Serotonin hypothesis of depression

Classically, several pieces of evidence are cited to support the serotonin theory (see Maes & Meltzer, 1995, for review). First, there is evidence of a reduced availability of the 5-HT precursor tryptophan. Studies suggest reduced plasma levels of tryptophan and also enhanced non-CNS pathways for tryptophan catabolism, such as the kynurenine pathway in the liver.

Second, there is evidence of changes in the normal physiology of serotonin metabolism. For example, there is reduced uptake of 5-HT into the platelets (a model of the neuronal 5-HT transporter system).

Third, there are several ways of demonstrating 5-HT receptor changes in depression. Early work relied on the use of brains from post-mortem studies of depressed suicides. Several studies reported increased 5-HT2 receptors, a factor that was felt to be secondary to low 5-HT content, and reduced 5-HT1A hippocampal and amygdala binding. A further approach was to use neuropharmacological challenge tests. These tests are used to determine the integrity of neurotransmitter systems. Standardised serotonergic drug challenges are given, and a physiological response is measured, such as hormone release or temperature change. The magnitude of the response is taken as an index of the activity of the system challenged. Many, although by no means all, of these studies have reported impairments in depression. One example is of a blunted prolactin response to fenfluramine, a 5-HT-releasing drug.

Fourth, the technique of tryptophan depletion (TD) suggests that there may be a causal relationship between 5-HT changes and depression. The TD paradigm involves administration of a mixture of amino acids without tryptophan. This leads to a large and rapid fall in plasma tryptophan, reduced brain tryptophan entry, and reduced 5-HT synthesis. TD in depressed subjects has not revealed consistent results, perhaps because the system is maximally dysregulated. However, TD depletion temporarily induces depressive symptoms in vulnerable groups such as remitted depressed patients, those with a family history of depression, and females (Reilly et al., 1997). This research provides powerful evidence that serotonergic function is causally related to mood states rather than merely showing a cross-sectional association. This technique may also have a predictive value, in that depressed patients in remission who show a mood-reducing effect of TD have higher rates of true relapse in the following 12 months (Moreno et al., 2000). This suggests that certain individuals may have a biological vulnerability to the short-term depressogenic effects of reduced brain 5-HT availability, a vulnerability which places them at increased risk of future major depression, possibly as a response to other biological or environmental causes of reduced 5-HT availability.

One anomaly is the observation that the mood-lowering effect of tryptophan depletion does not occur to a significant degree in remitted depressed patients receiving continuation treatment with desipramine, a noradrenergic-specific tricyclic (Delgado et al., 1999). They do, however, experience the effect if noradrenaline synthesis is inhibited; however, this procedure does not affect patients taking SSRIs (Delgado et al., 1999).

More recently, neuroimaging techniques have increased our knowledge about 5-HT changes in depression; these will be described later in the chapter.

One argument against the significance of serotonergic changes in depression comes from observations that several enduring character traits may be closely related to 5-HT function. Thus, while early studies of CSF concentrations of the 5-HT breakdown product 5-HIAA reported reduced levels in depression, more recent studies suggest that low CSF levels of 5-HIAA and other indices of reduced serotonergic function are linked more specifically to suicide, impulsivity, aggression, or other personality variables (Cleare & Bond, 1997; Mann, 1995). Thus, 5-HT changes in depression may reflect these factors.

A further issue is whether or not the serotonergic changes are state or trait related. Many of the neuroendocrine challenge tests, such as fenfluramine, normalise with treatment of the depression (Maes & Meltzer, 1995). However, the reduced 5-HT1 A receptor binding seen with positron emission tomography (PET) does not normalise after treatment with SSRI medication (Sargent et al., 2000). This suggests that some of the observed changes in depression may indeed be trait markers, and could therefore be linked to vulnerability or personality rather than the depressive state.

Noradrenergic theories

There is evidence of noradrenergic dysfunction in depression. Many antidepressants are potent inhibitors of the reuptake of noradrenaline, with little effect on serotonin reuptake. Neuroendocrine challenge studies have found evidence of reduced noradrenergic function. For example, there is a reduced GH response to the a2-agonists clonidine and desipramine, suggesting impaired a2 -receptor function. This abnormality remains blunted when patients are off medication and non-depressed, suggesting that it could be a trait marker. Post-mortem and platelet studies also provide some support for changes in a and j adrenergic receptors. Several studies have shown that low urinary levels of the noradrenaline metabolite MHPG predict a favourable response to tricyclics (Schatzberg et al., 2002).

A novel, though highly invasive, method has recently been described that provides further evidence of reduced catecholamine availability in the brain in depression (Lambert et al., 2000). Patients with treatment-resistant depression underwent catheterisation in the brachial artery for arterial blood and in the internal jugular vein for venous blood draining from the brain. The main findings were that there was a reduced concentration gradient in depression for noradrenaline and its metabolites and for the dopamine metabolite, homovanil-lic acid; this suggests reduced amounts of these neurotransmitters stemming from the brain.

Dopaminergic theories

There is some evidence of a reduced GH response to apomorphine, a dopamine receptor agonist, in depression, but results are inconsistent with this challenge (Schatzberg et al., 2002). Interest in the dopaminergic system has been rekindled by the introduction of bupropion, an antidepressant that works primarily on dopamine reuptake.

Cholinergic theories

Studies have shown an enhanced GH response to the anticholinesterase drug pyridostigmine, a measure of acetylcholine receptor function. Further evidence comes from the observation of reduced rapid eye movement (REM) latency and increased REM sleep in depression, effects that may represent increased cholinergic activity. Furthermore, depressed patients show supersensitivity to the REM sleep effects of cholinergics. Janowsky proposed the cholinergic-adrenergic balance theory of depression, hypothesising that increased choliner-gic function and reduced noradrenergic function were both important in generating symptoms in depression (Janowsky & Overstreet, 1995).

GABA-ergic theories

There is areduced GH response to baclofen, a GABA-B receptor agonist, suggesting reduced GABA receptor activity in depression (O'Flynn & Dinan, 1993). Plasma GABA may also be low (Schatzberg et al., 2002).

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