Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms.

Because of the high costs associated with ascertainment of families, most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. Although microsatellite markers spaced every 10 cM typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carried out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 single-nucleotide polymorphisms. Of the ~1100 families, 972 were informative for further analyses, and mean information content was 0.86 after pruning for linkage disequilibrium. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with bipolar II disorder (BPII) and 702 subjects with recurrent major depression. Three affection status models (ASMs) were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus recurrent major depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (non-parametric pairs LOD 3.4 for rs1046943 at 119 cM) and 9q21 (non-parametric pairs logarithm of odds (LOD) 3.4 for rs722642 at 78 cM) using only BPI and schizoaffective (SA), BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis, we observed 59 parametric LODs of 2 or greater, many of which are likely to be close to maximum possible scores. Although some linkage findings may be false positives, the results could help prioritize the search for rare variants using whole exome or genome sequencing.

Electrodermal activity among subtypes of depression.

To determine whether subgroups of depressed patients could be differentiated on the basis of electrodermal activity (EDA), the skin conductance of 36 depressed patients was recorded for two experimental conditions. In the first condition, subjects heard 10 85-dB tones after receiving instructions that were intended to relax the patients. In the second experimental condition, subjects heard 12 105-dB tones, one-half of which were signal tones containing a brief gap in the middle. The subjects were required to respond to the tones containing the gap by pressing a foot pedal. No differences in tonic or phasic EDA were detected on the basis of unipolar or bipolar subtype, response to the dexamethasone suppression test, severity of depression, medication status, or sex. However, patients who exhibited features of psychomotor retardation had significantly lower levels of tonic EDA than did their nonretarded counterparts. The EDA of the depressed patients as a group was uniformly low. These results are consistent with other reports indicating that, with the exception of the retarded/nonretarded distinction, there are no differences in EDA among the various subtypes of depression.

Olfactory identification and psychosis.

BACKGROUND: Olfactory identification performance has been investigated in several psychiatric populations, with deficits most commonly reported in patients with schizophrenia. In this study, olfactory identification performance was investigated in a more homogenous group of treatment-refractory patients with schizophrenia (T-RS) and in two additional psychiatric groups who demonstrate some similarities to the patients with schizophrenia in terms of symptomotology and medication regime. METHODS: The olfactory identification performance of 16 T-RS patients was assessed using the University of Pennsylvania Smell Identification Test (UPSIT) and compared to that of 16 normal control subjects and two other psychiatric patient groups: 19 affective disorder patients requiring maintenance antipsychotic medication and 20 affective disorder patients not receiving antipsychotic medication. RESULTS: The olfactory identification performance of T-RS patients was significantly lower than that of normal controls but not significantly different from either affective disorder group. The olfactory identification performance of affective disorder patients receiving antipsychotic medication was significantly lower than that of affective disorder patients not receiving antipsychotic medication. DISCUSSION: Results are discussed in the context of a possible link between psychotic symptomotology and olfactory identification performance.

Effects of chronic lithium treatment on retinal electrophysiologic function.

Some hypotheses suggest that lithium produces its therapeutic effect by reducing sensitivity to light at the level of the retina. In humans, acute administration of lithium is associated with a reduction in retinal light sensitivity. To determine whether similar retinal light sensitivity changes occur with chronic use, we studied 24 euthymic bipolar patients on chronic lithium treatment and 21 age- and sex-matched normal comparison subjects using electroretinography (ERG) and electro-oculography (EOG). No significant differences were found in ERG b-wave amplitudes or implicit times, or in EOG ratios, between the two groups. We conclude that chronic lithium use is not associated with differences in retinal light sensitivity when bipolar patients are compared to normal comparison subjects, and that there is no evidence for retinal toxicity with long-term lithium treatment.

Complex partial and pseudoseizure disorders.

The differentiation of ictal and nonictal seizure disorders is difficult, particularly in patients suffering from partial seizures with complex symptomatology. The authors state that observation of a patient's habitual seizure during EEG recording is the ideal diagnostic tool and describe their method of seizure activation with sphenoidal electrodes and simultaneous audiovisual monitoring. They emphasize the necessity for early, aggressive treatment of both ictal and nonictal seizure disorders, point out risks to the patient if the incorrect diagnosis is made, and urge further cooperation between psychiatrists and neurologists in this borderland area.

A controlled study of light therapy for bulimia nervosa.

OBJECTIVE: Winter worsening of mood and eating symptoms, similar to that of seasonal affective disorder, has recently been reported in patients with bulimia nervosa. To assess the effectiveness of light therapy for treatment of bulimia nervosa, the authors conducted a study of light therapy during winter comparing an active (bright white light) condition to a control (dim red light) condition in bulimic patients who were not selected for a seasonal pattern of bulimia. METHOD: After a 2-week baseline assessment, 17 female patients with a DSM-III-R diagnosis of bulimia nervosa underwent early morning light treatment with 2 weeks of bright white light exposure (10,000 lux for 30 min/day) and 2 weeks of dim red light exposure (500 lux for 30 min/day) in a counterbalanced, crossover design. Outcome measures included daily binge/purge diaries, objective and subjective measures of mood, and the Eating Attitudes Test. Expectation of response for each condition was also assessed before treatment. RESULTS: Although pretreatment expectation ratings were similar for each condition, the bright white light condition was superior to the dim red light condition for all mood and eating outcome measures. Patients with "seasonal" bulimia (N = 7) had significantly greater improvement after the bright white light treatment than patients with nonseasonal bulimia (N = 10). No significant order effects were noted, nor differential effects for patients taking concurrent antidepressant medications (N = 4). CONCLUSIONS: These data suggest that bright white light therapy is an effective short-term treatment for both mood and eating disturbances associated with bulimia nervosa, although the therapeutic effect may be greater in those patients with a seasonal pattern.

Low electrooculographic ratios in patients with seasonal affective disorder.

OBJECTIVE: Changes in retinal sensitivity to light have been hypothesized as etiological in seasonal affective disorder. This study was undertaken to investigate sensitivity to light in seasonal affective disorder using electrooculography (EOG), an objective measure of retinal light response. METHOD: In a mood disorders clinic, 19 depressed, drug-free patients with seasonal affective disorder, diagnosed by DSM-III-R criteria, were compared with 19 age- and sex-matched normal comparison subjects. All subjects had identical EOG testing performed during the winter. EOG (Arden) ratios were calculated from the EOG data. RESULTS According to multivariate analysis of variance, the EOG ratios in the patients with seasonal affective disorder were significantly lower than those of the normal comparison subjects, although there was considerable overlap in EOG ratios between patients and comparison subjects. CONCLUSIONS: These results suggest that seasonal affective disorder is associated with subtle retinal abnormalities at the level of the photoreceptor/retinal pigment epithelium complex, consistent with subsensitivity to light. A limitation of this study is that the retinal origins of the EOG response are nonspecific and still not completely elucidated.

Depressive symptoms and family history in seasonal and nonseasonal mood disorders.

OBJECTIVE: The authors' goal was to compare the symptoms and family history of seasonal affective disorder with those of nonseasonal mood disorders. METHOD: From a subspecialty mood disorders clinic, 34 patients with major depression, seasonal pattern (seasonal affective disorder), diagnosed with DSM-III-R criteria, were matched in age, sex, and diagnostic subtype (recurrent unipolar, bipolar I, or bipolar II) to 34 patients with nonseasonal mood disorders. Data on symptoms during the most recent depressive episode were obtained by chart review and compared by using chi-square tests. Family history data for first-degree relatives of patients with seasonal and nonseasonal mood disorders were gathered by using the family history method, and diagnoses were based on Family History Research Diagnostic Criteria. RESULTS: Patients with seasonal affective disorder reported significantly more hypersomnia, hyperphagia, and weight gain and reported less suicidal ideation and morning worsening of mood than the patients with nonseasonal mood disorders. No differences were found in family histories of mood disorders, other psychiatric disorders, and any psychiatric disorder between the groups with seasonal versus nonseasonal mood disorders. Alcoholism was found more frequently in the relatives of the patients with seasonal affective disorder. CONCLUSIONS: Differences in symptoms between seasonal and nonseasonal mood disorders provide some support for seasonal affective disorder as a diagnostic subtype of mood disorders. However, the genetic loading for mood disorders (of unspecified seasonality), as determined by the family history method, is similar for seasonal and nonseasonal mood disorders.

Clozapine in the treatment of parkinsonian patients with dopaminomimetic psychosis.

In a double-blind placebo-controlled study, we evaluated the effects of clozapine (75 to 250 mg/day, mean 170.8) on dopaminomimetic psychosis and parkinsonian disability. Clozapine prevented deterioration of psychosis during the increase of dopaminomimetics in the 3 patients who completed the study. Worsening of parkinsonism occurred in 3 of the 6 patients. In the dosage used, clozapine's usefulness was limited by its propensity to produce sedation, confusion, and increased parkinsonism.

Depression and multiple sclerosis.

The objective of the present study were (1) to ascertain the lifetime risk of a depression in a representative group of multiple sclerosis (MS) patients, (2) to assess the morbidity risks for depression among first-degree relatives of these MS patients, and (3) to compare these familial risks for first-degree relatives of MS patients with those for first-degree relatives of a primary depression population, i.e., depression but no MS. We psychiatrically evaluated 221 MS patients (index cases) using a structured clinical interview for the DSM-III-R and calculated the rate and lifetime risk of depression for these index cases using the product limit estimate of survival function. We obtained psychiatric histories for all first-degree relatives of index cases, and we calculated morbidity risks for depression for these relatives using the maximum likelihood approach and compared the risks using the likelihood ratio tests. Index cases had a 50.3% lifetime risk of depression. Morbidity risks for depression among first-degree relatives of index cases were decidedly lower when compared with morbidity risks among first-degree relatives of the reference population. Although there appears to be a very high rate of depression among MS patients, the data for their first-degree relatives do not support a clear genetic basis for this depression, or at least the same genetic basis that probably operates within families when depression occurs in the absence of MS.

Major depression, minor depression, and double depression: are they distinct clinical entities?

The clinical concept of "double depression," i.e., the superimposition of a major depressive disorder in a patient with dysthymic disorder, implies that there are at least some differences between dysthymia, major depression, and double depression. However, the relationship between these two syndromes remains unclear. The present study uses genetic methodology to explore any possible relationship between minor depression, double depression, and major depression. From 1988-1990, all consecutive unrelated inpatients and outpatients (index cases) presenting to a university-based mood disorders service had detailed family histories taken, using modification of the "family history method." Diagnoses for index cases and their first-degree relatives were made according to Research Diagnostic Criteria. For all index cases with a diagnosis of minor or intermittent depression, and minor/intermittent depression plus either single or recurrent depression ("double depression"), morbidity risks for mood disorders were calculated for first-degree relatives (parents, siblings, and children) using the maximum likelihood approach. Results showed no significant differences in morbidity risk calculations to first-degree relatives of index cases with minor/intermittent depression, major depression, or double depression. The data from this genetic perspective suggest that single depression, recurrent depression, minor depression, and double depression are indistinguishable.

Mood Disorder Service Genetic Database: morbidity risks for mood disorders in 3,942 first-degree relatives of 671 index cases with single depression, recurrent depression, bipolar I, or bipolar II.

There is increasing evidence that genetic factors play a role in the etiology of mood disorders. As a result, relatives of affected individuals are more often asking about their own risks to develop a mood disorder. From 1988 to 1990, all consecutive, unrelated inpatients and outpatients (index cases) presenting to the Mood Disorders Service, Department of Psychiatry, University of British Columbia, had detailed family histories taken, thus creating the Mood Disorders Service Genetic Database. Diagnoses for index cases and their first-degree relatives were made according to Research Diagnostic Criteria and Family History Research Diagnostic Criteria respectively. Morbidity risks for mood disorders were calculated for first-degree relatives (parents, siblings, children--aged 10 and above) of all index cases with a diagnosis of single depression, recurrent depression, bipolar I, or bipolar II disorder. Morbidity risks were calculated using the maximum likelihood approach. Morbidity risk data are presented according to the sex and diagnosis for the index case in an easy reference format for risk counselling. The risks are presented twice, including and excluding data for "high-risk" families whose genetic pedigree is suggestive of "autosomal dominant" inheritance.

Bipolar disorder: evidence for a major locus.

Complex segregation analyses were conducted on families of bipolar I and bipolar II probands to delineate the mode of inheritance. The probands were ascertained from consecutive referrals to the Mood Disorder Service, University Hospital, University of British Columbia and diagnosed by DSM-III-R and Research Diagnostic Criteria. Data were available on over 1,500 first-degree relatives of the 186 Caucasian probands. The purpose of the analyses was to determine if, after correcting for age and birth cohort, there was evidence for a single major locus. Five models were fit to the data using the statistical package SAGE: i) dominant, ii) recessive, iii) arbitrary mendelian inheritance, iv) environmental, and v) no major effects. A single dominant, mendelian major locus was the best fitting of these models for the sample of bipolar I and II probands when only bipolar relatives were defined as affected (polygenic inheritance could not be tested). Adding recurrent major depression to the diagnosis "affected" for relatives reduced the evidence for a major locus effect. Our findings support the undertaking of linkage studies and are consistent with the analyses of the National Institutes of Mental Health (NIMH) Collaborative Study data by Rice et al. (Arch Gen Psychiatry 44: 441-447, 1987) and Blangero and Elston (Genet Epidemiol 6:221-227, 1989).

Evidence for linkage disequilibrium between the dopamine transporter and bipolar disorder.

A role for the dopamine transporter (DAT) in bipolar disorder is implicated by several lines of pharmacological evidence, as well as suggestive evidence of linkage at this locus, which we have reported previously. In an attempt to identify functional mutations within DAT contributing a susceptibility to bipolar disorder, we have screened the entire coding region, as well as significant portions of the adjacent non-coding sequence. Though we have not found a definitive functional mutation, we have identified a number of single nucleotide polymorphisms (SNPs) that span the gene from the distal promoter through exon 15. Of the 39 SNPs that are suitable for linkage disequilibrium (LD) studies, 14 have been analyzed by allele-specific PCR in a sample of 50 parent-proband triads with bipolar disorder. A haplotyped marker comprised of five SNPs, spanning the region between exon 9 and exon 15, was constructed for each individual, and transmission/disequilibrium test (TDT) analysis revealed this haplotype to be in linkage disequilibrium with bipolar disorder (allele-wise TDT p = 0.001, genotype-wise TDT p = 0.0004). These data replicate our previous finding of linkage to markers within and near DAT in a largely different family set, and provide further evidence for a role of DAT in bipolar disorder. Published 2001 Wiley-Liss. Inc.

Possible locus for bipolar disorder near the dopamine transporter on chromosome 5.

The dopamine transporter (DAT) plays a key role in the regulation of dopaminergic neurotransmission by mediating the active reuptake of synaptic dopamine. It is an important candidate gene for bipolar disorder because of data implicating dopamine abnormalities in mania, and because it is the site of action of amphetamine, which has activating and psychotogenic properties. DAT has recently been cloned by its homology to a family of transporters, and mapped to chromosome 5p15.3. We tested DAT for linkage to bipolar disorder in a collection of 21 families from the general North American population (University of California, San Diego/University of British Columbia [UCSD/UBC] families), three Icelandic pedigrees, and Old Order Amish pedigree 110. We examined three markers at DAT, including a 5' TaqI RFLP (HDAT-TaqI), a highly polymorphic variable number of tandem repeats marker (VNTR) (HDAT-VNTR1), and a 3' 40-bp repeat marker (HDAT-PCR1), as well as two nearby microsatellite markers, D5S392 and D5S406. A maximum lod score of 2.38 was obtained at D5S392 in one of the UCSD/UBC families under an autosomal-dominant model. A lod score of 1.09 was also obtained under the same dominant model in the Amish at HDAT-PCR1. In the combined set of families, a maximum lod score of 1.76 was obtained under an autosomal-recessive model at HDAT-TaqI. Positive results were also obtained at several markers, using three nonparametric methods in the UCSD/UBC family set: the affected pedigree member method (P = 0.001), an affected sib pair method (ESPA, P = 0.0008), and the transmission disequilibrium test (P = 0.024). These results suggest the presence of a susceptibility locus for bipolar disorder near the DAT locus on chromosome 5.

Linkage studies suggest a possible locus for bipolar disorder near the velo-cardio-facial syndrome region on chromosome 22.

Velo-cardio-facial syndrome (VCFS) is a congenital anomaly characterized by multiple dysmorphisms, cleft palate, cardiac anomalies, and learning disabilities, that results from a microdeletion of chromosome 22q11. An increased prevalence of psychiatric illness has been observed, with both schizophrenia and bipolar disorder commonly being diagnosed. For these reasons, the VCFS region is an interesting candidate region for bipolar disorder. We examined this region in 17 bipolar families from three populations: 13 families from the general North American population (University of California, San Diego/University of British Columbia, UCSD/UBC), three larger families from New York, and a portion of Old Order Amish pedigree 110. Three microsatellite markers spanning 13 cM around the VCFS region were genotyped in all the families. A maximum lod score of 2.51 was obtained in the UCSD/UBC families under a dominant model at D22S303. In the combined family set, maximum lod scores of 1.68 and 1.28 were obtained at this marker under dominant and recessive models, respectively. Four additional markers were subsequently typed in selected positive families, and yielded positive lods at 6 of 7 markers spanning 18 cM in this region. Nonparametric, multipoint analyses using the affected pedigree member (APM) method also yielded suggestive evidence for linkage in both the UCSD/UBC family set (P = 0.0024) and in the combined families (P = 0.017). Affected sibpair analyses were similarly positive in the UCSD/UBC families (P = 0.017), and in the combined families (P = 0.004). These results are suggestive of a possible locus for bipolar disorder near the VCFS region on chromosome 22.

Genetic linkage study of bipolar disorder and the serotonin transporter.

The serotonin transporter (HTT) is an important candidate gene for the genetic transmission of bipolar disorder. It is the site of action of many antidepressants, and plays a key role in the regulation of serotonin neurotransmission. Many studies of affectively ill patients have found abnormalities in serotonin metabolism, and dysregulation of the transporter itself. The human serotonin transporter has been recently cloned and mapped to chromosome 17. We have identified a PstI RFLP at the HTT locus, and here report our examination of this polymorphism for possible linkage to bipolar disorder. Eighteen families were examined from three populations: the Old Order Amish, Iceland, and the general North American population. In addition to HTT, three other microsatellite markers were examined, which span an interval known to contain HTT. Linkage analyses were conducted under both dominant and recessive models, as well as both narrow (bipolar only) and broad (bipolar + recurrent unipolar) diagnostic models. Linkage could be excluded to HTT under all models examined. Linkage to the interval spanned by the microsatellites was similarly excluded under the dominant models. In two individual families, maximum lod scores of 1.02 and 0.84 were obtained at D17S798 and HTT, respectively. However, these data overall do not support the presence of a susceptibility locus for bipolar disorder near the serotonin transporter.

Electroconvulsive treatment of depression associated with neurosyphilis.

The authors describe a 67-year-old woman with nontabetic parenchymatous neurosyphilis associated with an affective disorder. It was not possible clinically to distinguish the relative contributions of psychiatric and neurologic etiologies to the patient's depressive and delusional symptoms. ECT proved effective for this patient, who might have otherwise been considered a treatment failure. The authors argue that the signs and symptoms of severe affective disorder should be treated if the presumed physical illness does not respond to therapy.

Antipsychotic drugs and seizures.

The authors examine the clinical problem of which antipsychotic drug to use when antipsychotics are indicated in patients with a seizuire disorder or who are susceptible to seizures. While definitive answers to this problem are still unknown, guidelines are offered for antipsychotic drug use in this situation, based on the author's understanding of psychotropics and epilepsy.

Dexamethasone suppression test results in delusional versus nondelusional depression: preliminary evidence of distinct clinical entities.

Two patients with major affective disorder--one unipolar and one bipolar--exhibited normal DSTs while psychotically depressed (mood congruent delusions), yet exhibited nonsuppression on the DST in the course of subsequent separate nonpsychotic depressive episodes. If valid, these results may provide further evidence for considering psychotic and nonpsychotic depression as clinically distinct entities.