Bipolar Disorder
Diseases

Valeria Serra e Viviana Nuvoli

Bipolar disorder (BPD) is a severe psychiatric disorder that affects approximately 1% of the world's population and it’s characterized by alternating episodes of elevated and depressed mood. Severe episodes have psychotic features similar to some of the symptoms of schizophrenia, that is, positive psychotic symptoms (hallucinations, delusions) in mania, and negative psychotic symptoms (lack of motivation, psychomotor retardation) in depression. There is now a fairly widespread consensus on the fact that the Bipolar Disorder is caused primarily, though not only, by abnormalities and defects of a biological type, first genetic, in fact numerous studies have shown a high regard to the familiarity of the disease, an increased chance of developing the disorder if your family has one or more persons with a disorder of mood.
Often the two poles of future disease characteristically belong to two different family members, so that one will be particularly dynamic, active and euphoric, and the other was melancholy, mournful and depressed. Twin studies have generally reported a concordance rate in monozygotic twins of approximately 60% compared to a rate in dizygotic twins of 15%. First-degree relatives of probands have a 7% risk for BPD, and a two-fold increase in risk for unipolar disorder. While the mode of inheritance remains unclear, segregation analyses of family data have generally suggested a complex mode of inheritance, although several recent large samples have reported evidence for autosomal dominant major gene effects.
Origin of mental illnesses
Che cos'è il disturbo bipolare

The genetics of bipolar disorder: genome ‘hot regions’

Traditionally, linkage analysis and positional cloning approaches have been used to try to identify the genes involved. This has led to the identification of a series of loci in the genome that exhibit linkage with the illness.
More than 10 genome-wide linkage scans have been published, and many additional scans which are in progress have reported some findings for selected chromosomal regions. A number of chromosomal loci have now been reported in multiple studies including: 4p, 5q, 10q, 12q, 13q, 16p, 18p, 18q, 21q, 22q. Some of these regions have met the proposed rigorous criteria for statistical significance and replication. A meta-analysis of 11 whole-genome linkage scans found the strongest evidence for susceptibility loci for BPD on 13q and 22q.
Linkage studies of bipolar disorder and schizophrenia have found overlapping evidence for susceptibility genes in four chromosomal regions (10p12-14, 13q32, 18p11.2, and 22q12- 13) using specifical marker.

In 2003 Researchers at the University of California have previously shown evidence (In a genome-wide linkage survey) suggesting that the chromosome 22q12 region contains a susceptibility locus for bipolar disorder (BPD). Two independent family sets yielded lod scores suggestive of linkage at markers in this region near the gene G protein receptor kinase 3 (GRK3).

The findings indicate that a mutation in a gene Grk3 that regulates sensitivity to brain neurotransmitters. GRK3 plays a key role in the regulation of biochemical processes in the brain, the complex system of neurotransmitters, whose mediation chemistry is the basis of our emotions and our behavior.

The mutation in this gene, occurs in a portion of the gene called the promoter, that regulates when the gene is turned on. The research team hypothesizes that this mutation causes the individual to become hypersensitive to dopamine, (one of the major neurotransmitters) and then be responsible for its poor regulation, producing significant alterations in the available quantity of the substance. Considering that dopamine plays an important role in the activities of thought, in motor behavior and pleasure, it is evident that its failure could trigger mood swings typical of bipolar disorder. One hypothesis is that the role GRK3 would be to lower the level of response to neurotransmitters such as dopamine.
The research team suggest that a dysregulation in the time or place of GRK3 expression results in aberrant neurotransmitter signaling and an increased susceptibility to develop BPD. The narrowest formulation of this hypothesis is that a failure of dopamine receptor homologous desensitization results in an effective hypersensitivity to dopamine and can cause a susceptibility to disease. A broader formulation takes into account the fact that GRK3 has been demonstrated to desensitize many GPCRs including adrenergic, muscarinic, histaminic, dopaminergic, CRF-1, and opioid receptors. GRK3 might, therefore, play an important role in the regulation of any one of many GPCRs, and the regulation might be either presynaptic or postsynaptic and might involve either stimulatory or inhibitory circuits. The complexity of these functions raises the possibility that different mutations each responsible for distinct changes in the time and place of GRK3 expression could have strikingly different effects on GPCR regulation and thus be associated with distinct subphenotypes of BPD.

Then, they have also shown GRK3 expression to be induced by amphetamine in an animal model of mania using microarray based expression profiling. To identify possible functional mutations in GRK3, they sequenced the putative promoter region, all 21 exons, and intronic sequence flanking each exon, in 14–22 individuals with BPD. They found six sequence variants in the 50-UTR/promoter region, but no coding or obvious splice variants, that increased susceptibility for disease.

One of these mutations, P-5, occurred three times more frequently in manic-depression patients than in non-afflicted individuals. The team determined that there were six mutations in the promoter region of the GRK3 gene. P-5 controls when the gene turns on and off, then a defect affects regulation of the gene. It may be turning on inappropriately, or turning off when it shouldn’t.

Dopamine is not the only substance involved in bipolar disorder, as it is to be attributed to a generalized alteration of the complex of brain neurotransmitters. At least one other substance, serotonin plays a central role in the disease, producing, due to an alteration in the quantity available, the typical symptoms of depression (serotonin deficiency) or mania (excessive serotonin).

Although there is still much to discover about it, you can outline for bipolar disorder for which genetic damage evolution produces significant alterations in brain chemistry that, in combination with many other variables of biological, social and personality produces the disease.

Mood swing in BPD.

The mood is one of the main regulatory mechanisms of human behavior, which, through the emotions allows us to better adaptation to external reality and to its pleasant or unpleasant. It's like a rope swing or metronome to which two extremes are the moods of despair and euphoria, with a series of intermediate states of mind more or less close to the two poles.

When the oscillations are crystallized you have bipolar disorder, where the transition from mania to depression often follow one another in unexpected ways.

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In the mood swings it is crucial the role of alterations in neurotransmitter systems such as those mediated by biogenic amines (serotonin, dopamine and norepinephrine).

The alterations of neurotransmitters.

Dopamine:

• The activity in dopaminergic neuronal circuits has a balance of both tonic (continuous activity) and phasic (due to stimulation). Increases in the states of both euphoric activity, while in dysphoria the increase in tonic activity is accompanied by a decrease in the activity phasic, due to desensitization of the D2 dopamine pre-synaptic receptor.
• Increased response to post-synaptic dopamine and / or the creation of special conditions pre-synaptic, as reduced re- uptake, increases the concentration in synaptic cleft. This affects the anger.
• In dopaminergic system enzymes, ion channels, synaptic proteins, second messengers and pathway of intracellular signals are the neurobiological substrates that modulate modulate the anger. There is also an involvement of other neurotransmitter systems such as cholinergic able to interact and regulate the dopamine system.

Serotonin:

• Low levels of serotonin metabolites are responsible for impulse dyscontrol then increased serotonergic tone predisposes to high levels of fear, while low levels of serotonin are associated with high impulsivity and depression.
• However, depression is also associated with a reduction of serotonin reuptake.
• Low concentrations of CSF 5-HIAA (the major metabolite of serotonin).
• Reduction of number of serotonin receptors in some brain areas.
• Reduction the ability of the receptor to bind its ligands: low functionality of the system.
• Alteration in systems of signal transduction that create malfunction of the entire cascade of reactions and degeneration of biological processes (adenylate cyclase can be inhibited and there is a reduction of the synthesis of cAMP).
• alteration of circadian rhythms.

Bibliography.

Giovanni B.Cassano. Lo spettro dell'umore
Squassina, Alessio. BIpolar disorder
A. Serretti and L. Mandelli. The genetics of bipolar disorder: genome ‘hot regions,’ genes, new potential candidates and future directionsBipolar disorder genes
UCSD. UCSD Researchers Identify Gene Involved In Bipolar Disorder
C A Ogden et al. Candidate genes, pathways and mechanisms for bipolar (manic–depressive) and related disorders: an expanded convergent functional genomics approach
Terry E. Goldberg et al. The Serotonin Transporter Gene and Disease Modification in Psychosis: Evidence for Systematic Differences in Allelic Directionality at the 5-HTTLPR Locus