Irving I. Gottesman's Collaboration in Psychiatric Genetics Research in Denmark.

Irving I. Gottesman played an important role for psychiatric genetic research in Denmark through more than 40 years of collaboration with Danish scientists, resulting in important twin and family studies based upon the unique national registers available in Denmark.

Rapid test for lung maturity, based on spectroscopy of gastric aspirate, predicted respiratory distress syndrome with high sensitivity.

AIM: Respiratory distress syndrome (RDS) is a major cause of mortality and morbidity in premature infants. By the time symptoms appear, it may already be too late to prevent a severe course, with bronchopulmonary dysplasia or mortality. We aimed to develop a rapid test of lung maturity for targeting surfactant supplementation. METHODS: Concentrations of the most surface-active lung phospholipid dipalmitoylphosphatidylcholine and sphingomyelin in gastric aspirates from premature infants were measured by mass spectrometry and expressed as the lecithin/sphingomyelin ratio (L/S). The same aspirates were analysed with mid-infrared spectroscopy. Subsequently, L/S was measured in gastric aspirates and oropharyngeal secretions from another group of premature infants using spectroscopy and the results were compared with RDS development. The 10-minute analysis required 10 µL of aspirate. RESULTS: An L/S algorithm was developed based on 89 aspirates. Subsequently, gastric aspirates were sampled in 136 infants of 24-31 weeks of gestation and 61 (45%) developed RDS. The cut-off value of L/S was 2.2, sensitivity was 92%, and specificity was 73%. In 59 cases, the oropharyngeal secretions had less valid L/S than gastric aspirate results. CONCLUSION: Our rapid test for lung maturity, based on spectroscopy of gastric aspirate, predicted RDS with high sensitivity.

A Danish Twin Study of Schizophrenia Liability: Investigation from Interviewed Twins for Genetic Links to Affective Psychoses and for Cross-Cohort Comparisons.

We studied schizophrenia liability in a Danish population-based sample of 44 twin pairs (13 MZ, 31 DZ, SS plus OS) in order to replicate previous twin study findings using contemporary diagnostic criteria, to examine genetic liability shared between schizophrenia and other disorders, and to explore whether variance in schizophrenia liability attributable to environmental factors may have decreased with successive cohorts exposed to improvements in public health. ICD-10 diagnoses were determined by clinical interview. Although the best-fitting, most parsimonious biometric model of schizophrenia liability specified variance attributable to additive genetic and non-shared environmental factors, this model did not differ significantly from a model that also included non-additive genetic factors, consistent with recent interview-based twin studies. Schizophrenia showed strong genetic links to other psychotic disorders but much less so for the broader category of psychiatric disorders in general. We also observed a marginally significant decline in schizophrenia variance attributable to environmental factors over successive Western European cohorts, consistent perhaps with improvements in diagnosis and in prenatal and perinatal care and with a secular decline in the prevalence of schizophrenia in that region.

Long-term stability of acute and transient psychotic disorders.

OBJECTIVE: To examine the temporal stability of the category 'acute and transient psychotic disorders' (ATPDs), ICD-10 Classification of Mental and Behavioural Disorders, including subtypes characterised by polymorphic, schizophrenic and predominantly delusional features. METHOD: We checked the readmission patterns of all patients aged 15-64 years (n = 5426), whether admitted to hospital or treated as outpatients, who were enrolled for the first time in the Danish Psychiatric Register with a diagnosis of ATPDs between 1995 and 2008. RESULTS: An increasing number of cases with ATPDs changed diagnosis in subsequent admissions after 1, 2 and 5 years, mainly either to schizophrenia and related disorders or affective disorders. In their last admission, on average after 7.3 years, there were 2429 patients listed with ATPDs, accounting for an overall stability of 44.8%. Females were less likely than males to develop another diagnosis. Among the ATPD subtypes, polymorphic psychotic disorder without schizophrenic symptoms had a higher stability than those featuring schizophrenic or predominantly delusional features. CONCLUSIONS: The low diagnostic stability of ATPDs reflects the lack of clearly defining features and argues against their validity as a distinct category.

Mortality and causes of death of acute and transient psychotic disorders.

BACKGROUND: Little is known about mortality associated with acute transient psychoses. This paper examines mortality and causes of death of ICD-10 F23 'Acute and transient psychotic disorders' (ATPD). METHOD: Data from all subjects aged over 15 years who were enrolled in 1996 in the Danish psychiatric register with a first-admission diagnosis of ATPD were linked to the national register of causes of death. The standardized mortality ratio (SMR) for overall mortality and specific categories were calculated. RESULTS: Over the period 1996-2001, 87 (17.3%) of 503 patients with ATPD had died, accounting for a mortality rate of 35.3 per 1,000 person/years. The SMR for all causes (2.9), natural causes (2.5), and unnatural causes (9.2) were significantly increased. Suicide had the greatest SMR (30.9). CONCLUSIONS: These findings argue for excess mortality of ATPD particularly from suicide.

Hippocampal volume and cell number in depression, schizophrenia, and suicide subjects.

Many studies suggest that the hippocampus is involved in the pathophysiology of psychiatric disorders, especially major depressive disorder (MDD) and schizophrenia. Especially, in vivo imaging studies indicate that the volume of hippocampus may be reduced in both disorders. Moreover, suicide may have a unique neurobiology. The aim of the present study is to investigate if depression, schizophrenia or suicide is associated with reduced postmortem volume of the hippocampal formation and/or changes in the numbers of neurons and/or glial cells in the different subregions of the hippocampus. We studied postmortem brain samples from 10 subjects with schizophrenia, 8 subjects with major depression, 11 suicide subjects with a history of depressive disorder, and 10 control subjects with no history of psychiatric or neurological diseases. The total volume and numbers of neurons and glial cells were estimated for the main hippocampal subregions using design-unbiased stereological techniques. We found the total volume and total numbers of neurons and glial cells similarly reduced by approximately 20% to 35% in depression and schizophrenia subjects relative to control subjects across all hippocampal regions. In suicide subjects, we only found increased neuron number in CA2/3 subregion. The volume and number of cells are reduced in depression and schizophrenia subjects relative to control subjects across all hippocampal regions. Our findings imply that the hippocampus may be a common site of pathophysiology in depression and schizophrenia. Community living suicide subjects seem to differ in hippocampal neurobiology compared to hospitalized subjects dying with MDD without suicide.

18F-FDG PET/CT for Very Early Response Evaluation Predicts CT Response in Erlotinib-Treated Non-Small Cell Lung Cancer Patients: A Comparison of Assessment Methods.

The purpose of this study was to determine which method for early response evaluation with 18F-FDG PET/CT performed most optimally for the prediction of response on a later CT scan in erlotinib-treated non-small cell lung cancer patients. Methods:18F-FDG PET/CT scans were obtained before and after 7-10 d of erlotinib treatment in 50 non-small cell lung cancer patients. The scans were evaluated using a qualitative approach and various semiquantitative methods including percentage change in SUVs, lean body mass-corrected (SUL) SULpeak, SULmax, and total lesion glycolysis (TLG). The PET parameters and their corresponding response categories were compared with the percentage change in the sum of the longest diameter in target lesions and the resulting response categories from a CT scan obtained after 9-11 wk of erlotinib treatment using receiver-operating-characteristic analysis, linear regression, and quadratic-weighted κ. Results: TLG delineation according to the PERCIST showed the strongest correlation to sum of the longest diameter (R = 0.564, P < 0.001), compared with SULmax (R = 0.298, P = 0.039) and SULpeak (R = 0.402, P = 0.005). For predicting progression on CT, receiver-operating-characteristic analysis showed area under the curves between 0.79 and 0.92, with the highest area under the curve of 0.92 (95% confidence interval [CI], 0.84-1.00) found for TLG (PERCIST). Furthermore, the use of a cutoff of 25% change in TLG (PERCIST) for both partial metabolic response and progressive metabolic disease, which is the best predictor of the CT response categories, showed a κ-value of 0.53 (95% CI, 0.31-0.75). This method identifies 41% of the later progressive diseases on CT, with no false-positives. Visual evaluation correctly categorized 50%, with a κ-value of 0.47 (95% CI, 0.24-0.70). Conclusion: TLG (PERCIST) was the optimal predictor of response on later CT scans, outperforming both SULpeak and SULmax The use of TLG (PERCIST) with a 25% cutoff after 1-2 wk of treatment allows us to safely identify 41% of the patients who will not benefit from erlotinib and stop the treatment at this time.

Family history of psychiatric illness as a risk factor for schizoaffective disorder: a Danish register-based cohort study.

BACKGROUND: Schizoaffective disorder may be related to both schizophrenia and bipolar disorders, but no population-based studies, to our knowledge, have investigated this association in families. OBJECTIVES: To determine whether a psychiatric history of schizoaffective disorder, bipolar disorder, or schizophrenia among parents and siblings is a risk factor for developing a schizoaffective disorder, and whether a specific pattern of family history of psychiatric illness exists in persons with schizoaffective disorder compared with persons with bipolar disorder or schizophrenia. DESIGN: Register-based cohort study. SETTING: Denmark. COHORT: The 2.4 million persons born in Denmark after 1952. MAIN OUTCOME MEASURES: Relative risks of the 3 illnesses estimated by Poisson regression. RESULTS: In total, 1925 persons had a schizoaffective disorder, 3721 had a bipolar disorder, and 12 501 had schizophrenia. The relative risk of schizoaffective disorder was 2.76 (95% confidence interval, 2.49-3.06) if a first-degree relative had a history of mental illness compared with a person with no first-degree relatives with such a history. There was an additional risk (95% confidence interval) of 2.57 (2.11-3.13), 3.23 (2.63-3.95), or 1.92 (1.43-2.57) if the first-degree relative had schizophrenia, bipolar disorder, or schizoaffective disorder, respectively, compared with other psychiatric admissions. When bipolar disorder was the outcome, bipolar disorder in first-degree relatives was by far the significantly strongest risk factor. When schizophrenia was the outcome, the significantly strongest risk factor was schizophrenia among first-degree relatives. CONCLUSION: Schizoaffective disorder is not simply a subgroup of either bipolar disorder or schizophrenia but may be genetically linked to both, with schizoaffective disorder being a subtype of each or a genetic intermediate form.

Short-term course and outcome of acute and transient psychotic disorders: Differences from other types of psychosis with acute onset.

BACKGROUND: The category of 'acute and transient psychotic disorders' (ATPDs) appeared in the ICD-10 Classification of Mental and Behavioural Disorders (ICD-10), but its distinctive features remain uncertain. AIM: To examine the course and outcome of ATPDs, pointing out differences from other types of psychosis. METHODS: A one-year follow-up investigation of patients enrolled at the former World Health Organization (WHO) Centre for Research and Training in Mental Health in Aarhus (Denmark) for the WHO collaborative study on acute psychoses. RESULTS: Of 91 patients aged 15-60 years presenting with acute psychosis, 47 (51.6%) were diagnosed with ATPD, and it occurred more commonly in females; yet, the other acute psychoses featured mainly mood disorders and affected equally both genders. After 1 year, the ATPD diagnosis did not change in 28 cases (59.6%); the remaining developed either affective psychoses (27.7%), or schizophrenia and schizoaffective disorder (12.8%). Nearly, all patients with unchanged diagnosis of ATPD enjoyed full recovery, while those with other types of acute psychosis had significantly higher rates of recurrence or incomplete remission. Duration of illness within 4 weeks and stressful events in the 3 months before symptom onset predicted 1-year favourable clinical outcome for acute psychoses. CONCLUSION: Although ATPDs fared better over the short-term than other acute psychoses, their diagnostic stability is relatively low.

A comprehensive nationwide study of the incidence rate and lifetime risk for treated mental disorders.

IMPORTANCE: Understanding the epidemiologic profile of the life course of mental disorders is fundamental for research and planning for health care. Although previous studies have used population surveys, informative and complementary estimates can be derived from population-based registers. OBJECTIVE: To derive comprehensive and precise estimates of the incidence rate of and lifetime risk for any mental disorder and a range of specific mental disorders. DESIGN, SETTING, AND PARTICIPANTS: We conducted a follow-up study of all Danish residents (5.6 million persons), to whom all treatment is provided by the government health care system without charge to the patient, from January 1, 2000, through December 31, 2012 (total follow-up, 59.5 million person-years). During the study period, 320,543 persons received first lifetime treatment in a psychiatric setting for any mental disorder; 489,006 persons were censored owing to death; and 69,987 persons were censored owing to emigration. Specific categories of mental disorders investigated included organic mental disorders, substance abuse disorders, schizophrenia, mood disorders, anxiety, eating disorders, personality disorders, mental retardation, pervasive developmental disorders, and behavioral and emotional disorders. EXPOSURES: Age and sex. MAIN OUTCOMES AND MEASURES: Sex- and age-specific incidence rates and cumulative incidences and sex-specific lifetime risks. RESULTS: During the course of life, 37.66% of females (95% CI, 37.52%-37.80%) and 32.05% of males (31.91%-32.19%) received their first treatment in a psychiatric setting for any mental disorder. The occurrence of mental disorders varied markedly between diagnostic categories and by sex and age. The sex- and age-specific incidence rates for many mental disorders had a single peak incidence rate during the second and third decades of life. Some disorders had a second peak in the sex- and age-specific incidence rate later in life. CONCLUSIONS AND RELEVANCE: This nationwide study provides a first comprehensive assessment of the lifetime risks for treated mental disorders. Approximately one-third of the Danish population received treatment for mental disorders. The distinct signatures of the different mental disorders with respect to sex and age have important implications for service planning and etiologic research.

The association between psychotic mania, psychotic depression and mixed affective episodes among 14,529 patients with bipolar disorder.

BACKGROUND: Psychotic and mixed affective episodes are prevalent in the course of bipolar disorder. Despite many studies on the implications of psychotic mania (PM), psychotic depression (PD) and mixed affective episodes (MAE), relatively little is known about the relationship between the three subtypes. The present study aimed to investigate whether the occurrence of PM, PD and MAE were associated with one another. METHODS: This is a nationwide register-based, historical prospective cohort study. Data was obtained from the Danish Psychiatric Central Research Register. Subjects were defined as all individuals assigned with an ICD-10 diagnosis of bipolar disorder between January 1st 1994 and December 31st 2010. Potential associations among psychotic and mixed affective episodes were tested by means of logistic regression. RESULTS: We identified 14,529 individuals with bipolar disorder with lifetime incidences of PM, PD and MAE of 19%, 15% and 17% respectively. We detected significant associations between PM and MAE (Adjusted Odds Ratio (AOR)=1.26, p=0.003), PD and MAE (AOR=1.24, p=0.001), and PM and PD (AOR=1.28, p=0.005). LIMITATIONS: Diagnoses were assigned as part of routine clinical practice. CONCLUSIONS: According to this register-based study, PD, PM and MAE are all associated with one another. This knowledge should be taken into consideration by clinicians when monitoring patients with bipolar disorder and by nosologists when defining the criteria and potential subtypes for mixed affective episodes for the upcoming DSM-5 and ICD-11.

Early surfactant guided by lamellar body counts on gastric aspirate in very preterm infants.

BACKGROUND: We have developed a rapid method, based on lamellar body counts (LBC) on gastric aspirate, for identifying newborns who will develop respiratory distress syndrome with a need for surfactant supplementation. OBJECTIVE: We set out to test whether it was possible to improve the outcome when used in a clinical trial. METHODS: We randomly assigned 380 infants born at 24-29 weeks' gestation and supported with nasal continuous positive airway pressure (nCPAP) to receive surfactant guided either by LBC (intervention group) or increasing need for oxygen (control group). The primary outcome was mechanical ventilation or death within 5 days. Secondary outcomes included need for oxygen expressed by arterial to alveolar oxygen tension ratio (a/APO2) at the age of 6 h and need for oxygen at day 28. RESULTS: The primary outcomes were equal (25%) in the two groups. The intervention group had higher a/APO2 than the control group at 6 h, median 0.64 versus 0.52 (p < 0.01), and the subgroup with gestational age 26-29 weeks needed fewer days of oxygen supplementation than the controls, median 2 vs. 9 days (p = 0.01), and fewer infants needed oxygen at day 28 (p = 0.04). Furthermore, there was a tendency in the intervention group towards a shorter duration of nCPAP. Too little or viscose aspirate in 23% of the cases was a limitation of the method. CONCLUSION: Using LBC test as indicator of lung maturity and early surfactant therapy in very preterm newborns, it is possible to reduce the need for oxygen supplementation.

Rethinking the classification of mixed affective episodes in ICD-11.

Mixed affective episode is a prevalent mood disorder characterized by the coexistence or rapid alternation of manic and depressive symptoms, which is associated with significant suffering and high risk of suicide. Unfortunately, the current diagnostic classification of mixed affective episodes in the ICD-10 lacks a detailed definition with relevant subtypes. This inconsistency has significant negative implications for both research into the disorders in the bipolar spectrum and for clinical practice. For this reason there is a need for special attention on this diagnosis in the revisions of the diagnostic manuals. In this manuscript we suggest a set of clear diagnostic criteria and exhaustive subtypes for the mixed affective episodes aimed at the upcoming ICD-11. The defined syndrome and its subtypes are in close congruence with the suggested DSM-5 "mixed episode specifier", which is an advantage for common understanding and for research across the ICD/DSM border.

[The concept of insanity in Danish penal and mental health codes]. / Sindssygdomsbegrebet i straffelov og psykiatrilov.

The medical terms insanity and psychosis are used synonymously to describe a condition with substantial changes in the "total" personality and loss of realism. In the 10th revision of the diagnostic classification system ICD-10 (1994) the intention was to replace the term "psychosis" with "psychotic" to indicate the presence of hallucinations and delusions. However, in Danish legislation - most importantly in the penal code and the Mental Health Act - the term "insanity" is still in use. This difference has lead to diagnostic uncertainty, especially in clinical and forensic psychiatric practice.

Use of ICD-10 diagnoses in Danish psychiatric hospital-based services in 2001-2007.

The Danish version of the ICD-10 chapter on mental and behavioural disorders has 380 different diagnoses when three digits are used. This study examines how many of the available diagnoses were used and to what extent in Danish psychiatric hospital-based services in the period from 2001 to 2007, through an analysis of the total number of diagnoses reported to the Danish Psychiatric Central Research Register (n=1,260,097). The 50th percentile (50.1%) was reached by using 16 diagnoses (4.2% of 380 available). The three most frequently registered diagnoses were paranoid schizophrenia, alcohol dependence and adjustment disorder, used 10.2%, 8.3% and 5.9% of the times, respectively. Seven diagnoses (1.8%) were used between 1 and 4 times during the 7-year period. One hundred nine (28.7% of available diagnoses) were used less than 100 times each. These data suggest that it may be sensible to reconsider the number of diagnoses needed in the revision of the ICD-10 chapter on mental and behavioural disorders.

Severe mental disorders in offspring with 2 psychiatrically ill parents.

BACKGROUND: Studies of couples of psychiatric patients with children allow us to calculate the effects of double predispositions on morbid risk in the offspring, which is of interest for molecular genetic research and for genetic counseling. OBJECTIVE: To determine the risks in offspring of receiving a diagnosis of schizophrenia, bipolar disorder, unipolar depressive disorder, or any diagnosis from parents who both have received a diagnosis of schizophrenia or bipolar disorder. DESIGN: National register-based cohort study. SETTING: Denmark. PARTICIPANTS: A population-based cohort of 2.7 million persons born in Denmark, alive in 1968 or born later than 1968, with a register link to their mother and father and aged 10 years or older in 2007. MAIN OUTCOME MEASURE: Risk of schizophrenia or bipolar disorder, calculated as cumulative incidences by age 52 years. RESULTS: The risk of schizophrenia in 270 offspring of 196 parent couples who were both admitted to a psychiatric facility with a diagnosis of schizophrenia was 27.3% (increasing to 39.2% when schizophrenia-related disorders were included) compared with 7.0% in 13 878 offspring from 8006 couples with only 1 parent ever admitted for schizophrenia and 0.86% in 2 239 551 offspring of 1 080 030 couples with neither parent ever admitted. The risk of bipolar disorder was 24.9% in 146 offspring of 83 parent couples who were ever admitted with bipolar disorder (increasing to 36.0% when unipolar depressive disorder was included) compared with 4.4% in 23 152 offspring from 11 995 couples with only 1 parent ever admitted and 0.48% in 2 239 553 offspring of 1 080 030 couples with neither parent ever admitted. Risks of schizophrenia and bipolar disorder in offspring of couples with 1 parent with schizophrenia and the other with bipolar disorder were 15.6% and 11.7%, respectively. The maximal risks of any psychiatric disorders in the offspring of parents both with schizophrenia or both with bipolar disorder were 67.5% and 44.2%, respectively. CONCLUSIONS: Derived risks may be informative for counseling. Patterns of transmission may support evolving assumptions about genetic overlap for traditional categories.

Incidence and diagnostic stability of ICD-10 acute and transient psychotic disorders.

OBJECTIVE: The 10th Revision of the International Classification of Diseases (ICD-10) introduced a new diagnostic category, F23 acute and transient psychotic disorders (ATPD) to embrace clinical concepts such as the French bouffée délirante, Kleist and Leonhard's cycloid psychoses, and the Scandinavian reactive and schizophreniform psychoses. The relative rarity of these disorders and insufficient follow-up studies with adequate numbers of patients makes ATPD classification as uncertain as their validity. The aim of this study was to evaluate incidence and validity of ATPD in terms of diagnostic stability. METHOD: A 6-year analysis of readmission patterns of all subjects listed in the Danish psychiatric central register as having been first-ever admitted to hospital or treated in outpatient services with a diagnosis of ATPD from January 1 to December 31, 1996, was conducted. RESULTS: The incidence of ATPD was 9.6 per 100 000 population, with a higher rate of females than males (9.8 vs 9.4). Incidence rates by age group were higher for males than for females, with a marked reversal of this pattern above 50 years. This contrasted with incidence of schizophrenia that was almost twice as high in males as in females, particularly in the 20-29 year age group. Of 416 cases with a first-admission diagnosis of ATPD, an increasing number tended to change on subsequent admissions, nearly half to another F2 category schizophrenia and related disorders. The overall stability rate reached only 39%. CONCLUSIONS: Although demographic differences from schizophrenia are topics that deserve further research, poor diagnostic stability argues against attempts to separate ATPD from borderland disorders.

The relationship of reactive psychosis and ICD-10 acute and transient psychotic disorders: evidence from a case register-based comparison.

BACKGROUND: ICD-10 introduced a new diagnostic category, F23 'acute and transient psychotic disorders' (ATPD), to embrace clinical concepts such as bouffée délirante, cycloid psychosis, psychogenic (reactive) psychosis and schizophreniform psychosis. The purpose of this study was to examine the relationship between the concept of reactive psychosis (RP), equivalent to the ICD-8 298 category of 'other psychoses', and ATPD. SAMPLING AND METHOD: Since January 1, 1994, ICD-10 has replaced ICD-8 as official classification in Denmark. Patients given an ICD-8 298 diagnosis on their last admission in 1992-1993 were identified from the Danish Psychiatric Central Register, and the ICD-8 diagnoses assigned were compared with their ICD-10 diagnoses when readmitted in 1994-1995. RESULTS: Diagnosis of RP was recorded in 19.2% of patients with functional psychoses in 1992-1993, whereas ATPD overall prevalence accounted for 8.7% of those with non-organic psychotic and affective disorders in 1994-1995. Thirty-eight per cent of patients with an ICD-8 298 diagnosis were readmitted during the years 1994-1995. Schizophrenia and related disorders (F2) and affective disorders (F3) accounted for three quarters of ICD-10 diagnoses. The most frequently used ATPD subcategories were F23.3 'other acute delusional psychotic disorders', F23.0 'acute polymorphic psychotic disorder without symptoms of schizophrenia' and F23.9 'acute and transient psychotic disorder unspecified'. A significant majority were female and associated acute stress was recorded only in 5.3% of cases. CONCLUSIONS: ICD-8 298 register diagnosis of RP showed little empirical continuity to ATPD and conformed more to F23.3 acute delusional disorder among ATPD subtypes.