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.

MN blood groups and bipolar disorder: evidence of genotypic association and Hardy-Weinberg disequilibrium.

BACKGROUND: MN blood groups have been studied in the past as a genetic marker of biopolar disorder (BD). Several previous studies reported an association of the illness with lower frequency of blood group NN. METHODS: We analyzed distribution of MN blood groups in a sample of 174 patients with BD, 176 with unipolar depression, 98 with schizophrenia, and 331 healthy controls. In addition, we tested whether the inferred genotypes. conform to Hardy-Weinberg equilibrium (HWE). RESULTS: The frequency of NN phenotype was significantly lower among the bipolar patients than in any of the other three groups (p < .001). The genotype frequencies in the BD group deviated significantly from those expected under HWE (p < .01). CONCLUSIONS: These results suggest a possible locus on chromosome 4 (4q28-q31.1) associated with genetic susceptibility to bipolar illness.

Patterns of DST positivity in remitted affective disorders.

BACKGROUND: While the Dexamethasone Suppression Test (DST) has been extensively used in cross-sectional observations of patients with major affective disorders, studies have tended to ignore the longitudinal application of the DST in patients stabilized on long-term prophylactic medication. METHODS: Monthly DST's were performed on 19 patients, 16 with bipolar disorder and 3 with recurrent major depression. All cases had an excellent response to lithium treatment, and family history positive for bipolar disorder. The average duration of observation was 4 years. RESULTS: All patients remained clinically stable throughout the period of observation. Eleven patients showed intermittent DST positivity ranging from 10% to 60% of tests, and 2 patients exhibited no positivity. Six patients had fewer than 10% positive DST's. Females showed significantly higher positivity than males. The frequency of positivity did not correlate with current age, age of illness onset, duration of illness, duration of lithium treatment, or season. The risk of primary affective disorders in first-degree relatives was also unrelated to the frequency of positivity. CONCLUSIONS: While the highly selected and small sample population limits generalizability, our observations suggest that clinically sufficient lithium prophylaxis does not automatically prevent intermittent HPA dysregulation. We hope that a better understanding of this phenomenon will offer new approaches to the long-term management of mood disorders.

Less frequent lithium administration and lower urine volume.

OBJECTIVE: This study was designed to determine whether patients maintained on a regimen of lithium on a once-per-day schedule have lower urine volumes than do patients receiving multiple doses per day. METHOD: This was a cross-sectional study of 85 patients from a lithium clinic who received different dose schedules. Patients were admitted to the hospital for measurement of lithium level, creatinine clearance, urine volume, and maximum osmolality. RESULTS: Multiple daily doses of lithium were associated with higher urine volumes. The dosing schedule, duration of lithium treatment, and daily dose of lithium did not affect maximum osmolality or creatinine clearance. CONCLUSIONS: Urine volume can be reduced by giving lithium once daily and/or by lowering the total daily dose. Lithium-induced polyuria seems to be related to extrarenal as well as to renal effects.

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.

Lithium responsive bipolar disorder, unilineality, and chromosome 18: A linkage study.

Over the last three years several studies have investigated the hypothesis of linkage between bipolar disorder and markers on chromosome 18. Although independent groups have reported positive results, it is still not clear how these should be interpreted, as linkage spans a considerably large segment of the chromosome. In this study we have investigated linkage with chromosome 18 markers in 19 families of lithium-responsive bipolar patients, as a way to select a more homogeneous population. In addition, we have investigated whether there is evidence of a parent-of-origin effect as suggested by previous studies. Eleven markers spanning the whole chromosome were typed and linkage analysis was carried out using parametric and nonparametric methods. Analysis of the whole sample provided nonsignificant linkage results. However, when the sample included only unilineal families, and was further stratified according to parental origin, two chromosomal regions provided modestly positive lod scores. Maximum lod scores of 1.04 (P = 0.001) at D18S53 and 0.87 (P = 0.045) at D18S61 were observed for maternal and paternal pedigrees, respectively. Nonparametric analysis yielded similar results. In conclusion, our results are congruent with previous reports that suggest an advantage of unilineal pedigrees in linkage analysis of bipolar disorder and cannot rule out a parent-of-origin effect in this genomic region.

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.

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.

Varieties of lithium benefit.

Over the years much effort has gone into clarifying lithium's mechanism of action. It has been well-documented, and reviewed in the present symposium, that the effects of lithium on the human body are widespread, however it remains unclear which of the many effects is the one which mediates clinical benefit. One of the obstacles to progress has probably been an incomplete integration of clinical and laboratory approaches to the problem. In this paper we briefly summarize the main observations in the clinical dimension. The best-documented clinical effects of lithium have been mood stabilization, antimanic effects and antiaggressive action. Several other effects have, however, been observed and reported, some still controversial but all deserving our attention. We conclude that one can observe not one but several distinct, qualitatively separable benefits, with different clinical characteristics. It appears important that in any future laboratory search for the relevant mechanisms of action of lithium, we keep this clinical multiplicity in mind.

Lithium response and the sequence of episode polarities: preliminary report on a Hamilton sample.

This is a preliminary report on a study which replicated the finding of a significant relationship between the response to long-term lithium stabilization and the sequence of episode polarities (depressive/manic) in bipolar and schizoaffective (bipolar) patients. The lithium response and the clinical course data were assessed independently, in a blind manner, utilizing a data collection which has been gathered in earlier studies. There was a significant association between lithium response (stability achieved on long-term lithium treatment) and the sequence of episode polarities. The main determinant of this association was a close link between lithium response and the MDI sequence of episode polarities. The observed association may be explained in several ways: as an artifact; due to the exclusively antimanic effect of lithium; due to true psychobiological differences between mania and depression; as a result of the differences between bipolar type one and type two patients; and finally due to bipolar heterogeneity. Considering the data available to date the explanation via bipolar heterogeneity appears to be the most likely one.

Neuroendocrine strategies in affective disorders.

Neuroendocrine strategies in affective disorders have explored both resting values of hormones and hormonal responses to stimuli such as hypoglycemia, TRH, LHRH, dexamethasone, methadone and morphine. The abnormalities established to date have involved growth hormone, cortisol and TSH responses in particular. Prolactin has not been investigated to the same extent. We therefore describe several prolactin studies exemplifying selected neuroendocrine strategies. Our studies of prolactin responses included acute cases of either primary or secondary depression, stabilized bipolar patients, and healthy controls both off and on lithium. We found prolactin response to hypoglycemia significantly reduced in primary but not secondary depressions. Lithium administration led to flattened prolactin responses to hypoglycemia in stabilized bipolar patients but not in healthy controls. The flattened response in patients was observed already after 3 weeks of lithium, and remained flattened after years of treatment. The findings suggest a greater degree of prolactin response reduction in those patients showing most pronounced stability on lithium treatment.

Prolactin response to hypoglycemia in acute depression.

1. We tested a group of acutely depressed patients with a neuroendocrine battery and confirmed the alterations of growth hormone response to hypoglycemia and TSH response to TRH reported by others. 2. In addition, in the same patient sample we found markedly reduced response of prolactin to hypoglycemia. 3. Prolactin response remained low when the patients were retested during depression, however, normalization took place on recovery. 4. An attempt is made to explain these findings by underlying neurotransmitter abnormalities.

The effect of lithium administration on LH response in healthy volunteers.

1. As part of a systematic investigation of the effects of lithium administration on neuroendocrine function we investigated the luteinizing hormone (LH) response to luteinizing hormone releasing hormone (LHRH) of healthy males. 2. In healthy volunteers after 3 weeks of therapeutic doses of lithium the LH response to LHRH was significantly increased in comparison with the responses prior to lithium administration. 3. An attempt is made to explain these findings by underlying neurotransmitter changes.

Effect of chronic lithium on sensitivity to light in male and female bipolar patients.

1. Sensitivity to white light was quantified in euthymic bipolar male and female patients maintained on long term lithium therapy and age and sex matched unmedicated controls. 2. The Dark Adaptation Threshold procedure was used to assess sensitivity of both the cone and rod photoreceptors to short pulses of light. 3. Male and female controls did not differ in sensitivity to light. 4. Male patients in comparison to both controls and female patients evidenced reduced sensitivity to light during the cone and rod portion of the dark adaptation procedure. 5. Female patients did not differ from controls on sensitivity to light. 6. Using these and other published data the results were interpreted as suggesting that lithium reduces sensitivity to light during adaptation to dark.

Lithium effects on neuroendocrine function.

We studied growth hormone and prolactin responses to insulin hypoglycemia and TSH response to TRH in symptom-free bipolar patients and healthy controls. There were no significant differences in prolactin and growth hormone responses to hypoglycemia between stabilized bipolar patients and healthy controls, both tested medication-free. When lithium was administered to both groups, only bipolar patients showed a dramatic reduction in prolactin and growth hormone responses. Both bipolar patients in remission and healthy controls showed an increase of TSH response to TRH when treated with lithium in comparison with the testings before lithium administration. The subjects, both patients and volunteers, showed a comparable degree of hypoglycemia on and off lithium. The observed difference in responsiveness of bipolar patients warrants further systematic investigation and offers interesting possibilities for practical utilization.

Investigations of melatonin secretion in man.

Overnight melatonin secretion shows substantial and significant intraindividual stability and large interindividual variation. Melatonin concentrations obtained between 1 and 5 a.m. significantly correlate with overall melatonin secretion (expressed as the area under the curve) while a single determination of serum melatonin does not adequately reflect the entire night secretion. Secretion correlates positively with "neuroendocrine responsiveness" (rating responses in other neuroendocrine challenge tests) and there is trend for negative correlation with age. In volunteers the administration of the usual therapeutic dose of lithium did not alter the overnight melatonin secretion. However, there was an elevation of isolated secretory values at the early morning timepoints. In comparison with volunteers, lithium administration tended to reduce the overnight melatonin secretion in bipolar patients, however, the difference did not reach statistical significance.

Effects of lithium, nortriptyline and dexamethasone on insulin sensitivity.

The effects of lithium, dexamethasone, nortriptyline and their combinations on insulin sensitivity, expressed as a drop of plasma glucose in response to insulin challenge, were investigated in healthy volunteers. Short-term (three weeks) lithium treatment did not appear to exert any influence on the insulin sensitivity. Dexamethasone administered alone (2 mg given 57 hours prior to the test) had no effect on the insulin sensitivity of drug-free healthy subjects. However, after three weeks of lithium treatment the dexamethasone premedication resulted in slight flattening of glucose response to insulin in the same persons. Nortriptyline administered for three weeks to healthy volunteers, pretreated with dexamethasone, increased insulin sensitivity. These findings may have clinical implications regarding the treatment of depressed diabetic patients, and may provide information about the regulation of insulin sensitivity.

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.

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.

Autosomal recessive inheritance of affective disorders in families of responders to lithium prophylaxis?

In this paper we report the results of a study of the mode of inheritance in affective disorders responsive to lithium. Earlier we described a series of 71 families in which the genetic transmission was compatible with a single-gene model. We have now carried out an independent replication study on 25 newly recruited families in a different geographical location. The autosomal recessive model from our original study could not be rejected with the new data. In a subsequent analysis of the pooled sample of 96 families, a recessive model with a common predisposing allele (q = 0.16) and sex-specific penetrance (0.35 in males, 0.66 in females) fitted the data best. On the other hand, X-chromosome and polygenic models could be rejected. The finding of a major-gene effect represents a specific hypothesis that can be tested by molecular genetic techniques.