Depression monoamine hypothesis

The original monoamine hypothesis of depression states that depressions are associated with a deficiency of catecholamines, particularly norepinephrine, at functionally important adrenergic receptor sites in the brain. Elation conversely may be associated with an excess of such amines. The hypothesis was articulated in 1966 only after the mechanism of action of the tricyclic antidepressant desipramine and of the psychostimulants... 

VMATs are irreversibly inhibited by the potent antihypertensive drug reserpine. The depressive effects of reserpine helped to formulate the original monoamine hypothesis of affective disorders. Reseipine also appears to interact with the transporters near the site of substrate recognition. Tetrabenazine, which is used in treatment of movement disorders, inhibits VMAT2 much more potently than VMAT1, consistent with the less hypotensive action of this agent. 

The monoamine hypothesis predicts that drugs which increase the concentration of noradrenaline and/or 5-HT in the synapse should relieve depression. This could be achieved in two ways, as illustrated in Figure 20.1 ... 

Reserpine and iproniazid research led to the monoamine hypothesis of depression. This hypothesis proposed that a reduction in the monoamine neurotransmitters caused depression. As described in the sidebar on pages 82-83, only a small number of neurons use serotonin as a neurotransmitter, but these cells project to widespread regions of the brain. The same holds true for norepinephrine and dopamine. Although not widely used in the nervous system, these neurotransmitters are apparently involved in networks of neurons that greatly influence a person s mood. Synaptic transmission between neurons in other areas of the brain—such as neurons that process visual information, for instance—often carry specific messages, such as the presence of an object at a certain point in the person s visual field. In contrast, the monoamine neurotransmitters underlie information processing of a more general nature, some of which correlates with mood. 

Depending on the outcome of this research, future antidepressants may or may not target serotonin or other monoamines. What is immediately clear is that while the monoamine hypothesis has prompted a lot of useful research, depression is not as simple as this hypothesis would indicate. 

Like the monoamine hypothesis of depression, such a simple hypothesis was appeaUng but, perhaps predictably, a Uttle too simple to be true. Further research using a technique known as positron emission tomography (PET) showed the relationship between dopamine and schizophrenia is more complex. PET detects radioactive emissions of certain isotopes these isotopes are incorporated into a molecule and injected into a patient. The machine measures the radioactivity with detectors positioned aroimd the body. PET lets researchers study the distribution of certain molecules in Uving tissue since, imUke autoradiography, the tissue is not sliced and treated chemically. The amoimt of radioactivity must be small, however, to avoid harming the human subjects. 

The monoamine hypothesis of depression develops from the finding that drugs reducing monoamine neurotransmission cause depression. Monoamines include serotonin, norepinephrine, and dopamine. 

In the mid-1960 s, Schiidkraut and Bunney and Davis, independently developed the monoamine hypothesis of mood disorders. To date, a great wealth of data has been generated to test this theory (see also the section Mechanism of Action in Chapter 7) (21, 22). Because the early development of psychotropic agents was based on the concept that altering norepinephrine (NE) or serotonin activity could benefit depression or mania, it is not surprising that the action of these drugs... 

The monoamine hypothesis of depression (Figure 30-2) suggests that depression is related to a deficiency in the amount or function of cortical and limbic serotonin (5-HT), norepinephrine (NE), and dopamine (DA). 

The monoamine hypothesis, like the neurotrophic hypothesis, is at best incomplete. Many studies have not found an alteration in function or levels of monoamines in depressed patients. In addition, some candidate antidepressant agents under study do not act directly on the monoamine system. These include glutamate antagonists, melatonin agonists, and glucocorticoid-specific agents. Thus, monoamine function appears to be an important but not exclusive factor in the pathophysiology of depression. 

Hirschfeld RM History and evolution of the monoamine hypothesis of depression. J Clin Psychiatry 2000 61(Suppl 6) 4. 

Hindmarch, I. (2001). Expanding the horizons of depression beyond the monoamine hypothesis. Hum Psychopharmacol, 16,203-18. 

Owens, M.J. (2004). Selectivity of antidepressants from the monoamine hypothesis of depression to the SSRI revolution and beyond. J Clin Psychiatry, 65, 5-10. 

FIGURE 5-14. According to the monoamine hypothesis, in the case of depression the neurotransmitter is depleted, causing neurotransmitter deficiency. 

FIGURE 5 — 15. Monoamine oxidase inhibitors act as antidepressants, since they block the enzyme MAO from destroying monoamine neurotransmitters, thus allowing them to accumulate. This accumulation theoretically reverses the prior neurotransmitter deficiency (see Fig. 5—14) and according to the monoamine hypothesis, relieves depression by returning the monoamine neuron to the normal state. 

Depletion of monoamine neurotransmitters (cf. Fig. 5—60 and Fig. 5—61) has already been discussed as the central theme of the monoamine hypothesis of depression (see Figs. 5—13 and 5—14). The neurotransmitter receptor hypothesis of depression takes this theme one step further—namely, that the depletion of neurotransmitter causes compensatory up regulation of postsynaptic neurotransmitter receptors (Fig. 5—62). 

As discussed in Chapter 5 (Figs. 5—63 and 5—64), the monoamine hypothesis of gene expression proposes that depression itself is linked to abnormal functioning of neurotransmitter-inducible gene expression, particularly neurotrophic factors such as... 

To understand the biological basis of depression, including the monoamine hypothesis, the neurotransmitter receptor hypothesis and the hypothesis of reduced activation of brain neurotrophic factors. 

The monoamine hypothesis of depression suggests that depression is predominantly caused by deficiency of serotonin. 

Yamada, M. and Higuchi, T. Functional genomics and depression research beyond the monoamine hypothesis. Eur. Neuropsychopharmacol. 12 (2002) 235-244. 

Despite decades of research, there is no evidence to support the monoamine theory of depression (see Chapter 9). Studies of noradrenalin are inconsistent, with as many finding raised levels in people with depression as those finding reduced levels (Dubovsky, Davies, Dubovsky 2002). Evidence on serotonin is similarly inconsistent, and eminent mainstream psychopharmacologists admit that there is no evidence of serotonin dysfunction in depression (Lacasse Leo 2005). Nevertheless, the monoamine hypothesis has survived and remains influential. Contradictory evidence has been overlooked or reframed as supportive. For example, Schildkraut reported research that clearly showed that imipramine decreased noradrenalin levels in the brain, but hypothesised that despite reduced concentrations, the activity of noradrenalin might nevertheless be increased (Schildkraut, Winokur, Applegate 1970). 

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