated the relationship between IMT and age of first depressive episode in a sample of 202 adults (age range 40−81 years) with major depression (MDD).
Depression status was assessed using the Structured Clinical Interview Schedule and the Hamilton Depression Rating Scale. Patients underwent a physical examination in which a medical history was obtained. IMT was measured from the left and right common carotid arteries. Simple regression analyses were used to investigate the association between IMT and self-reported age of first depressive episode.
IMT was associated with a later onset of first major depressive episode (b = .225, P = .0005) and this association remained significant after controlling for age, Framingham Stroke Risk Profile, smoking pack years, physical activity, high- and low-density lipoprotein, body mass index, triglyceride levels, and history of chronic medical conditions (b = .142, P = .028). Each .10 mm increase in IMT was associated with a 2.6-year later reported occurrence of first major depressive episode (MDE). Similarly, higher levels of IMT were associated with fewer previous MDEs (b = −.149, P = .020) and this effect remained significant in our multivariate model (b = −.140, P = .030). In contrast, IMT was not associated with current depressive severity (b = −.024, P = .720).
Greater levels of IMT are associated with a later onset of depression and fewer previous depressive episodes among middle-aged and older adults, independent of cardiovascular co-morbidities. These findings provide preliminary evidence that increased vascular burden may be associated with a later onset of depression.
PMCID: PMC2690231  PMID: 19041688
Intima-media thickness; Vascular disease; Depression; Vascular depression
16.  Intimate Partner Violence and Incident Depressive Symptoms and Suicide Attempts: A Systematic Review of Longitudinal Studies 
PLoS Medicine  2013;10(5):e1001439.
Karen Devries and colleagues conduct a systematic review of longitudinal studies to evaluate the direction of association between symptoms of depression and intimate partner violence.
Please see later in the article for the Editors' Summary
Depression and suicide are responsible for a substantial burden of disease globally. Evidence suggests that intimate partner violence (IPV) experience is associated with increased risk of depression, but also that people with mental disorders are at increased risk of violence. We aimed to investigate the extent to which IPV experience is associated with incident depression and suicide attempts, and vice versa, in both women and men.
Methods and Findings
We conducted a systematic review and meta-analysis of longitudinal studies published before February 1, 2013. More than 22,000 records from 20 databases were searched for studies examining physical and/or sexual intimate partner or dating violence and symptoms of depression, diagnosed major depressive disorder, dysthymia, mild depression, or suicide attempts. Random effects meta-analyses were used to generate pooled odds ratios (ORs). Sixteen studies with 36,163 participants met our inclusion criteria. All studies included female participants; four studies also included male participants. Few controlled for key potential confounders other than demographics. All but one depression study measured only depressive symptoms. For women, there was clear evidence of an association between IPV and incident depressive symptoms, with 12 of 13 studies showing a positive direction of association and 11 reaching statistical significance; pooled OR from six studies = 1.97 (95% CI 1.56–2.48, I2 = 50.4%, pheterogeneity = 0.073). There was also evidence of an association in the reverse direction between depressive symptoms and incident IPV (pooled OR from four studies = 1.93, 95% CI 1.51–2.48, I2 = 0%, p = 0.481). IPV was also associated with incident suicide attempts. For men, evidence suggested that IPV was associated with incident depressive symptoms, but there was no clear evidence of an association between IPV and suicide attempts or depression and incident IPV.
In women, IPV was associated with incident depressive symptoms, and depressive symptoms with incident IPV. IPV was associated with incident suicide attempts. In men, few studies were conducted, but evidence suggested IPV was associated with incident depressive symptoms. There was no clear evidence of association with suicide attempts.
Please see later in the article for the Editors' Summary
Editors' Summary
Depression and suicide are responsible for a substantial proportion of the global disease burden. Depression—an overwhelming feeling of sadness and hopelessness that can last for months or years—affects more than 350 million people worldwide. It is the eleventh leading cause of global disability-adjusted life-years (a measure of overall disease burden), and it affects one in six people at some time during their lives. Globally, about a million people commit suicide every year, usually because they have depression or some other mental illness. Notably, in cross-sectional studies (investigations that look at a population at a single time point), experience of intimate partner violence (IPV, also called domestic violence) is strongly and consistently associated with both depressive disorders and suicide. IPV, like depression and suicide, is extremely common—in multi-country studies, 15%–71% of women report being physically assaulted at some time during their lifetime. IPV is defined as physical, sexual, or psychological harm by a current or former partner or spouse; men as well as women can be the victims of IPV.
Why Was This Study Done?
It may seem obvious to assume that IPV is causally related to subsequent depression and suicidal behavior. However, cross-sectional studies provide no information about causality, and it is possible that depression and/or suicide attempts cause subsequent IPV or that there are common risk factors for IPV, depression, and suicide. For example, individuals with depressive symptoms may be more accepting of partners with characteristics that predispose them to use violence, or early life exposure to violence may predispose individuals to both depression and choosing violent partners. Here, as part of the Global Burden of Disease Study 2010, the researchers investigate the extent to which experience of IPV is associated with subsequent depression and suicide attempts and vice versa in both men and women by undertaking a systematic review and meta-analysis of longitudinal studies that have examined IPV, depression, and suicide attempts. A systematic review uses predefined criteria to identify all the research on a given topic, meta-analysis combines the results of several studies, and longitudinal studies track people over time to investigate associations between specific characteristics and outcomes.
What Did the Researchers Do and Find?
The researchers identified 16 longitudinal studies involving a total of 36,163 participants that met their inclusion criteria. All the studies included women, but only four also included men. All the studies were undertaken in high- and middle-income countries. For women, 11 studies showed a statistically significant association (an association unlikely to have occurred by chance) between IPV and subsequent depressive symptoms. In a meta-analysis of six studies, experience of IPV nearly doubled the risk of women subsequently reporting depressive symptoms. In addition, there was evidence of an association in the reverse direction. In a meta-analysis of four studies, depressive symptoms nearly doubled the risk of women subsequently experiencing IPV. IPV was also associated with subsequent suicide attempts among women. For men, there was some evidence from two studies that IPV was associated with depressive symptoms but no evidence for an association between IPV and subsequent suicide attempt or between depressive symptoms and subsequent IPV.
What Do These Findings Mean?
These findings suggest that women who are exposed to IPV are at increased risk of subsequent depression and that women who are depressed are more likely to be at risk of IPV. They also provide evidence of an association between IPV and subsequent suicide attempt for women. The study provides little evidence for similar relationships among men, but additional studies are needed to confirm this finding. Moreover, the accuracy of these findings is likely to be affected by several limitations of the study. For example, few of the included studies controlled for other factors that might have affected both exposure to IPV and depressive symptoms, and none of the studies considered the effect of emotional violence on depressive symptoms and suicide attempts. Nevertheless, these findings have two important implications. First, they suggest that preventing violence against women has the potential to reduce the global burden of disease related to depression and suicide. Second, they suggest that clinicians should pay attention to past experiences of violence and the risk of future violence when treating women who present with symptoms of depression.
Additional Information
Please access these websites via the online version of this summary at
This study is further discussed in a PLOS Medicine Perspective by Alexander Tsai
The US National Institute of Mental Health provides information on all aspects of depression and of suicide and suicide prevention (in English and Spanish)
The UK National Health Service Choices website provides detailed information about depression, including personal stories about depression, and information on suicide and its prevention; it has a webpage about domestic violence, which includes descriptions of personal experiences
The World Health Organization provides information on depression, on the global burden of suicide and on suicide prevention, and on intimate partner violence (some information in several languages)
MedlinePlus provides links to other resources about depression, suicide, and domestic violence (in English and Spanish)
The charity Healthtalkonline has personal stories about depression and about dealing with suicide
PMCID: PMC3646718  PMID: 23671407
17.  Lifetime Prevalence of Mental Disorders in Lebanon: First Onset, Treatment, and Exposure to War  
PLoS Medicine  2008;5(4):e61.
There are no published data on national lifetime prevalence and treatment of mental disorders in the Arab region. Furthermore, the effect of war on first onset of disorders has not been addressed previously on a national level, especially in the Arab region. Thus, the current study aims at investigating the lifetime prevalence, treatment, age of onset of mental disorders, and their relationship to war in Lebanon.
Methods and Findings
The Lebanese Evaluation of the Burden of Ailments and Needs Of the Nation study was carried out on a nationally representative sample of the Lebanese population (n = 2,857 adults). Respondents were interviewed using the fully structured WHO Composite International Diagnostic Interview 3.0. Lifetime prevalence of any Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) disorder was 25.8%. Anxiety (16.7%) and mood (12.6%) were more common than impulse control (4.4%) and substance (2.2%) disorders. Only a minority of people with any mental disorder ever received professional treatment, with substantial delays (6 to 28 y) between the onset of disorders and onset of treatment. War exposure increased the risk of first onset of anxiety (odds ratio [OR] 5.92, 95% confidence interval [CI] 2.5–14.1), mood (OR 3.32, 95% CI 2.0–5.6), and impulse control disorders (OR 12.72, 95% CI 4.5–35.7).
About one-fourth of the sample (25.8%) met criteria for at least one of the DSM-IV disorders at some point in their lives. There is a substantial unmet need for early identification and treatment. Exposure to war events increases the odds of first onset of mental disorders.
In a survey of 2,857 adults in Lebanon, Elie Karam and colleagues found a lifetime prevalence of any DSM-IV psychiatric disorder of 25.8%.
Editors' Summary
Mental illnesses—persistent problems with thinking, with feelings, with behavior, and with coping with life—are very common. In the UK about a quarter, and in the US, almost half, of people have a mental illness at some time during their life. Depression, for example, persistently lowers a person's mood and can make them feel hopeless and unmotivated. Anxiety—constant, unrealistic worries about daily life—can cause sleep problems and physical symptoms such as stomach pains. People with impulse-control disorders, have problems with controlling their temper or their impulses which may sometimes lead to hurting themselves or other people. These and other mental illnesses seriously affect the work, relationships, and quality of life of the ill person and of their family. However, most people with mental illnesses can lead fulfilling and productive lives with the help of appropriate medical and nonmedical therapies.
Why Was This Study Done?
Recent epidemiological surveys (studies that investigate the factors that affect the health of populations) have provided important information about the burden of mental disorders in some industrialized countries. However, little is known about the global prevalence of mental disorders (the proportion of people in a population with each disorder at one time) or about how events such as wars affect mental health. This information is needed so that individual countries can provide effective mental-health services for their populations. To provide this information, the World Mental Health (WMH) Survey Initiative is undertaking large-scale psychiatric epidemiological surveys in more than 29 countries. As part of this Initiative, researchers have examined the prevalence and treatment of mental disorders in Lebanon and have asked whether war in this country has affected the risk of becoming mentally ill.
What Did the Researchers Do and Find?
The researchers randomly selected a sample of nearly 3,000 adults living in Lebanon and interviewed them using an Arabic version of the World Health Organization's “Composite International Diagnostic Interview” (CIDI 3.0). This interview tool generates diagnoses of mental disorders in the form of “DSM-IV codes,” the American Psychiatric Association's standard codes for specific mental disorders. The researchers also asked the study participants about their experience of war-related traumatic events such as being a civilian in a war zone or being threatened by a weapon. The researchers found that one in four Lebanese had had one or more DSM-IV disorder at some time during their life. Major depression was the single most common disorder. The researchers also calculated that by the age of 75 years, about one-third of the Lebanese would probably have had one or more DSM-IV disorder. Only half of the Lebanese with a mood disorder ever received professional help; treatment rates for other mental disorders were even lower. The average delay in treatment ranged from 6 years for mood disorders to 28 years for anxiety disorders. Finally, exposure to war-related events increased the risk of developing an anxiety, mood, or impulse-control disorder by about 6-fold, 3-fold, and 13-fold, respectively.
What Do These Findings Mean?
These findings indicate that the prevalence of mental illness in Lebanon is similar to that in the UK and the US, the first time that this information has been available for an Arabic-speaking country. Indeed, the burden of mental illness in Lebanon may actually be higher than these findings suggest, because the taboos associated with mental illness may have stopped some study participants from reporting their problems. The findings also show that in Lebanon exposure to war-related events greatly increases the risk of developing for the first time several mental disorders. Further studies are needed to discover whether this finding is generalizable to other countries. Finally, these findings indicate that many people in Lebanon who develop a mental illness never receive appropriate treatment. There is no shortage of health-care professionals in Lebanon, so the researchers suggest that the best way to improve the diagnosis and treatment of mental disorders in this country might be to increase the awareness of these conditions and to reduce the taboos associated with mental illness, both among the general population and among health-care professionals.
Additional Information.
Please access these Web sites via the online version of this summary at
Read a related PLoS Medicine Perspective article
IDRAAC has a database that provides access to all published research articles related to mental health in the Arab World
The UK charity Mind provides information on understanding mental illness
The US National Institute of Mental Health provides information on understanding, treating, and preventing mental disorders (mainly in English but some information in Spanish)
MedlinePlus provides a list of useful links to information about mental health
Wikipedia has a page on DSM-IV codes (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The World Mental Health Survey Initiative and the Lebanese WHM study are described on the organizations' Web pages
PMCID: PMC2276523  PMID: 18384228
18.  Does Age at Onset of First Major Depressive Episode Indicate the Subtype of Major Depressive Disorder?: The Clinical Research Center for Depression Study 
Yonsei Medical Journal  2014;55(6):1712-1720.
The purpose of this study was to evaluate the effects of age at onset of the first major depressive episode on the clinical features of individuals with major depressive disorder (MDD) in a large cohort of Korean depressed patients.
Materials and Methods
We recruited 419 MDD patients of age over 18 years from the Clinical Research Center for Depression study in South Korea. At the start of the study, the onset age of the first major depressive episode was self-reported by the subjects. The subjects were divided into four age-at-onset subgroups: childhood and adolescent onset (ages <18), early adult onset (ages 18-44), middle adult onset (ages 45-59), and late onset (ages 60+). Using analysis of covariance (ANCOVA) and ordinal logistic regression analysis with adjusting the effect of age, the relationships between clinical features and age at onset of MDD were evaluated.
There was an apparent, but inconsistent correlation between clinical features and age at onset. Earlier onset MDD was significantly associated with higher proportion of female gender [adjusted odds ratio (AOR)=0.570, p=0.022], more previous suicide attempts (AOR=0.635, p=0.038), greater number of previous depressive episodes (F=3.475, p=0.016) and higher scores on the brief psychiatric rating scale (F=3.254, p=0.022), its negative symptom subscale (F=6.082, p<0.0001), and the alcohol use disorder identification test (F=7.061, p<0.0001).
Early age at onset may increase the likelihood of distinguishable MDD subtype, and age at onset of the first major depressive episode is a promising clinical indicator for the clinical presentation, course, and outcome of MDD.
PMCID: PMC4205714  PMID: 25323911
Major depressive disorder; age at onset; clinical indicator; subtype
19.  Seizures in Alzheimer Disease 
Archives of neurology  2009;66(8):992-997.
Transient symptoms in Alzheimer disease (AD) are frequent and include seizures, syncope, and episodes of inattention or confusion. The incidence of seizures in AD and predictors of which patients with AD might be more predisposed to them is based primarily on retrospective studies and is not well established.
To determine the incidence and predictors of new-onset unprovoked seizures.
Prospective cohort study.
Three academic centers.
Four hundred fifty-three patients with probable AD observed prospectively from mild disease stages since 1992.
Main Outcome Measure
Informant interviews every 6 months included questions about whether the patient had a seizure (convulsion, fainting, or “funny” spell) and whether diagnosis or treatment for epilepsy or seizure was made. Two epileptologists independently retrospectively reviewed all available medical records for 52 patients with positive responses to either of these questions, and using a specific checklist form, events were diagnosed as to whether they were unprovoked seizures (intrarater concordance, κ=0.67). Diagnosis of unprovoked seizures constituted the event in survival analyses. Potential predictors included sex, age, race/ethnicity, educational achievement, duration of illness, baseline cognition and function, depression, medical comorbidities, and time-dependent use of cholinesterase inhibitors and neuroleptic agents, apolipoprotein E genotype, and previous electroencephalographic findings.
Over the course of 3518 visit-assessments (per patient: mean, 7.8; maximum, 27), 7 patients (1.5%) developed seizures. Younger age was associated with higher risk (hazard ratio, 1.23; 95% confidence interval, 1.08–1.41; P=.003 for each additional year of age) of seizure incidence. No other predictor was significant. The overall incidence of seizures was low (418 per 100 000 person-years of observation) although significantly higher than expected for idiopathic unprovoked seizures in similar age ranges of the general population (hazard ratio, 8.06; 95% confidence interval, 3.23–16.61).
Unprovoked seizures are uncommon in AD, but they do occur more frequently than in the general population. Younger age is a risk factor for seizures in AD.
PMCID: PMC2768279  PMID: 19667221
20.  The Edinburgh Addiction Cohort: recruitment and follow-up of a primary care based sample of injection drug users and non drug-injecting controls 
BMC Public Health  2010;10:101.
Injection drug use is an important public health problem. Epidemiological understanding of this problem is incomplete as longitudinal studies in the general population are difficult to undertake. In particular little is known about early life risk factors for later drug injection or about the life course of injection once established including the influence of medical and social interventions.
Individuals thought to be drug injectors were identified through a single primary medical care facility in Edinburgh between 1980 and 2006 and flagged with the General Registry Office. From October 2005 - October 2007, these cases were traced and invited to undergo interview assessment covering early life experience, substance use, health and social histories. Age and sex matched controls for confirmed cases (alive and dead) were later recruited through the same health facility. Controls for living cases completed the same structured interview schedule. Data were also collected on cases and controls through linkage to routine primary care records, death registrations, hospital contact statistics and police and prison records. All interviews were conducted with the knowledge and permission of the current GP.
The initial cohort size was 814. At start of follow up 227 had died. Of the remaining 587: 20 had no contact details and 5 had embarked from the UK; 40 declined participation; 38 did not respond to invitations; 14 were excluded by their GP on health or social grounds and 22 had their contact details withheld by administrative authorities. 448 were interviewed of whom 16 denied injection and were excluded. Of 191 dead cases with medical records 4 were excluded as their records contained no evidence of injection. 5 interviewed cases died before follow up was concluded though these individuals were counted as "live" cases. 1 control per case (dead and alive) was recruited. Linkage to Scottish Morbidity Records data (available from 1981 onwards) on general acute inpatient and day cases, mental health inpatient and day cases and cancer was provided by Information Services, NHS Scotland, for all cases interviewed and all dead cases. The Scottish Prison Service provided records for 198 (46%) of cases interviewed, 48 cases not interviewed and 34 (18%) of dead cases. For a sub-sample of 100 interviewees a search of the Lothian and Borders police database was made for official criminal records and 94 had criminal records. Data linkage for controls is ongoing.
Injecting drug users recruited from a community setting can be successfully followed-up through interviews and record linkage. Information from injecting cases is being analysed in terms of injecting patterns and possible influences on these. Comparisons between cases and controls will allow identification of possibly modifiable early life risk factors for drug injection and will also clarify the burden of disease associated with injection and the influence on this of different health and social interventions.
PMCID: PMC2841670  PMID: 20187928
21.  The Early Course of Depression: A Longitudinal Investigation of Prodromal Symptoms and Their Relation to the Symptomatic Course of Depressive Episodes 
Journal of abnormal psychology  2010;119(3):459-467.
The current study explored longitudinal evidence for prodromal symptoms of depression episodes. A model based on previous findings of the relations between prodromal and residual symptoms was described and used to generate hypotheses tested in this study. Data were analyzed from 160 participants from the Cognitive Vulnerability to Depression (CVD) Project (Alloy & Abramson, 1999) who experienced an episode of depression during the prospective follow-up period and 60 CVD participants who did not. Congruent with the hypothesis, individuals who subsequently developed an episode of depression experienced significantly greater numbers of depression symptoms in the period of time leading up to the acute episode compared with those who did not develop a depressive episode. Seven depression symptoms were particularly likely to appear before the onset of an acute episode. Further, all three predictions from the model were supported: the durations of prodromal and residual phases were correlated, the prodromal and residual symptom profiles were quite similar, and the order of symptom onset was significantly and highly negatively correlated with the order of symptom remission. Additionally, residual symptom profiles were similar to subsequent prodromal symptom profiles in individuals who experienced more than one depressive episode. These findings are discussed in terms of the importance of understanding the earliest prodromal symptoms to appear and their relation to the symptomatic course of depression episodes. Implications for early intervention are also discussed.
PMCID: PMC2916193  PMID: 20677835
Depression; prodrome; symptoms; course
22.  Delirium episodes during the course of clinically diagnosed Alzheimer's disease. 
A retrospective review was conducted of 122 charts of patients with clinically diagnosed Alzheimer's disease (CDAD) who had participated in a longitudinal dementia study at the Mayo Clinic from 1965 to 1970. DSM-III-R diagnoses were assigned based on the longitudinal description of symptoms detailed in the Mayo Clinic medical records of the hospitalizations; clinic, home, and nursing home visits; and state hospital admissions. Thirty patients (25%) were found to have a delirium episode during their course of CDAD that occurred during inpatient admissions; 50% (15 of 30) of the delirium episode occurred in patients ages 80 to 89. Among patients with a delirium episode, 50% died within one year of the delirium episode and 64% died within two years. Of 13 patients, 10 (77%) had multiple delirium episodes within two years. Admitting diagnoses were mainly primary degenerative dementia of the Alzheimer's type (PDDAT) or PDDAT with delirium. Only 3 (10%) demented patients experienced delirium episodes during a medical admission. No deaths occurred during hospitalization for the years covered by this study. A psychiatric consultation was requested in only 17 (14%) patients; 88% of these patients received diagnoses involving PDDAT, late onset. An additional diagnosis included depressive disorders. Psychopharmacology was the major management strategy (82% of patients with a delirium episode received medication) with a resolution of symptoms within 48 hours. At discharge, only 2 (7%) patients failed to clear the increased degree of confusion.
PMCID: PMC2608571  PMID: 10641498
23.  Pain in castration-resistant prostate cancer with bone metastases: a qualitative study 
Bone metastases are a common painful and debilitating consequence of castration-resistant prostate cancer (CPRC). Bone pain may predict patients' prognosis and there is a need to further explore CRPC patients' experiences of bone pain in the overall context of disease pathology. Due to the subjective nature of pain, assessments of pain severity, onset and progression are reliant on patient assessment. Patient reported outcome (PRO) measures, therefore, are commonly used as key endpoints for evaluating the efficacy of CRPC treatments. Evidence of the content validity of leading PRO measures of pain severity used in CRPC clinical trials is, however, limited.
To document patients' experience of CRPC symptoms including pain, and their impact on health-related quality of life (HRQL), semi-structured in-depth qualitative interviews were conducted with 17 patients with CRPC and bone metastases. The content validity of the Present Pain Intensity (PPI) scale from the McGill Pain Questionnaire (MPQ), and the 'Average Pain' and 'Worst Pain' items of the Brief Pain Inventory Short-Form (BPI-SF) was also assessed.
Patients with CRPC and bone metastases present with a constellation of symptoms that can have a profound effect on HRQL. For patients in this study, bone pain was the most prominent and debilitating symptom associated with their condition. Bone pain was chronic and, despite being generally well-managed by analgesic medication, instances of breakthrough cancer pain (BTcP) were common. Cognitive debriefing of the selected PRO measures of pain severity highlighted difficulties among patients in understanding the verbal response scale (VRS) of the MPQ PPI scale. There were also some inconsistencies in the way in which the BPI-SF 'Average Pain' item was interpreted by patients. In contrast, the BPI-SF 'Worst Pain' item was well understood and interpreted consistently among patients.
Study findings support the importance of PRO measures of pain severity as key endpoints for evaluating the efficacy of treatments for CRPC, particularly for patients with bone metastases where episodes of BTcP are common. Qualitative evidence from CRPC patients supports the content validity of the BPI-SF ''Worst Pain' item and promotes use of this item for measuring pain severity in this population.
PMCID: PMC3222603  PMID: 21992720
24.  Correlates of continued smoking versus cessation among survivors of smoking-related cancers 
Psycho-oncology  2012;22(4):799-806.
We examined correlates of continued smoking versus cessation among a sample of survivors of smoking-related cancers who were actively smoking at the time of cancer diagnosis.
Participants with a history of smoking and a smoking-related cancer diagnosis (lung, oral, pharynx, larynx, esophagus, bladder, stomach, cervix, kidney, pancreas, acute myeloid leukemia) within the past four years were identified in the electronic medical record. We recruited 613 individuals to complete a mail-based survey and received 139 completed surveys (22.7% response rate). We focused on 105 participants who smoked at the time of diagnosis and dichotomized them to having either quit since diagnosis (48.6%; n=51) or continued smoking (51.4%; n=54). We assessed sociodemographics, type of cancer and treatment(s), and psychosocial factors (depressive symptoms, social support, hope, quality of life). We then conducted structured interviews with a subset of 21 survey respondents.
Binary logistic regression indicated that, controlling for age, gender, ethnicity, marital status, and income, factors associated with continued smoking versus cessation included being diagnosed with other smoking-related cancers versus lung or head and neck cancer (OR=11.21, CI 2.85, 44.02) and having significant depressive symptoms (OR=1.25, CI 1.08, 1.45). Qualitative findings highlighted motivators for cessation (impact of being diagnosed with cancer, doctor advice to quit, social influences) and barriers to cessation (hopelessness, stress, addiction).
These findings highlight the need to address depressive symptoms among cancer survivors, particularly those continuing to smoke, and the importance of exploring messages cancer survivors are given regarding the need for cessation post cancer diagnosis.
PMCID: PMC3425712  PMID: 22488864
Smoking; smoking cessation; survivors; depression; cancer; oncology
25.  Prognostic significance of functional somatic symptoms in adolescence: a 15-year community-based follow-up study of adolescents with depression compared with healthy peers 
BMC Psychiatry  2012;12:90.
There is a lack of population-based long-term longitudinal research on mental health status and functional physical/somatic symptoms. Little is known about the long-term mental health outcomes associated with somatic symptoms or the temporal relationship between depression and such symptoms. This 15-year study followed up adolescents with depression and matched controls, screened from a population-based sample, who reported different numbers of somatic symptoms.
The total population of 16–17-year-olds in Uppsala, Sweden, was screened for depression in 1991–1993. Adolescents who screened positive and an equal number of healthy controls took part in a semi-structured diagnostic interview. In addition, 21 different self-rated somatic symptoms were assessed. Sixty-four percent of those adolescents participated in a follow-up structured interview 15 years later.
Somatic symptoms in adolescence predicted depression and other adult mental disorders regardless of the presence of adolescent depression. In adolescents with depression, the number of functional somatic symptoms predicted, in a dose response relationship, suicidal behavior, bipolar episodes, and psychotic episodes as well as chronic and recurrent depression. Contrary to expectations, the somatic symptoms of abdominal pain and perspiration without exertion better predicted depression than all DSM-IV depressive symptoms. Abdominal pain persisted as an independent strong predictor of depression and anxiety, even after controlling for other important confounders.
Somatic symptoms in adolescence can predict severe adult mental health disorders. The number of somatic symptoms concurrent with adolescent depression is, in a stepwise manner, linked to suicidal attempts, bipolar disorders, psychotic disorders, and recurrent and chronic depression. These findings can be useful in developing treatment guidelines for patients with somatic symptoms.
PMCID: PMC3439696  PMID: 22839681
Adolescent depression; Long-term follow-up; Functional somatic symptoms; Anxiety and suicidal behavior

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