Serotonin hypothesis of depression

Meltzer HY, Lowey MT. The serotonin hypothesis of depression. In Meltzer HY,ed. Psychopharmacology The Third Generation of Progress. Raven, New York, 1987, pp. 233-248. 

Selective 5-HT Reuptake Inhibitors (SSRIs) Serotonin Hypothesis of Depression... 

Maes M, Meltzer HY (1995) The serotonin hypothesis of major depression. In Bloom EE, Kupfer DJ (eds) Psychopharmacology the foimth generation of progress, pp 933-944 Mann JJ (1998) The neimobiology of suicide. Nat Med 4 25-30... 

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. 

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

Paralleling these clinical developments were basic pharmacological studies, which noted that reserpine ( 5, 6, 7 and 8) and a-methyidopa produced depression in patients treated for hypertension ( 9,10 and 11). The fact that the MAOIs and TCAs functionally increased norepinephrine (NE) activity while reserpine lowered its activity led Schiidkraut (12) and Bunney and Davis (13) to independently formulate the NE hypothesis of depression. This same line of reasoning was also applied to serotonin (5-HT) (14, 15). 

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 of depression suggests that depression is predominantly caused by deficiency of serotonin. 

In the 1960s researchers formulated, and later refined, the so-called monoamine hypothesis of depression. This hypothesis states that symptoms of depression are due to alterations in the functioning of certain neurotransmitters known as monoamines, notably norepinephrine, serotonin, and to a lesser degree, dopamine. Roles for other neurotransmitters have been identified in recent years. The foundation of this hypothesis rests on the finding that all antidepressant medications known at the time had, to some extent, the ability to increase the availability of these neurotransmitters at the synaptic level. Patients and the general public often refer to this hypothesis as chemical imbalance. ... 

This data, coupled with numerous positive outcome studies of the effectiveness of antidepressants, has led to the development of the monoamine (or biogenic amine) hypothesis of depression. The theory holds that depressive symptoms are ushered in by a malfunction of either norepinephrine (NE) or serotonin (5-HT) neurons, which play critical roles in the functioning of the limbic system and the adjacent hypothalamus. The basic neuronal malfunction is felt to be identical for either NE or 5-HT neurons, thus what follows (a description of the pathophysiology of NE neurons) can also be seen to occur in individuals in whom 5-HT neurons are affected. For reasons that are not well understood, patients with major depression (with vegetative symptoms) appear to suffer from either NE or 5-HT dysfunction, but probably not both simultaneously (although some exceptions exist). 

The monoamine hypothesis of depression was proposed in 1965 to describe the biochemical basis of depression. Basically, it proposes that depression is caused by a depletion of monoamines (e.g. noradrenaline and/or serotonin) from the synapses. This reduces synaptic activity in the brain causing depression. Conversely, it suggests that mania is caused by an excess of monoamines in synapses, with excessive synaptic activity in the brain resulting in excessive euphoria. In bipolar disorder, patients have mood changes that cycle between depression and mania (Fig. 49.2). 

Antidepressants cover a wide range of indications and include depression, obsessive-compulsive disorders, anxiety, pain, panic, eating disorders or social phobia. The monoamine hypothesis of depression is an often-used term that describes a concept that arose over 50 years ago when a direct link was observed between major depression and imbalance/deficiency of available monoamines such as serotonin and catecholamines. 

After neurotransmitter molecules have influenced the firing of a receiving neuron (more technically called a postsynaptic neuron), some of them are destroyed by enzymes in the synaptic cleft (the synapse), some are reabsorbed by the sending presynaptic neuron in a process that is called reuptake , and the rest remain in the space between the two neurons. The chemical-imbalance hypothesis is that there is not enough serotonin, norepinephrine and/or dopamine in the synapses of the brain. This is more specifically termed the monoamine theory of depression, because both serotonin and norepinephrine belong to the class of neurotransmitters called monoamines. 

When the chemical-imbalance theory was introduced more than 40 years ago, the main evidence in favour of it was the contention that antidepressants, which were thought to increase the availability of serotonin and/or other neurotransmitters in the brain, seemed to be effective in the treatment of depression. As Alec Coppen wrote in 1967, one of the most cogent reasons for believing that there is a biochemical basis for depression or mania is the astonishing success of physical methods of treatment of these conditions. 26 The situation has not changed very much since then. People still cite the supposed effectiveness of antidepressants as fundamental support for the chemical-imbalance hypothesis. This theory, they say, is supported by the indisputable therapeutic efficacy of these drugs .27... 

I suppose that some ingenious minds will be able to find a way of accommodating the chemical-balance hypothesis to these data, but I suspect that the accommodation will require convoluted circumventions, like those used by the Flat Earth Society in their efforts to maintain their defunct theory in the face of photographic evidence from space. If depression can be equally affected by drugs that increase serotonin, drugs that decrease it and drugs that do not affect it at all, then the benefits of these drugs cannot be due to their specific chemical activity. And if the therapeutic benefits of antidepressants are not due to their chemical composition, then the widely proffered chemical-imbalance theory of depression is without foundation. It is an accident of history produced serendipitously by the placebo effect. 

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 amine hypothesis of major depression. Depression appears to be associated with changes in serotonin or norepinephrine signaling in the brain (or both) with significant downstream effects. Most antidepressants cause changes in amine signaling. AC,... 

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