Depression

2

Theories and Models of the Disorder

2.1    Biological Models

Historically, depression has always been seen as, at least in part, somatic or biological in origin. Modern genetic studies, biochemical analyses, and scanning methods support this position. Diagnostic distinctions have been made on the basis of assumed primary biologic (endogenous) versus primarily environmentally driven (exogenous) depressions. Modern theories of the nature of the biological contribution have evolved over the last few decades as investigative research techniques have evolved.

2.1.1      Genetics

Genetic studies indicate that depression has a genetic component that interacts with the environment to produce the disorder

The degree to which genetics contribute to the occurrence of a disorder is studied by three primarily methodologies. Family studies start with a patient proband and identify the percentage of relatives of varying degree who also have the disorder. The studies are relatively easy to do, but do not separate the effects of genetics from the effects of shared environments. Twin studies compare the co-twins of proband twins who have the disorder. Monozygotic co-twins who share 100% of genetic material should be twice as likely to have the disorder as dizygotic co-twins who share 50% of genetic material. In these studies, environments are relatively constant, so a purer assessment of genetics is possible. In adoption studies, the children of ill parents who are adopted at a young age are compared to children who grow up with their biological parents. If they have the same elevated rates of the disorder, then genetics rather than environment is assumed to be responsible.

All three methodologies support the presence of a genetic component to depression. The precise estimates of the accounted-for variance vary considerably, but it is generally agreed that genetics are a significant, but not substantial, contributor that accounts for less than 50% of occurrence. Shared environment seems to play a relatively small role, whereas individual life events contribute significantly. The genetic contribution is greater for more severe, recurrent, melancholic, or psychotic depressions. A major role of genetics appears to be to increase the impact of negative life events in precipitating episodes of depression. Genetics provide the biological diathesis or vulnerability that interacts with environmental stress.

Studies comparing the heritability of bipolar versus unipolar depression find that the genetic component of bipolar is greater than that for unipolar disorder. In the families of bipolar probands, both bipolar and unipolar relatives are common. In contrast, primarily unipolar relatives are found in the families of unipolar probands. It is generally agreed that both disorders involve multiple genes, i.e., neither is due to a single dominant or recessive gene. The difference between bipolar and unipolar families has been taken to mean that the two disorders share some genes, but it may require a greater concentration of genes to produce bipolar disorder. Thus, in bipolar families you find more ill relatives, some with high concentrations of genes and some with low concentrations. In unipolar families where probands have lower concentrations, only unipolar relatives with low concentrations are likely.

2.1.2      Monoamine Hypotheses

Early biological models of depression assumed that the deficiencies in the neurotransmitters affected by antidepressant medications were the cause of depression

Tricyclics were the first generation of antidepressants

The idea that mental illness is the result of chemical imbalances in the brain arose from studies of the effects and mechanisms of action for medications on specific disorders. Deficiencies in neurotransmitters were hypothesized to be the basis of disorders when medications were found to increase the neurotransmitter levels. The monoamines are a group of neurotransmitters that contain a single amino group connected to a two-carbon chain. Monoamines are derived from amino acids interacting with thyroid hormones. In the 1950s and 1960s, researchers associated the neurotransmitters norepinephrine and serotonin with depression, and dopamine with schizophrenia. The idea that monoamine neurotransmitters were implicated in depression was referred to as the monoamine hypothesis. The earliest antidepressants were the tricyclics (Table 7), so named because their molecular structures contain three rings of atoms. The tricyclics, such as imipramine, amitriptyline, and clomipramine, increased the presence of norepinephrine and serotonin in the synapse by inhibiting their reuptake. Some of these tricyclics also influenced dopamine and other neurotransmitters as well.

SSRIs were the second generation of antidepressants and have largely replaced the tricyclics

The next generation of medications for depression was more selective in their effect and produced fewer side effects. Among these medications are the selective serotonin reuptake inhibitors (SSRIs, Table 8), and the selective serotonin and norepinephrine reuptake inhibitors (SNRIs, Table 9). An interesting variation on the neurotransmitter theory has been proposed in a book by Parker and Manicavasagar (2005) of the University of New South Wales. These authors propose an alternative conceptualization of clinical depression as consisting of three levels. The mildest is nonmelancholic depression characterized primarily by depressed mood. Second is melancholic depression, which they see as having psychomotor disturbance as its central distinguishing feature and as potentially being either unipolar or bipolar. At the most severe is psychotic depression characterized by its psychotic features. The variation on the neurotransmitter approach is to identify nonmelancholic depression as due primarily to deficiencies in serotonin, whereas melancholic depression involves the additional complication of increasing norepinephrine involvement. Finally, dopamine involvement is added to the mix in psychotic depression. They recommend different treatment approaches characterized especially by different medication approaches for the three levels of disorder. Their full theory also looks at interactions with personality dimensions with psychotherapy, and it provides management suggestions for types of depression associated with different personality types.

SNRIs are the third generation of antidepressants

Today, monoamine hypotheses as theories of depression are seen as somewhat simplistic. They do not do justice to the many interconnected systems affected in depression. Many additional neurotransmitters may be involved, and drugs that affect many different systems seem to influence depression. It is also not clear why, when neurotransmitter levels are elevated with medications, several weeks are required before clinical improvement is seen.

2.1.3      Neuroendocrine Models

Another way of looking at the nervous system as it affects depression is to examine the functioning of the neuroendocrine system. People who have diseases of the endocrine glands often present with depressive symptoms. In particular, the hypothalamic–pituitary–adrenal (HPA) axis and cortisol secretion have been a focus of interest. The HPA axis involves a complex set of interconnections between brain neurotransmitters, certain hormones, and various organs. Response to stress involves the neurotransmitters (serotonin, norepinephrine, and others) and also involves the pituitary...