Bipolar (Manic–Depressive) Disorders: Genetic and Neurotransmitter Hypotheses

Genetic Hypotheses

Available evidence indicates that familial factors are important determinants of who will develop manic–depressive disorder. Numerous studies have shown that relatives of manic–depressive probands (identified cases) have higher rates of manic– depressive disorder than controls or unipolar probands. Overall, rates of manic–depressive disorder in first-degree relatives (parents, siblings, children) of probands with manic–depressive disorder are elevated 5 to 10 times over rates found in the general population. In the latter group, the rates are 0.5 to 1.5%. while in the former group rates are 5 to 15%. Interestingly, rates of unipolar depression in first-degree relatives are about twofold elevated over those in the general population. Because of the rate of depression in the general population (5–20%), this means that a twofold increase is a rate of about 20%. Important for genetic counseling, this in turn means that the probability that a manic– depressive proband will have a unipolar child is greater than the probability that they will have a manic–depressive child (5–15% versus 20%); note that it is most likely that they will have neither (100 minus 25–35%).

Most genetic research has been done on manic–depres-sive type I disorder. However, manic–depressive type II also ap-pears to have a familial component. Manic–depressive type II probands have more manic–depressive type I disorder and more manic–depressive type II disorder than unipolar depressives and less type I disorder than type I probands. Familial occurrence does not differentiate between inborn and environmental factors. Familial aggregation could be due to sharing genetic material, nongenetic congenital factors (e.g., similar inherited or acquired intrauterine factors, or exposure to similar perinatal risk factors), or physiologic or psychological environmental factors.

Data from other types of studies indicate that at least part of this risk is due to biological, and likely genetic factors. Twin studies indicate that monozygotic have higher concordance rates for manic–depressive disorder than do dizygotic twins 60 to 80% for monozygotic twins versus 20 to 30% for dizygotic twins. Linkage studieshave suggested that in certain families manic–depressive disorder may be linked to specific genes. On the other hand, studies of monozygotic twins also indicate that only 40 to 70% are concordant for manic–depressive disorder. Thus, although there is clearly a genetic component to this ill-ness, genetics is not destiny.

Several genetic loci have been proposed but independent confirmations have been lacking. Overall, the number of families in which a single gene has been associated with manic–depres-sive disorder is small. Further, no single locus has been replicated in multiple studies. It is likely that genes may confer susceptibil-ity to the disorder without actually determining that the disorder occurs. That is, to have the disorder one must have both the gene and another factor.

A related approach to investigating genetic contributions to manic–depressive disorder is to look for differences in genes that code for components of systems thought to be involved in the pathophysiology of the disorder. Chief among such candidate genes have been those responsible for dopamine and serotonin receptors, transporters and metabolic enzymes. The recent study by Mundo and coworkers (2001) showed that individuals who developed manic symptoms when treated with serotonin-active antidepressants had higher rates of the gene coding for a par-ticular form of the serotonin transporter, compared with those similarly treated who did not develop manic symptoms. In addi-tion, several studies have indicated that the gene coding for the norepinephrine-metabolizing enzyme catechol-O-methyl trans-ferase (COMT) may be associated with the rapid cycling form of manic–depressive disorder.

In addition, recent evidence raises the possibility that the expression of a psychiatric illness that is coded genetically may not be due simply to the presence or absence of specific genes, but rather to modifying pieces of DNA in close proximity to important genes. Specifically, small sections of DNA, three base-pairs in length (called trinucleotide repeats), appear to be overrepresented in genetic disorders with prominent psychiatric symptoms.

Neurotransmitter Hypotheses

Many theories have something of value to contribute regarding the pathologic basis of manic–depressive disorder. Nonetheless we do not yet have data to indicate whether the disorder is basi-cally a disorder of a particular neurotransmitter, a particular neu-roanatomic locus, or a particular physiologic system. Integration of these hypotheses awaits development of new methodologies for clinical neurobiologic investigations

Second-messenger System Hypotheses

When neurotransmitters bind to postsynaptic neuronal receptors, a series of intracellular events are initiated that are mediated by chemical systems linked to those receptors. So-called G-proteins link the receptors to second-messenger systems, which in turn are linked to protein kinases that control the synthesis and opera-tion of cellular components.

The cyclic AMP and phosphatidyl inositol systems are the most extensively studied of these second-messenger systems. Recent data have generated substantial interest in the phosphati-dyl inositol system as a possible mediator of the clinical effects of lithium in manic–depressive disorder, particularly since this second-messenger system is linked to subtypes of adrenergic, serotonergic, dopaminergic and cholinergic neurotransmitter systems. Persons with manic–depressive disorder have altera-tions in platelet phosphatidyl inositol levels and responsiveness of neutrophil phosphoinositol accumulation.

Neuroendocrine Hypotheses

Typical neuroendocrine studies investigate peripheral or cer-ebrospinal fluid abnormalities of a particular system in persons with mood disorders and in controls and propose that either the neuroendocrine system itself or the neurotransmitter system that controls the hormone is in some way linked to the pathophysiol-ogy of the mood disorder of interest. Taken together, the literature does not identify particular endocrine findings as characteristic of manic–depressive disorder.

The thyroid axis may be of particular relevance to the pathophysiology of mood disorders since it serves not only as a dependent variable that is studied as a function of mood (as most neuroendocrine systems have been), but because the thyroid axis has also been studied as an independent variable of some impact. Several studies have shown that thyroid hormone administration may actually ameliorate mood disorders in certain paradigms. Further, in the rapid cycling variant of manic–depressive dis-order, evidence indicates that supplementation with high doses of the thyroid hormone thyroxine (T₄) may induce remission in persons who are refractory to standard. The mechanism for these effects has been the subject of much speculation. Various mod-els posit that the brain is functionally hypothyroid either due to changes in hormone synthesis, transport, or metabolism, or due to increased demand; alternatively, other models propose that thebrain has an excess of a thyroid-related substance, which admin-istration of exogenous thyroid hormone diminishes.