Rif S. El-Mallakh

Genomewide Linkage Analyses of Bipolar Disorder: A New Sample of 250 Pedigrees from the National Institute of Mental Health Genetics Initiative

We conducted genomewide linkage analyses on 1,152 individuals from 250 families segregating for bipolar disorder and related affective illnesses. These pedigrees were ascertained at 10 sites in the United States, through a proband with bipolar I affective disorder and a sibling with bipolar I or schizoaffective disorder, bipolar type. Uniform methods of ascertainment and assessment were used at all sites. A 9-cM screen was performed by use of 391 markers, with an average heterozygosity of 0.76. Multipoint, nonparametric linkage analyses were conducted in affected relative pairs. Additionally, simulation analyses were performed to determine genomewide significance levels for this study. Three hierarchical models of affection were analyzed. Significant evidence for linkage (genomewide P<.05) was found on chromosome 17q, with a peak maximum LOD score of 3.63, at the marker D17S928, and on chromosome 6q, with a peak maximum LOD score of 3.61, near the marker D6S1021. These loci met both standard and simulation-based criteria for genomewide significance. Suggestive evidence of linkage was observed in three other regions (genomewide P<.10), on chromosomes 2p, 3q, and 8q. This study, which is based on the largest linkage sample for bipolar disorder analyzed to date, indicates that several genes contribute to bipolar disorder.

The Na,K-ATPase hypothesis for bipolar illness

A cellular model for bipolar illness is presented. It is propounded that alterations in the activity of the membrane sodium- and potassium-activated adenosine triphosphatase pump (Na,K-ATPase) may be responsible for alterations in neuronal excitability and activity. Specifically, a reduction in Na,K-ATPase activity can lead to both mania and depression by increasing membrane excitability and decreasing neurotransmitter release, respectively. Supporting evidence is reviewed, and clinical and research implications are discussed.

Family-based association of FKBP5 in bipolar disorder.

The FKBP5 gene product forms part of a complex with the glucocorticoid receptor and can modulate cortisol-binding affinity. Variations in the gene have been associated with increased recurrence of depression and with rapid response to antidepressant treatment. We sought to determine whether common FKBP5 variants confer risk for bipolar disorder. We genotyped seven tag single-nucleotide polymorphisms (SNPs) in FKBP5, plus two SNPs previously associated with illness, in 317 families with 554 bipolar offspring, derived primarily from two studies. Single marker and haplotypic analyses were carried out with FBAT and EATDT employing the standard bipolar phenotype. Association analyses were also conducted using 11 disease-related variables as covariates. Under an additive genetic model, rs4713902 showed significant overtransmission of the major allele (P=0.0001), which was consistent across the two sample sets (P=0.004 and 0.006). rs7757037 showed evidence of association that was strongest under the dominant model (P=0.001). This result was consistent across the two datasets (P=0.017 and 0.019). The dominant model yielded modest evidence for association (P<0.05) for three additional markers. Covariate-based analyses suggested that genetic variation within FKBP5 may influence attempted suicide and number of depressive episodes in bipolar subjects. Our results are consistent with the well-established relationship between the hypothalamic–pituitary–adrenal (HPA) axis, which mediates the stress response through regulation of cortisol, and mood disorders. Ongoing whole-genome association studies in bipolar disorder and major depression should further clarify the role of FKBP5 and other HPA genes in these illnesses.

Mood State at Study Entry as Predictor of the Polarity of Relapse in Bipolar Disorder

Of the placebo-controlled maintenance studies conducted in bipolar disorder, few have enrolled patients who present depressed. In fact, only lithium and lamotrigine have been studied over the long term with placebo-controlled designs in recently manic and recently depressed bipolar patients. Given the magnitude of the unmet medical need and the data suggesting that symptomatic patients with bipolar disorder spend the majority of their time depressed, this is unfortunate. Our review of the pre-lithium literature and more recent publications suggests that mood state at study entry predicts the polarity of relapse and the response to treatment. Accordingly, a need exists to enroll recently depressed patients in maintenance studies to elucidate the complete spectrum of efficacy of putative mood stabilizers and improve the long-term treatment of bipolar depression. Patients presenting depressed for a maintenance study tend to relapse into depression; those presenting manic, into hypomania/mania/mixed states. This is particularly true during the first several months of the randomized treatment. The polarity of the index episode tends to predict the polarity of relapse into a subsequent episode in a ratio of about 2:1 to 3:1. We conclude that putative mood stabilizers must be tested in recently manic and recently depressed patients to determine their spectrum of prophylactic efficacy.

Alpha2 isoform of the Na,K-adenosine triphosphatase is reduced in temporal cortex of bipolar individuals

BACKGROUND The pathophysiology of bipolar illness has been associated with changes in transmembrane ion flux and redistribution of biologically active ions. The recent identification of multiple isoforms of Na,K-adenosine triphosphatase (ATPase) alpha and beta subunits raises the possibility of altered pump isoform expression. METHODS We determined Na,K-ATPase alpha subunit expression in postmortem temporal cortex gray matter from individuals suffering from bipolar disorder, schizoaffective disorder, schizophrenia, and matched normal controls. Quantification of isoform expression was accomplished via densitometric scanning of Western blots utilizing isoform-specific antibodies. RESULTS Bipolar individuals exhibited a significant reduction in the abundance of the alpha 2 isoform of Na,K-ATPase compared to normal controls. Schizophrenic and schizo-affective brains were not significantly different from normal controls. CONCLUSION These data suggest that previously observed abnormalities in regulation and distribution of ions in bipolar illness may be related to specific alpha 2 dysregulation.

Psychiatric Disposition of Patients Brought in by Crisis Intervention Team Police Officers

Background: As part of an effort to improve police interactions with mentally ill citizens, and improve mental health care delivery to subjects in acute distress, the University of Louisville, in conjunction with the Louisville Metro Police, established the crisis intervention team (CIT). CIT is composed of uniformed officers who receive extensive training in crisis intervention and psychiatric issues and who are preferentially called to investigate police calls that may involve a mentally ill individual. Methods: In an effort to determine the characteristics of the individuals brought to the emergency psychiatric service (EPS) by CIT officers, a comparative (CIT vs. mental inquest warrant [MIW, a citizen-initiated court order to bring someone for psychiatric evaluation because of concerns regarding dangerousness] vs non-CIT/non-MIW), descriptive evaluation was performed. Results: With the exception of a higher rate of schizophrenic subjects brought in by CIT (43.0% vs. 22.1, non-CIT, P=.002), the demographics, diagnosis, and disposition of CIT-referred subjects were not different in any way from non-CIT patients. Subjects referred on MIWs were more likely to be admitted to a psychiatric hospital than non-MIW patients (71.6 vs. 34.8, P <.0001), but CIT-referred hospitalization rates were not different from hospitalization rates of self-referred subjects (20.7 vs. 33.3, ns). Conclusions: CIT officers appear to do a good job at identifying patients in need of psychiatric care.

LITHIUM PREVENTS OUABAIN-INDUCED BEHAVIORAL CHANGES : TOWARD AN ANIMAL MODEL FOR MANIC DEPRESSION

Both mania and bipolar depression have been associated with decrements in the activity of the sodium and potassium-activated adenosine triphosphatase (Na,K-ATPase) membrane pump. Although the role of this observation in the pathophysiology of bipolar illness is unclear, it has been proposed that this defect could be central to the pathogenesis of the illness. In an effort to test this hypothesis, the authors examined the efficacy of lithium pretreatment in attenuating behavioral changes secondary to acute administration of a single intracerebroventricular (i.c.v.) dose of the Na,K-ATPase-inhibiting compound, ouabain, in the Sprague-Dawley rat. Ouabain (10(-3)M) significantly decreased motor activity in automated activity monitors. Lithium pretreatment for 7 d totally prevented this effect. These preliminary data suggest that i.c.v. ouabain administration in the rat may prove to be a viable animal model for bipolar illness.

An animal model for mania: preliminary results.

1. In human bipolar patients mania and bipolar depression are both characterized by decreased membrane Na,K-AtPase activity. Additionally, digoxin neurotoxicity in patients frequently presents with symptoms of mania or depression. 2. These findings suggest that central nervous system Na,K-ATPase inhibition may play a pathophysiologic role in bipolar illness. 3. The authors tested this hypothesis by administering intracerebroventricular (i.c.v.) ouabain to rats at sublethal doses. The authors then measured behavioral activity as total square crossings in an open field. 4. Motoric activity was significantly increased by i.c.v. administration of 5 microliters of ouabain at 10(-3) M. This preliminary study suggests that i.c.v. ouabain administration may provide a useful animal model of mania that is based on observed biochemical changes in humans.

Possible role of endogenous ouabain-like compounds in the pathophysiology of bipolar Illness

A large number of studies have documented a mood-state-related decrease in blood cell sodium, potassium-activated adenosine triphosphatase (Na, K-ATPase) activity in acutely ill bipolar patients. While it has been proposed that this enzymatic change may be central to the pathophysiology of bipolar illness, its genesis has remained obscure. Recent advances in the isolation and characterization of endogenously produced ouabain- or digoxin-like compounds suggest a possible mechanism by which these mood-state-related changes can come about. We herein propose that the hypothalamic-pituitary-adrenal dysregulation frequently documented in major mood disorders may underlie a pathological increase in the production of endogenous ouabain-like compounds which excessively suppresses Na, K-ATPase activity and results in pathological mood and energy alteration.

Mimicking human bipolar ion dysregulation models mania in rats

Psychiatric diseases in general, and bipolar illness in particular, are difficult to model in animals since the subjective nature of the core symptoms appears to preclude objective observation of behavioral changes. An adequate animal model of a psychiatric condition must fulfill three core criteria: share pathophysiological characteristics of the human condition (face validity), have similar behavioral manifestations as the human disease (construct validity), and improve with medications that improve the symptoms seen in afflicted humans (predictive validity). The ouabain model for bipolar illness mimics a widely reproduced biologic abnormality in mania: reduced sodium pump activity. An intracerebroventricular (ICV) administration of 5microL 10(-3)M ouabain induces motoric hyperactivity preventable by lithium, carbamazepine, and haloperidol. ICV ouabain may also produce environmentally dependent hypoactivity. The model, however, has not yet been examined for other potential manic behavior in rats such as reduced need for sleep, increased sexual activity, or increased irritability. While additional characterization of the model is required, the ouabain model for bipolar illness is the only available animal model that fulfills the three criteria for an adequate animal model for bipolar illness.