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.

Solar insolation in springtime influences age of onset of bipolar I disorder.

OBJECTIVE: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder. METHOD: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density. RESULTS: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001). CONCLUSION: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge.

Novel integrative genomic tool for interrogating lithium response in bipolar disorder.

We developed a novel integrative genomic tool called GRANITE (Genetic Regulatory Analysis of Networks Investigational Tool Environment) that can effectively analyze large complex data sets to generate interactive networks. GRANITE is an open-source tool and invaluable resource for a variety of genomic fields. Although our analysis is confined to static expression data, GRANITE has the capability of evaluating time-course data and generating interactive networks that may shed light on acute versus chronic treatment, as well as evaluating dose response and providing insight into mechanisms that underlie therapeutic versus sub-therapeutic doses or toxic doses. As a proof-of-concept study, we investigated lithium (Li) response in bipolar disorder (BD). BD is a severe mood disorder marked by cycles of mania and depression. Li is one of the most commonly prescribed and decidedly effective treatments for many patients (responders), although its mode of action is not yet fully understood, nor is it effective in every patient (non-responders). In an in vitro study, we compared vehicle versus chronic Li treatment in patient-derived lymphoblastoid cells (LCLs) (derived from either responders or non-responders) using both microRNA (miRNA) and messenger RNA gene expression profiling. We present both Li responder and non-responder network visualizations created by our GRANITE analysis in BD. We identified by network visualization that the Let-7 family is consistently downregulated by Li in both groups where this miRNA family has been implicated in neurodegeneration, cell survival and synaptic development. We discuss the potential of this analysis for investigating treatment response and even providing clinicians with a tool for predicting treatment response in their patients, as well as for providing the industry with a tool for identifying network nodes as targets for novel drug discovery.

Influence of birth cohort on age of onset cluster analysis in bipolar I disorder.

PURPOSE: Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database. METHODS: The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared. RESULTS: There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups. CONCLUSION: These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.

Benign paroxysmal positional vertigo and migraine: analysis of 186 cases.

OBJECTIVE: This retrospective study assessed several clinical, case history and functional parameters to investigate benign paroxysmal positional vertigo (BPPV) in patients with migraine. METHODS: Two groups of patients were compared: those affected by BPPV and migraine (group A), as defined by International Headache Society criteria, and those with BPPV without migraine or with another form of headache (group B). The following parameters were investigated: onset of BPPV, recovery time, residual dizziness, recurrence of BPPV, atypical eye movement patterns and Meniere-like vertigo in the inter-critical BPPV period. RESULTS: Mean age at BPPV onset was 39 years +/- 9.2 in Group A and 53 years +/- 7.3 in Group B (p = 0.00). No significant difference emerged in the number of manoeuvres needed to achieve recovery (Group A: 1.7 +/- 0.94; Group B: 1.9 +/- 0.89; p > 0.05). Highly recurrent BPPV (at least 4 documented episodes) was observed in 15 patients from group A (19.4%) and in 8 patients from group B (7.3%). Atypical eyes movements and Meniere-like vertigo were more frequent in migraineurs with highly recurrent BPPV (Chi square = 5.76; p < 0.016). CONCLUSIONS: A high prevalence of BPPV and earlier onset in migraine are the main findings of this study. There is a higher incidence of a range of neurotological patterns in the intervals between BPPV episodes in migraineurs with recurrent vertigo. No direct pathophysiological link between migraine and BPPV has yet been established; comorbidity seems to affect clinical features in a sub-population of patients and make BPPV more debilitating.

APOE and Alzheimer disease: a major gene with semi-dominant inheritance.

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.

Age at onset in bipolar disorder: Investigation of the role of TaqIA polymorphism of DRD2 gene in a Sardinian sample.

Bipolar disorder (BD) is a highly heterogeneous and heritable psychiatric illness. Age at onset has been shown to be a powerful tool for dissecting both the phenotypic and genetic complexity of BD. In this article, we present findings from an association study between the DRD2 TaqIA polymorphism and age at onset, showing that both alleles and genotypes at this locus associate with early onset BD.

Fifteen-year follow-up of thyroid function in lithium patients.

OBJECTIVE: To study prospectively the course of clinically relevant thyroid dysfunction in a cohort of patients on long-term lithium treatment. METHOD: Patients (no.=150) who had undergone a cross-sectional evaluation of their thyroid function in 1989, when they were at different stages of lithium treatment, were followed up for thyroid circulating thyroid antibodies, hypothyroidism, hyperthyroidism, and thyroidectomy, during a further period of lithium exposure of up to 15 yr. RESULTS: Annual rates of newly developed circulating thyroid antibodies and hypothyroidism were 1.7 and 1.5%, respectively. Subjects with thyroid antibodies had a higher chance of requiring substitution treatment with levothyroxine for hypothyroidism compared with subjects with no evidence of thyroid antibodies (6.4% annual rate compared to 0.8%; relative risk: 8.4; 95% confidence interval: 2.9-24.0). One case of hyperthyroidism was observed over 976 patient-yr. Three patients underwent thyroidectomy during followup (two for multinodular goiter and one for multicentric papillary carcinoma). CONCLUSIONS: Lithium may be associated with hypothyroidism in particular in the presence of circulating thyroid antibodies. Incidence of thyroid antibodies is comparable with that reported for the general population. Hyperthyroidism and thyroid cancer are rare.

Therapeutic drug monitoring of gentamicin in neonatal intensive care unit: experience in 68 newborns.

A proper dosing regimen is fundamental when antibiotics with a low therapeutic index, as aminoglycosides (AMG), are used. AMG pharmacokinetics present a strong interindividual and intraindividual variability in neonates; in the premature neonate AMG clearance is reduced and the half-life is longer, leading to higher serum trough concentrations. Neonates may require therapeutic drug monitoring (TDM) and a "tailored" therapeutic regimen. The aim of this work is to present our personal experience wtih TDM of gentamicin in 68 newborns and to compare it with data available in the literature.

Pharmacogenomics: state of the research and perspectives in clinical application.

The person-to-person variability of drug response is a major problem in clinical practice and in drug development. It can lead to therapeutic failure or adverse drug reactions (ADRs) in individuals or subpopulation of patients. In addition to the high occurence of ADRs and the associated morbidity and mortality, substantial costs are incurred. Potential risk factors for drug inefficacy or toxicity include drug-drug interactions, the patient's age, renal and liver functions or other disease factors, and lifestyle variables such as smoking and alcohol consumption. In addition, it has become clear in recent years that genetic factors may also significantly modify drug responses or increase the risk for ADRs. Genetic variations in genes (polymorphisms) for drug-metabolizing enzymes, drug receptors, and drug transporters have been associated with individual variability in the efficacy and toxicity of drugs. It is now widely accepted that migraine is a polygenic and multifactorial disorders, thus considered to be a genetic complex disease. Genetic studies on migraine suggested a role of CACNA1A and DRD2 genes as susceptibility genes in this disorder.

Association studies in candidate genes: strategies to select SNPs to be tested.

OBJECTIVE: When numerous single nucleotide polymorphisms (SNPs) have been identified in a candidate gene, a relevant and still unanswered question is to determine how many and which of these SNPs should be optimally tested to detect an association with the disease. Testing them all is expensive and often unnecessary. Alleles at different SNPs may be associated in the population because of the existence of linkage disequilibrium, so that knowing the alleles carried at one SNP could provide exact or partial knowledge of alleles carried at a second SNP. We present here a method to select the most appropriate subset of SNPs in a candidate gene based on the pairwise linkage disequilibrium between the different SNPs. METHOD: The best subset is identified through power computations performed under different genetic models, assuming that one of the SNPs identified is the disease susceptibility variant. RESULTS: We applied the method on two data sets, an empirical study of the APOE gene region and a simulated study concerning one of the major genes (MG1) from the Genetic Analysis Workshop 12. For these two genes, the sets of SNPs selected were compared to the ones obtained using two other methods that need the reconstruction of multilocus haplotypes in order to identify haplotype-tag SNPs (htSNPs). We showed that with both data sets, our method performed better than the other selection methods.

Association of personal and familial suicide risk with low serum cholesterol concentration in male lithium patients.

OBJECTIVE: We sought to establish whether low cholesterol concentration may be associated with a personal history of attempted suicide or a family history of completed suicide in psychiatric out-patients on maintenance lithium treatment, who represent a population at risk for suicide. METHOD: We retrospectively reviewed charts regarding 783 out-patients consecutively admitted to a lithium clinic from 1976 to 1999. Individual age- and gender-specific quartile of serum cholesterol concentration were correlated against personal lifetime suicide attempts and completed suicide in first-degree relatives. RESULTS: The proportion of men with a personal lifetime history of attempted suicide, especially if violent, and that of men with history of completed suicide in a first-degree relative were significantly higher among the group with cholesterol concentration in the lowest quartile compared to the group with cholesterol levels above the 25th percentile. CONCLUSION: Low cholesterol concentration should be studied further as a potential biological/genetic marker of suicide risk.

Evidence that cyproterone acetate improves psychological symptoms and enhances the activity of the dopaminergic system in postmenopause.

The psychological symptoms assessed with a validated psychometric scale, SCL-90, were significantly higher in postmenopausal women (PMW; 60 subjects) than in premenopausal women (20 subjects). In the same PMW, the activity of the dopaminergic system, assessed with the PRL response to the dopamine-blocking agent sulpiride, was significantly lower than that in premenopausal women. During a period of 12 weeks the 60 PMW were randomly divided into 3 groups: no treatment (group A; n = 20), treatment with estradiol (E(2)) alone (patches with a E(2) release of 50 microg/24 h; group B; n = 20), and treatment with hormonal replacement therapy [estradiol valerate (EV) at a daily dose of 2 mg for 11 days and EV at the same daily doses plus cyproterone acetate (CPA) at a daily dose of 1 mg/day for 10 days; group C; n = 20). At the 12th week of the observation, only in group C women were the psychological symptoms significantly decreased, and the indirect evaluation of the dopaminergic system activity through PRL response to sulpiride showed a significant increase. During the same period, no changes in testosterone levels were observed in any group of PMW, whereas a significant increase in E(2) levels was found in both groups B and C. Although it is likely that the improvement in psychological symptoms with EV and CPA was due to progestin, we cannot rule out the possibility that greater estrogen exposure may have played a role.

Dopaminergic hypersensitivity in migraine: clinical and genetic evidence.

Migraine is a common disorder characterized by recurrent pain attacks of mild-severe intensity associated with autonomic and occasionally neurological symptoms. The migraine attack is a complex process that involves both central and peripheral structures. Various pathogenetic hypotheses have been proposed but the pathophysiology of the disease is still unknown. The study of the pathophysiology of migraine includes the investigation of neurotransmitter systems and their potential role in the development of the attack. Several studies performed since the '60s have demonstrated the key role of serotonin. The theory whereby hypersensitivity of the dopaminergic system may be involved in the pathogenesis of migraine has been supported by various authors on the basis of clinical, pharmacological and recent genic evidence. Recent neurophysiological studies performed using new techniques have led to a correlation of migraine with central nervous system disorders characterized by an altered neuronal excitability. Migraine seems to be characterized by a low threshold of neuronal excitability which is in turn regulated by genetic factors involving the dopaminergic system. A genetically determined hypersensitivity of the dopaminergic system may be involved in the onset of the migraine attack.

Family-based association study between bipolar disorder and DRD2, DRD4, DAT, and SERT in Sardinia.

Association analysis of candidate genes may represent a strategy for clarifying the genetic components involved in bipolar disorder. Polymorphism at dopamine receptor genes DRD2, DRD4, and dopamine and serotonin transporter genes (DAT, SERT) has been used in previous association studies. Some authors have reported positive association between certain alleles and bipolar disorder, using the case-control design. In this family-based association study of DRD2, DRD4, DAT, and SERT, the distribution of parental nontransmitted alleles was compared with that of alleles transmitted to 53 Sardinian probands suffering from bipolar disorder. The transmission disequilibrium test (TDT) was used to detect any disproportionate transmission of alleles by heterozygous parents to affected children. No differences were found between the allele distribution of polymorphisms at DRD2, DRD4, DAT, and SERT in probands and parental nontransmitted chromosomes. TDT did not reveal any difference between transmitted and nontransmitted alleles. Our results do not support the hypothesis of a role for DRD2, DRD4, DAT, or SERT in bipolar disorder. Previously reported positive associations between DRD2 or SERT and bipolar disorder were conceivably due to stratification dependent on the case-control design, even though our sample might have failed to detect small associations due to limited power.

Maternal inheritance of manic depression in hemizygotes for the G6PD-Mediterranean mutation. Indirect evidence for Xq28 transmission in Sardinia.

Both X-linkage and a parent-of-origin effect have been hypothesized in manic-depressive disorder. We have previously shown an allelic association between X-linked G6PD deficiency and manic depression in Mediterranean populations. To test both X-linkage and a parent-of-origin effect in manic depression further, we have studied 274 Sardinian manic-depressive probands and their parents. Excess of maternal transmission (P = 0.005) of major affective disorder was found in male probands carrying the G6PD-Mediterranean mutation. Our results provide indirect molecular support for an association between manic depression and the Xq28 chromosome region in Sardinia. Further studies on Xq28 using tests of allelic association and transmission disequilibrium with multiple DNA markers are required, to clarify the nature of the association we have found. Our study cannot implicate or exclude a direct role for G6PD deficiency in the aetiology of manic depression.

Induction of Fos-like-immunoreactivity in the central extended amygdala by antidepressant drugs.

The induction of the early gene c-fos was evaluated through Fos immunohistochemistry in areas belonging to the extended amygdala after acute administration of two antidepressants, citalopram and imipramine. Both citalopram and imipramine at the dose of 5 and 20 mg/kg, respectively, induced Fos-like immunoreactivity (FLI) in the central amygdaloid nucleus, lateral division of the bed nucleus of the stria terminalis (BSTL), and interstitial nucleus of the posterior limb of the anterior commissure (IPAC). The shell of the nucleus accumbens, which forms a continuum with the central extended amygdala, showed a decrease of FLI after administration of either citalopram or imipramine. The mechanism of action and the brain areas affected by antidepressants are still a matter of debate. By showing that the central extended amygdala is a common site of action for two different antidepressant types, these results provide new insight into the mechanism of action of antidepressants.

Suicidal behavior on and off lithium prophylaxis in a group of patients with prior suicide attempts.

One hundred patients who had attempted suicide before commencing lithium prophylaxis were followed up. Outcome was analyzed in terms of attempted or completed suicide after a mean of 10 years since admission to the lithium clinics. Of 10 patients who committed suicide, 9 had discontinued adequate lithium prophylaxis for a period ranging from 2 weeks to 7 years before death. Having discontinued lithium therapy was associated with suicide also in the subgroup of patients for whom lithium had not completely prevented episodes during lithium treatment. Suicide risk was 24 times as high during periods off compared with periods on adequate lithium prophylaxis. Incidence of attempting suicide was similar during the periods before receiving or after discontinuing lithium treatment, whereas it was 5 to 6 times lower during prophylaxis. Continuous and adequate lithium prophylaxis should be considered in the presence of high suicide risk, even if the prophylactic effect on the underlying mood disorder may be incomplete.

Association between dopamine receptor genes and migraine without aura in a Sardinian sample.

BACKGROUND: Migraine seems to be caused by a combination of environmental and genetic factors. Clinical and pharmacologic evidence supports the hypothesis that dopaminergic transmission is involved in the pathogenesis of migraine. OBJECTIVE: The current report concerns a genetic study to test the involvement of genes for dopamine (DA) receptors D2 (DRD2), D3 (DRD3), and D4 (DRD4) in migraine without aura, particularly in a subgroup with enhanced DA sensitivity. METHODS: For the first time, a family-based association method--the Transmission Disequilibrium Test (TDT)--was used to examine an isolated population, such as Sardinians. We studied 50 nuclear families of patients affected by migraine without aura. The subgroup of dopaminergic migraineurs was selected based on the presence of both nausea and yawning immediately before or during the pain phase of migraine. RESULTS: No association was detected using the TDT between DRD3, DRD4, and migraine without aura either in the overall sample or in the subgroup. No difference was observed in DRD2 allelic distribution in the overall sample, although the allelic distribution at the DRD2 locus differed significantly in the subgroup of dopaminergic migraineurs (p = 0.004). Allele 1 of the TG dinucleotide intronic noncoding polymorphism of the DRD2 locus was the individual allele that appeared to be in disequilibrium with migraine without aura (p = 0.02). CONCLUSIONS: Our data suggest that a genetic approach could be useful in providing molecular support to the hypothesis that hypersensitivity of the dopaminergic system may represent the pathophysiologic basis of migraine, at least in a subgroup of patients.

Calcitonin decreases lithium plasma levels in man. Preliminary report.

Lithium kinetics were studied in four manic-depressive women treated with calcitonin for post-menopausal osteoporosis. During calcitonin therapy all patients showed a significant decrease of lithium blood levels, and an increase in lithium renal clearance was observed in two out of two patients. According to these data, lithium therapy needs to be adjusted in patients undergoing concomitant treatment with calcitonin.