Looking Beyond the Monoamine Hypothesis

Looking Beyond the Monoamine Hypothesis

Johan A Den Boer
European Neurological Disease 2006
Published: October 2008
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The monoamine hypothesis has dominated research into the pathophysiology and pharmacotherapy of depression for a long time. This has led to the development of antidepressants that are now more selective than the early tri- and tetracyclics from which they have evolved. Alternative hypotheses such as those involving adult neurogenesis or components of the hypothalamic–pituitary–adrenal (HPA) axis are either too premature or have not led to drugs with improved antidepressant activity. Recent new approaches include DNA techniques (identifying genes and gene expression) 1,2 and proteomics (a complete inventory of all proteins).3,4 To date, they have not contributed to the development of new drugs. Although many exciting developments are occurring, it does not appear as easy to develop the next generation of antidepressant drugs that do not influence monoamines. In the meantime there may be no choice other than to make the best of the existing hypotheses. This is not as hopeless as it may seem, because there is still considerable potential in the concept of monoamine reuptake inhibition.


Monoamines, Neuroimaging and Sub-components of the Depressive Syndrome

The monoamine hypothesis of depression 5 does not only propose the crucial involvement of monoamines in the therapeutic effects of antidepressant drugs but also suggests that depression is directly related to decreased monoaminergic transmission. In view of recent developments in molecular biology, it is relevant to consider what the actual position of this hypothesis is and whether recent findings (e.g. based on neuroimaging techniques) still support its validity.

There are new data that fit well into the monoamine hypothesis. Many of them originate from positron emission tomography (PET) studies. By using selective radioligands, evidence was found for reduced pre- and post-synaptic 5-hydroxy-tryptamine (5-HT)1A receptor binding in depression. Drevets et al.6 demonstrated that the mean 5-HT1A-receptorbinding potential (BP) was reduced in the mesiotemporal cortex and raphe area in unmedicated depressives relative to controls using PET and (11C) WAY-100635. A similar reduction was evident in the parietal cortex, striate cortex and left orbital cortex/ventrolateral pre-frontal cortex. These data are consistent with those of Sargent et al.,7 who found decreased 5-HT1A-receptor-binding potential (BP) in unmedicated depressed patients relative to healthy controls in the raphe, mesiotemporal cortex, insula, anterior cingulate, temporal polar cortex, ventrolateral pre-frontal cortex and orbital cortex. However, a subgroup of the subjects was scanned both pre- and post-paroxetine treatment and the 5-HT1A receptor BP did not significantly change in any area.

Most brain imaging studies conducted in patients with major depression episodes (MDE) have been able to identify abnormalities associated with MDE.8,9 There is a large inter-individual variability in severity and psychopathological features associated with MDE. This might be related to the habit of treating major depression as a unitary construct, while recent evidence suggests that depression consists of several sub-components.

A recent PET study with 11C-labelled 3-amino- 4-(2-dimethylaminomethylphenylsulfanyl) benzonitrile ((11C)DASB), a selective radioligand for the 5-HT transporter (5-HTT), in patients suffering from MDE investigated the contribution of another factor associated with depressed moods – namely, the presence of dysfunctional attitudes and the relationship thereof with the 5-HTT binding potential.10 Dysfunctional attitudes are negatively biased assumptions and judgements about the world and oneself and constitute a negative cognitive interpretative bias of the future. Most studies have investigated the relationship with depression as a syndrome and have ignored the presence of other variables such as dysfunctional attitudes. Interestingly, no differences in 5-HTT BP were found among the entire sample of depressed patients compared with healthy controls. Depressed patients with high regional 5-HTT BP (up to 21%) had higher levels of dysfunctional attitudes. It has been suggested that an increased density of the 5-HTT may lead to increased 5-HT clearance from the synapse, leading to reduced availability of synaptic 5-HT.

Milak et al.11 have investigated the association between different psychopathological clusters of the Hamilton Depression Rating Scale (HDRS) and resting glucose metabolism using 18 fluoride-fluorodeoxyglucose ((18F)-FDG) PET. They found distinct correlations between three HDRS factors and regional glucose metabolism. The first factor, psychic depression, showed a positive correlation with metabolism in the basal ganglia, thalamus and cingulate cortex. The second factor, sleep disturbance, showed a positive correlation with metabolism in limbic structures and basal ganglia, and the third factor, loss of motivation, was negatively correlated with parietal and superior frontal cortical areas. Interestingly, this study shows that positive correlations with aspects of depression severity are subcortical ventral, ventral pre-frontal and limbic structures, whereas negative correlations are found in dorsal cortical areas.11

According to these neuroimaging studies, serotonin is likely to play a role in the neurobiology of depression in at least a subgroup of patients, but is not necessarily confined to the syndrome of depression. A more fruitful approach would be to search correlates between processes in the brain and subcomponents of MDE, such as motivation, anhedonia, depressed mood, dysfunctional attitudes and sleep disturbances, instead of trying to find neuronal correlates for depression as a syndrome.

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