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 ... 

The monoamine hypothesis made a good story. There is only one problem with it. It does not really fit the data. It didn t fit the data that were available in the 1960s when the theory was developed, and it does not fit the data that have accumulated since then. 

Hindmarch, I., Beyond the Monoamine Hypothesis Mechanisms, Molecules and Methods , European Psychiatry 17, Suppl3 (2002) 294-99... 

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). 

Finally, perhaps the most convincing line of evidence supporting the monoamine hypothesis is the fact that (at the time of this writing) all available antidepressants appear to have significant effects on the monoamine system. All classes of antidepressants appear to enhance the synaptic availability of 5-HT, norepinephrine, or dopamine. Attempts to develop antidepressants that work on other neurotransmitter systems have not been effective to date. 

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. 

One of the weaknesses of the monoamine hypothesis is the fact that amine levels increase immediately with antidepressant use, but maximum beneficial effects of antidepressants are not seen for many weeks. The time required to synthesize neurotrophic factors has been proposed as an explanation for this delay of antidepressant effects. Appreciable protein synthesis of products such as BDNF typically takes 2 weeks or longer and coincides with the clinical course of antidepressant treatment. 

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. 

In order to understand the monoamine hypothesis, it is necessary first to understand the normal physiological functioning of monoaminergic neurons. The principal monoamine neurotransmitters in the brain are the catecholamines norepinephrine (NE, also called noradrenaline) and dopamine (DA) and the indoleamine serotonin (5HT). 

Another problem with the monoamine hypothesis is the fact that the timing of antidepressant effects on neurotransmitters is for different from the timing of the antidepressant effects on mood. That is, antidepressants boost monoamines immedi-... 

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). 

C. The monoamine hypothesis of antidepressant action on gene expression... 

The Monoamine Hypothesis of Antidepressant Action on Gene Expression... 

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