Recurrent Unipolar Disorder Research Articles

An Exploratory Case-Control Study for Mitochondrial DNA G10398A in Bipolar I Disorder Patients with a Family History of Affective Disorders.

The mitochondrial DNA (mtDNA) G10398A polymorphism has been associated with bipolar disorder (BD). It leads to an amino acid substitution within NADH dehydrogenase subunit, thereby altering the mitochondrial complex I function. This exploratory case-control study assesses the association of mtDNA G10398A with the risk of BD and its relationship to clinical variables in Indian patients. Cases met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of BD-I in remission and had a family history of BD or recurrent unipolar disorder in biological relatives. The healthy controls (HC) had no known illness and were screened negative for Family Interview for Genetic Studies. Participants were assessed using Clinical Pro forma, NIMH-Life Chart Method and Alda lithium response scale. The mtDNA G10398A was assessed with real-time polymerase chain reaction using TaqMan assay. A total of 82 participants were recruited across cases and controls, with 42 patients (50% with maternal history) and 40 healthy individuals with similar demographic profiles. The mean age of onset was 25.16 (standard deviation [SD] 7.6) years, with illness for 11.59 years (SD: 7.18). Allele A was found in 50% of cases compared to 32.5% HC (odds ratio = 2.08; 95% confidence interval [CI]: 0.85-5.09). Findings remain non-significant for patients with maternal mood disorders (allele A: 38.9%; 21/42). Cases with allele G had significantly higher body mass index (BMI) (P = 0.008) than those with allele A. The study adds information on mtDNA 10398A amongst Indian patient samples and healthy individuals. No significant group difference was found with respect to mtDNA G10398A. The positive association of allele G with higher BMI has potential clinical relevance that can be further investigated in larger samples.

A linkage and exome study of multiplex families with bipolar disorder implicates rare coding variants of ANK3 and additional rare alleles at 10q11-q21.

BackgroundBipolar disorder is a highly heritable psychiatric condition for which specific genetic factors remain largely unknown. In the present study, we used combined whole-exome sequencing and linkage analysis to identify risk loci and dissect the contribution of common and rare variants in families with a high density of illness.MethodsOverall, 117 participants from 15 Australian extended families with bipolar disorder (72 with affective disorder, including 50 with bipolar disorder type I or II, 13 with schizoaffective disorder–manic type and 9 with recurrent unipolar disorder) underwent whole-exome sequencing. We performed genome-wide linkage analysis using MERLIN and conditional linkage analysis using LAMP. We assessed the contribution of potentially functional rare variants using a gene-based segregation test.ResultsWe identified a significant linkage peak on chromosome 10q11-q21 (maximal single nucleotide polymorphism = rs10761725; exponential logarithm of the odds [LODexp] = 3.03; empirical p = 0.046). The linkage interval spanned 36 protein-coding genes, including a gene associated with bipolar disorder, ankyrin 3 (ANK3). Conditional linkage analysis showed that common ANK3 risk variants previously identified in genome-wide association studies — or variants in linkage disequilibrium with those variants — did not explain the linkage signal (rs10994397 LOD = 0.63; rs9804190 LOD = 0.04). A family-based segregation test with 34 rare variants from 14 genes under the linkage interval suggested rare variant contributions of 3 brain-expressed genes: NRBF2 (p = 0.005), PCDH15 (p = 0.002) and ANK3 (p = 0.014).LimitationsWe did not examine non-coding variants, but they may explain the remaining linkage signal.ConclusionCombining family-based linkage analysis with next-generation sequencing data is effective for identifying putative disease genes and specific risk variants in complex disorders. We identified rare missense variants in ANK3, PCDH15 and NRBF2 that could confer disease risk, providing valuable targets for functional characterization.

The Mood Spectrum in Unipolar and Bipolar Disorder: Arguments for a Unitary Approach

Objective: This study examined the extent to which individuals with a lifetime diagnosis of recurrent unipolar disorder endorse experiencing manic/hypomanic symptoms over their lifetimes and compared their reports with those of patients with bipolar I disorder. Method: The study group included 117 patients with remitted recurrent unipolar depression and 106 with bipolar I. Subjects had their clinical diagnosis confirmed by the Mini International Neuropsychiatric Interview and were administered the Structured Clinical Interview for the Mood Spectrum, which assesses lifetime symptoms, traits, and lifestyles that characterize threshold and subthreshold mood episodes as well as “temperamental” features related to mood dysregulation. Results: The patients with recurrent unipolar depression endorsed experiencing a substantial number of manic/hypomanic symptoms over their lifetimes. In both patients with recurrent unipolar depression and patients with bipolar I disorder, the number of manic/hypomanic items endor...

Diagnostic reliability of bipolar II disorder.

Although the diagnostic reliability of major depression and mania has been well established, that of hypomania and bipolar II (BPII) disorder has not. This remains an important issue for clinicians, especially for those undertaking genetic studies of BP disorder since bipolar I (BPI) and BPII disorders often cluster in the same families. We have assessed our diagnostic reliability of BP disorders, recurrent unipolar disorder, and their constituent episodes (major depression, mania, and hypomania) using interview and best-estimate diagnostic procedures used in a genetic study of families with BPI disorder. Reliability was assessed for (1) co-rated Schedule for Affective Disorders and Schizophrenia-Lifetime version interviews of 37 subjects including 15 with BP disorders; (2) test-retest Schedule for Affective Disorders and Schizophrenia-Lifetime version interviews of 26 subjects including 13 with BP disorders; and (3) best-estimate diagnoses made by 2 noninterviewing psychiatrists on 524 subjects in a genetic linkage study of BPI disorder. Diagnoses were based on Research Diagnostic Criteria for a Selected Group of Functional Disorders, except that recurrent major depression as well as hypomania was required for a diagnosis of BPII disorder. On co-rated interviews, we observed complete agreement between interviewers for diagnosing major depressive, manic, and hypomanic episodes. For test-retest interviews, the Cohen kappa coefficients were 0.83 for manic, 0.72 for hypomanic, and 1.0 for major depressive episodes. At the best-estimate level, the Cohen kappa coefficients were 0.99 for BPI, 0.99 for BPII, and 0.98 for recurrent unipolar disorder. Good interrater reliability for BPII can be achieved when the interviews and best-estimate diagnoses are done by experienced psychiatrists.

The human genome: susceptibility loci.

Back to table of contents Previous article Next article Images in NeuroscienceFull AccessThe Human Genome: Susceptibility LociWade H. Berrettini, M.D., Ph.D., Wade H. BerrettiniSearch for more papers by this author, M.D., Ph.D., Philadelphia, Pa.Published Online:1 Jun 2001https://doi.org/10.1176/appi.ajp.158.6.865AboutSectionsView articleView PDFView EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail View articleMany psychiatric illnesses, such as bipolar disorder and schizophrenia, are complex genetic disorders, in which genetic heterogeneity is assumed. However, identifying chromosomal regions linked to these syndromes (susceptibility loci) has its challenges. In family linkage analysis, failure of subsequent studies to confirm previously nominated susceptibility loci is commonplace. Several methodological issues are at play in this failure to confirm, including the power of the individual studies, the inherent limitations of linkage analysis, and variation among population samples. Despite this, multiple susceptibility loci have been identified for several psychiatric diagnoses, including schizophrenia and bipolar disorder. Most probably, these susceptibility loci interact with each other and the environment to produce the clinical syndromes. Susceptibility loci are identifiable regions of a chromosome that are inherited with the illness in families, and they are assumed to include the illness vulnerability allele that partially explains illness risk in these families.Geneticists now see that some of these susceptibility loci for schizophrenia overlap with loci for bipolar disorder. The figure identifies the loci for bipolar disease alone (B), for schizophrenia alone (S), and for bipolar and schizophrenia (*). While bipolar disorder and schizophrenia are two distinct psychiatric diagnostic categories, each with its own characteristic symptoms, course of illness, and pharmacology, they have several similarities: age at onset, lifetime risk, suicide risk, gender distribution, and heritability estimates. Family studies indicate that the first-degree relatives of bipolar probands and the first-degree relatives of schizophrenia probands are at higher than normal risk for schizoaffective and recurrent unipolar disorders, suggesting some shared familial risk. The molecular data represented here support the idea of shared genetic risk. The family study and molecular data suggest that these two groups of disorders may be more closely related than previously considered. Novel genes corresponding to the loci will be identified over the next decade. Characterization of these susceptibility alleles will allow for correlation between the genetic data and clinical phenotype. Because environmental factors drive gene expression, knowledge of the environmental risk factors will certainly inform data from the molecular level.Address reprint requests to Dr. Tamminga, Maryland Psychiatric Research Center, University of Maryland, P.O. Box 21247, Baltimore, MD 21228. Image is an updated version of one published in Biological Psychiatry (W.H. Berrettini, 48:531–538; copyright 2000 by the Society of Biological Psychiatry); reprinted by permission of Elsevier Science. Figure. Ideograms of human chromosomes showing susceptibility loci for bipolar disorder, schizophrenia, and both disorders. The identifying symbols are placed to the right of the structures to which they refer. FiguresReferencesCited byDetailsCited ByCurrent Opinion in Psychiatry, Vol. 16 Volume 158Issue 6 June 2001Pages 865-865 Metrics History Published online 1 June 2001 Published in print 1 June 2001

Genetics of psychiatric disease.

Genetic epidemiologic studies reveal that relatives of bipolar (BIP) probands are at increased risk for recurrent unipolar (RUP), BIP, and schizoaffective (SA) disorders, while relatives of schizophrenia (SZ) probands are at increased risk for SZ, SA, and RUP disorders. The overlap in familial risk may reflect shared genetic susceptibility. Recent genetic linkage studies have defined confirmed susceptibility loci for BIP disorder for multiple regions of the human genome, including 4p16, 12q24, 18p11.2, 18q22, 21q21, 22q11-13, and Xq26. Studies of SZ kindreds have yielded robust evidence for susceptibility at 18p11.2 and 22q11-13, both of which are implicated in susceptibility to BIP disorder. Similarly, confirmed SZ vulnerability loci have been mapped for 6p24, 8p and 13q32. Strong statistical evidence for a 13q32 BIP susceptibility locus has been reported. Thus, both family and molecular studies of these disorders suggest shared genetic susceptibility. These two group of disorders may not be so distinct as current nosology suggests.

Interpersonal Psychotherapy and Antidepressant Medication

Few data are available to guide treatment selection in major depression. With increasing pressure to maximize the efficiency and minimize the costs of treatment, it is important to have information that could guide treatment selection or point to treatment strategies that have a high probability of success. We used a successive cohort approach to compare 2 highly similar groups of women with recurrent unipolar disorder (DSM-III-R or DSM-IV): one in which the combination of interpersonal psychotherapy (IPT) and pharmacotherapy was initiated at the outset of treatment and a second in which IPT alone was provided first and only those who did not remit with IPT alone were offered the combination treatment. In the group in which the combination was initiated at the outset of treatment (N = 180), the remission rate was 66%, comparable to the remission rate observed in most outpatient treatment studies of major depression. In contrast, among the women in the second cohort who were first treated with IPT alone and only those who did not remit were given combination therapy (N = 159), the remission rate was 79%, significantly greater than that observed in the group that received combination treatment from the outset (chi2 = 6.55, p = .02). These results suggest that the strategy of offering IPT to women with recurrent unipolar disorder and, in the absence of remission, adding antidepressant pharmacotherapy can be a highly effective treatment, one that may be particularly attractive to women in the childbearing years. Although slower in its onset of action, this sequential strategy is likely to enable the clear majority of such women to achieve a full remission of depressive symptoms.

A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2.

Bipolar disorder is a severe mental illness characterized by mood swings of elation and depression. Family, twin, and adoption studies suggest a complex genetic etiology that may involve multiple susceptibility genes and an environmental component. To identify chromosomal loci contributing to vulnerability, we have conducted a genome-wide scan on approximately 396 individuals from 22 multiplex pedigrees by using 607 microsatellite markers. Multipoint nonparametric analysis detected the strongest evidence for linkage at 13q32 with a maximal logarithm of odds (lod) score of 3.5 (P = 0. 000028) under a phenotype model that included bipolar I, bipolar II with major depression, schizoaffective disorder, and recurrent unipolar disorder. Suggestive linkage was found on 1q31-q32 (lod = 2. 67; P = 0.00022) and 18p11.2 (lod = 2.32; P = 0.00054). Recent reports have linked schizophrenia to 13q32 and 18p11.2. Our genome scan identified other interesting regions, 7q31 (lod = 2.08; P = 0. 00099) and 22q11-q13 (lod = 2.1; P = 0.00094), and also confirmed reported linkages on 4p16, 12q23-q24, and 21q22. By comprehensive screening of the entire genome, we detected unreported loci for bipolar disorder, found support for proposed linkages, and gained evidence for the overlap of susceptibility regions for bipolar disorder and schizophrenia.

Exclusion of linkage between bipolar affective disorder and chromosome 16 in 12 Australian pedigrees.

Several recent reports of possible susceptibility loci for bipolar affective disorder (BAD) have identified sites on a number of chromosomes. Specifically, two Danish studies have suggested the presence of a susceptibility locus for BAD on chromosome 16p13. As the first step of a whole genome scan, we screened 12 Australian families with markers at 16p13 and also a number of markers spanning the entirety of chromosome 16. Linkage analysis was undertaken using both the parametric lod score method (two- and multipoint) with different models and diagnostic thresholds, and the nonparametric affected pedigree member (APM) method. Results of lod score analysis convincingly excluded the 16p13 region from linkage to BAD in these families, while APM provided no support for linkage. Furthermore, using the broad definition of BAD, with individuals affected by bipolar I and II and recurrent unipolar disorders included, the entire chromosome was excluded from linkage to BAD with autosomal-dominant transmission at a maximum age-specific penetrance of 60%, and with autosomal-dominant and recessive modes of transmission at a maximum age-specific penetrance level of 90%. Diagnostic thresholds which did not include unipolar affected individuals were somewhat less informative. However, a majority (between 63-96%, depending upon the model) of the chromosome was clearly excluded using narrow diagnostic thresholds. Moreover, no positive lod scores were obtained at theta = 0.00 for any tested model or diagnostic threshold. Our results indicate that no linkage exists between BAD and chromosome 16 markers in this group of Australian families.

Should Depression Be Considered a Lifetime Disorder: Evidence from the Pittsburgh Studies of Maintenance Therapy

A series of studies carried out at the University of Pittsburgh point strongly to the lifetime nature of recurrent unipolar disorder and to the need for a long-term perspective in the development of treatment strategies. In our initial investigation (Frank et al., 1990), remitted recurrent unipolar patients were randomly assigned to full dose ≈220 mg imipramine) maintenance pharmacotherapy, monthly maintenance psychotherapy, the combination or placebo for a period of three years. Full dose medication was highly effective (p < 0.0001) in preventing new episodes, with maintenance psychotherapy showing a modest protective effect (p = 0.05). In a second investigation (Kupfer et assignment. A third investigation (Frank et al., 1993), focused on those patients in the original study who had experienced a recurrence in the absence of active pharmacotherapy. Following successful treatment of their recurrence and a 20-week continuation treatment phase, these subjects were randomly assigned to either full or half-dose pharmacotherapy for a three-year period. Full-dose imipramine was associated with fewer recurrences and longer survival time than the half-dose strategy (p < 0.07). Taken together, these studies of recurrent unipolar patients present a picture of a disorder requiring long-term (if not life-long) prophylaxis in a manner similar al., 1992), subjects who survived the initial three-year trial in one of the two active medication conditions, were randomly assigned to an additional two years of full-dose pharmacotherapy or placebo. Once again, active medication was significantly superior to placebo (p < 0.006) in protecting against new episodes, this time in a group of patients who had all previously sustained a remission of almost 3.5 years prior to random to that apparently required in manic-depressive illness. What remains to be elucidated is: (1) whether more frequent maintenance psychotherapy can provide adequate protection against recurrence and (2) whether there are subgroups of recurrent unipolar patients who can ultimately discontinue treatment without adverse consequences.

Low plasma GABA is a stable trait marker of mood disorders

unipolar types are at high risk for other psychiatric disorders. The data on the relationship of affective disorders to anxiety disorders have been inconclusive. Panic disorder, for example, has been seen as stemming from a common vulnerability with major depression (Breier et al., 1985) and as a separate disorder (Weissman et al., 1993). Recent evidence suggests a link with bipolar disorder (Savino et al., 1993). We have conducted a preliminary analysis of the clinical data obtained from 238 SADS-L interviews on the affected family members (41 BP !, 117 BP il, 4 Schizeaffective-manic type, and 76 Recurrent Unipolar Disorders) of bipolar probands ascertained for a genetic linkage study of bipolar disorder. Chi-squarc analysis was performed on the frequency of comorbid panic disorder in bipolar and unipolar subjects. For this analysis the diagnosis of panic disorder was applied if subject's symptoms met RDC inclusion criteria, whether or not there was concurrent depression. A significantly higher proportion of subjects with a bipolar disorder also had panic disorder, compared to subjects with recurrent unipolar disorder (14.8% versus 2.6%, chi square 7.89, df-i , p<.O05). The finding suggests a relationship between familial bipolar phenotypes (BP ! or II) and panic disorder symptoms. Whether this relationship is specific to a subset of bipolar families and why bipolar rather than unipolar family members are at greater risk merits further study.

Influence of clinical subtype, sex, and lineality on age at onset of major affective disorder in a family sample

The authors analyzed data from a family sample ascertained for a genetic linkage study of bipolar disorder to address the following questions: Do the major clinical subtypes of familial affective disorder have distinct distributions of age at onset? What factors other than clinical subtype affect these distributions? After controlling for these factors, do the differences in age at onset persist among the subtypes? Eighty-two families were ascertained through a treated proband with bipolar disorder who had a family history of two or more affected siblings or one affected sibling and one affected parent. After participating in an interview conducted by a psychiatrist using the Schedule for Affective Disorders and Schizophrenia--Lifetime Version, 274 probands and their first-degree relatives were diagnosed as having bipolar I, bipolar II, or recurrent unipolar disorder according to Research Diagnostic Criteria. Age at first major affective episode and other clinical data were collected. Onset age distributions were similar for bipolar I and bipolar II disorder but significantly different for recurrent unipolar disorder. This finding persisted after adjustment for a significantly earlier onset among females. Subjects with affective disorder in both parental lines (bilineal) also experienced a significantly earlier onset. Substance abuse, physical illness, and sex of the affected parent had no significant impact on onset age. Although differences in age at onset may reflect several factors, these results provide indirect support for the view that bipolar I and bipolar II disorders are genetically related phenotypes and suggest that bilineal families may be more complex than previously assumed.

Imipramine and weight gain during the long-term treatment of recurrent depression

The recently completed long-term maintenance trial of full-dose imipramine for recurrent unipolar disorder provided an opportunity to examine the extent to which such doses (200–300 mg daily) are associated with persistent and adverse side effects, particularly weight change. In 115 patients we monitored weight change during the three-year maintenance treatment phase to the point of trial completion, recurrence or termination. No differences were noted between individuals receiving active medication (average gain of 5.8 lbs. during an average treatment period of 725 days) versus those randomized to the ‘no-drug’ cells (average gain of 2.8 lbs. during an average treatment period of 422 days). Numerous other factors such as body mass index, previous weight gain and gender did not play a differential role in establishing why some individuals gained weight during long-term treatment of depression regardless of specific treatment.

Bipolar II: Combine or keep separate?

Data on prior course, characteristics of index episode, and familial aggregation of patients with bipolar II disorder is discussed. The data supports the separation of this condition from both bipolar I and recurrent unipolar disorder.