Prediction of lithium response using clinical data.

OBJECTIVE: Promptly establishing maintenance therapy could reduce morbidity and mortality in patients with bipolar disorder. Using a machine learning approach, we sought to evaluate whether lithium responsiveness (LR) is predictable using clinical markers. METHOD: Our data are the largest existing sample of direct interview-based clinical data from lithium-treated patients (n = 1266, 34.7% responders), collected across seven sites, internationally. We trained a random forest model to classify LR-as defined by the previously validated Alda scale-against 180 clinical predictors. RESULTS: Under appropriate cross-validation procedures, LR was predictable in the pooled sample with an area under the receiver operating characteristic curve of 0.80 (95% CI 0.78-0.82) and a Cohen kappa of 0.46 (0.4-0.51). The model demonstrated a particularly low false-positive rate (specificity 0.91 [0.88-0.92]). Features related to clinical course and the absence of rapid cycling appeared consistently informative. CONCLUSION: Clinical data can inform out-of-sample LR prediction to a potentially clinically relevant degree. Despite the relevance of clinical course and the absence of rapid cycling, there was substantial between-site heterogeneity with respect to feature importance. Future work must focus on improving classification of true positives, better characterizing between- and within-site heterogeneity, and further testing such models on new external datasets.

Reliability of Addenbrooke's Cognitive Examination III in differentiating between dementia, mild cognitive impairment and older adults who have not reported cognitive problems.

Diagnosing dementia can be challenging for clinicians, given the array of factors that contribute to changes in cognitive function. The Addenbrooke's Cognitive Examination III (ACE-III) is commonly used in dementia assessments, covering the domains of attention, memory, fluency, visuospatial and language. This study aims to (1) assess the reliability of ACE-III to differentiate between dementia, mild cognitive impairment (MCI) and controls and (2) establish whether the ACE-III is useful for diagnosing dementia subtypes. Client records from the Northern Health and Social Care Trust (NHSCT) Memory Service (n = 2,331, 2013-2019) were used in the analysis including people diagnosed with Alzheimer's disease (n = 637), vascular dementia (n = 252), mixed dementia (n = 490), MCI (n = 920) and controls (n = 32). There were significant differences in total ACE-III and subdomain scores between people with dementia, MCI and controls (p < 0.05 for all), with little overlap between distribution of total ACE-III scores (< 39%) between groups. The distribution of total ACE-III and subdomain scores across all dementias were similar. There were significant differences in scores for attention, memory and fluency between Alzheimer's disease and mixed dementia, and for visuospatial and language between Alzheimer's disease-vascular dementia (p < 0.05 for all). However, despite the significant differences across these subdomains, there was a high degree of overlap between these scores (> 73%) and thus the differences are not clinically relevant. The results suggest that ACE-III is a useful tool for discriminating between dementia, MCI and controls, but it is not reliable for discriminating between dementia subtypes. Nonetheless, the ACE-III is still a reliable tool for clinicians that can assist in making a dementia diagnosis in combination with other factors at assessment.

Anticipation in bipolar affective disorder: is age at onset a valid criterion?

Anticipation has been suggested among the genetic mechanisms of bipolar disorder (BD), prompting the search for unstable DNA sequences. Past studies of anticipation in BD have generally relied on observed shift in the age at onset between parental and offspring generations. Such a shift, however, may be caused by a number of other factors difficult to correct for. We investigated age at onset distributions in a sample of 161 related subjects and in a sample of "pseudofamilies" consisting of 320 unrelated subjects selected from a large epidemiological cohort using Monte-Carlo simulation to mimic the family sample. Comparison of age at onset distributions in both samples shows a difference between the generations, but of a similar magnitude in each sample. This suggests that age at onset alone may not be a sufficient criterion of anticipation. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:804-807, 2000.

Association and linkage studies of CRH and PENK genes in bipolar disorder: a collaborative IGSLI study.

Corticotropin-releasing hormone (CRH) and proenkephalin (PENK) are hypothalamic peptides involved in the stress response and hypothalamic-pituitary axis regulation. Previous research has implicated these peptides in the pathogenesis of affective disorders. In this study we investigated two polymorphisms located in the genes that code for CRH and PENK by means of association and linkage analyses. A total of 138 bipolar patients and 108 controls were included in the association study. In addition, 24 families were available for linkage analysis, including six families of probands with documented periodic positivity of dexamethasone suppression tests (DST) during remission. We found no association of bipolar disorder with either gene. Similarly, we did not find any evidence of linkage (P = 0.56 for CRH and 0.52 for PENK) in the entire sample or in the subsample of families of DST positive probands. In conclusion, our study does not support the hypothesis that genes coding for CRH or PENK contribute to the genetic susceptibility to bipolar disorder. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:178-181, 2000.

Genetic aspects in chronic schizophrenia. Morbidity risks and contributory factors.

112 schizophrenics, over 55 years old, and their relatives were studied. Aims of the study were (1) to evaluate the assumption that using an appropriate selection of probands and methods of the morbid risk estimation, one may expect to obtain a higher (and probably more realistic) value of risk to children; and (2) to assess the possible influence of patients' and relatives' characteristics on the magnitude of the morbid risk. The main results were (1) the values of risks (0.04 +/- 0.02 for spouses; 0.08 +/- 0.02 for siblings; 0.17 +/- 0.04 for offspring); (2) the risk to siblings and to children increased with the numbers of other relatives affected; (3) no clinical symptoms in probands (evaluated throughout the lifetime course of the disease) were associated with an increased/decreased value of risk to any class of relatives.

MAOA: association and linkage studies with lithium responsive bipolar disorder.

A number of association studies have investigated the role of the monoamine oxidase A (MAOA) gene in the susceptibility to bipolar disorder. Although some studies have reported positive findings, there remains some controversy, because results from different studies have not been consistent. A common explanation for inconsistencies between studies is genetic heterogeneity. We have focused on lithium responsive bipolar disorder as a way to reduce heterogeneity. In this study, we investigated the role of MAOA in lithium responsive bipolar patients using association and linkage study designs. The investigation used 138 patients and 108 normal controls. In addition, 25 families were also studied. Our results were not supportive of a major role of MAOA in the predisposition to bipolar disorder.

The circadian rhythm in plasma melatonin concentration of the urbanized man: the effect of summer and winter time.

Plasma melatonin rhythms were measured in healthy urbanized persons between July 4 and 5 and between January 13 and 14. In contrast to findings in other mammals studied thus far, no difference in the duration of elevated night melatonin concentration was observed between summer and winter. In winter, melatonin rhythms were phase-delayed by about 1.5 h as compared with summer patterns.

Maintenance of a circadian phase adjustment of the human melatonin rhythm following artificial long days.

In winter, a 5-day exposure of 4 human subjects to a skeleton photoperiod, with 3 h of bright light in the evening and again in the morning, phase advanced the morning serum melatonin offset by 1-3 h as compared with the original winter melatonin rhythm pattern. The phase advance persisted for 3 days even after the bright light withdrawal. The data indicate that the long skeleton photoperiod had a prevailing phase-advancing effect on the melatonin rhythm and its underlying pacemaker. The maintenance of the phase advance might be due to the fixed sleep-wake schedule.

Human circadian rhythm in serum melatonin in short winter days and in simulated artificial long days.

Serum melatonin rhythm was studied in 6 human subjects experiencing short winter days resembling light/dark (LD) 8:16 h and in 6 subjects exposed at the same time to a long, LD 16:8 h skeleton photoperiod, with 3 h of bright light in the evening and again in the morning; 4 out of the 6 subjects entrained to the simulated summer photoperiod within 3 days. In the synchronized subjects, the nocturnal melatonin signal was 3 h shorter than in those experiencing just winter days. The data indicate that humans are able to respond to environmental day length by forming a proper endogenous photoperiodic signal.

Early morning bright light phase advances the human circadian pacemaker within one day.

One day after a single exposure to bright light from 03.00 to 09.00 h the morning declines in the serum melatonin concentration were phase-advanced in all subjects relative to pre-exposure patterns by 1.2-2.6 h. The evening melatonin rise was phase-advanced in 5 out of 6 subjects by 0.6-2.2 h. The data suggest that an underlying human circadian pacemaker controlling the melatonin rhythm may be phase-advanced within one day; however, the evening melatonin rise and the morning decline do not necessarily phase-shift by the same amount.

Evidence supporting the independent inheritance of primary affective disorders and primary alcoholism in the families of bipolar patients.

BACKGROUND: This study explored the nature of the association between bipolar disorder and alcoholism. METHODS: The authors studied 814 first-degree relatives of 121 bipolar patients, divided on the basis of response to lithium prophylaxis. Logistic regression analysis was used to analyze the contribution of demographic, familial and clinical variables to the risk of primary alcoholism in the relatives. RESULTS: The risk of primary alcoholism in relatives was not related to the degree of affective loading in the family or to the proband's lithium response. CONCLUSION: This study does not support a shared genetic liability between bipolar disorder and alcoholism. LIMITATIONS: This study lacked a control group, but the analysis accounted for this. CLINICAL RELEVANCE: These disorders are not alternative forms of the same illness.

Lithium response and genetics of affective disorders.

The authors have carried out an investigation of psychiatric morbidity in families of patients who responded and failed to respond to long-term lithium treatment. The study included 121 probands with RDC primary affective disorders and 903 first-degree relatives and spouses. Seventy-one probands were responders and 50 were nonresponders to long-term lithium treatment. Extended to 20 years, the follow-up of patients and their families provided substantial information relevant for the diagnosis and reliable assessment of lithium response. The diagnoses were based on all available information, SADS-L interviews and RDC criteria. The principal statistical methods were survival analysis and Cox regression analysis. The results revealed a significantly higher frequency of bipolar disorder in the relatives of lithium responders (3.8% vs. 0%). Schizophrenia was more common in the families of nonresponders (2.4% vs. 0.3%). There were no significant differences in the rates of other psychiatric disorders. Both family history and the proband's diagnosis contribute independently to predicting response to long-term lithium.

Polyglutamine coding genes in bipolar disorder: lack of association with selected candidate loci.

BACKGROUND: Several studies have suggested that expanded trinucleotide repeats, particularly CAG, may have a role in the etiology of BD. Results obtained with the repeat expansion detection technique (RED) have indicated that bipolar patients have an excess of expanded CAG repeats. However, it is not clear which loci account for this difference. METHODS: Using lithium-responsive bipolar patients in order to reduce heterogeneity, we investigated five loci that are expressed in the brain and contain translated CAG repeats. A sample of 138 cases and 108 controls was studied. Genotypes were coded quantitatively or qualitatively and repeat distributions were compared. RESULTS: No difference was found in allele distribution between cases and controls for any of the loci studied. In one locus - L10378 - patients had a tendency to present shorter alleles (28.1 versus 27.9 repeats; t=2.55, df=205, P=0.011), however, this difference disappeared after correction for multiple testing. LIMITATIONS: The study has limitations common to most candidate gene association studies, that is, limited number of loci investigated and limited power to detect loci that account for a small proportion of the total genetic variability. CONCLUSIONS: Our results suggest that the loci investigated have no major role in the genetic predisposition to bipolar disorder.

The association study of DRD2, ACE and AGT gene polymorphisms and metamphetamine dependence.

We investigated the association between metamphetamine dependence and TaqI A polymorphism of the dopamine receptor D2 gene (DRD2), I/D polymorphism in angiotensin-converting enzyme (ACE) and M235T polymorphism of the angiotensinogen gene (AGT) in 93 unrelated metamphetamine-dependent subjects and 131 controls. Our results did not prove any association of TaqI A polymorphism of the DRD2 gene, I/D polymorphism of ACE gene, and M235T polymorphism of AGT gene with the metamphetamine dependence in Caucasians of Czech origin. However, a significant difference in allele I frequency between male and female control groups for the I/D ACE polymorphism (p<0.03) was found.