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Depression: a short textbook for GP's |
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2.4 Theories of Depression The Biogenic Amine Hypothesis
We here explore some of the major theories that have been proposed to explain the pathology of depressive disorder. Researchers do not know exactly how or why the process of neurotransmission is altered in depression, but decades of research have implicated two key monoamine neurotransmitters, noradrenaline and serotonin.
The Biogenic Amine Hypothesis. In the early 1950s, researchers noticed that drugs that decreased monoamines precipitated depression, and drugs that increased monoamines relieved depression. The Biogenic Amine Hypothesis states that depression is caused by a deficiency of monoamines, particularly noradrenaline and serotonin.
According to this hypothesis, depression can be alleviated by drugs that increase the availability of noradrenaline and serotonin. One method of increasing monoamines centers around the action of MAO. Remember that MAO degrades neurotransmitters.
Blocking the action of MAO leads to an increased availability of neurotransmitters. When the action of MAO is blocked, neurotransmitters are not metabolised, so they accumulate in the presynaptic neuron. Drugs which block the metabolism of noradrenaline and serotonin via inhibition of MAO are called MAO inhibitors, or MAOIs. MAOIs were among the first clinically proven antidepressants. Taken chronically, MAOIs also produce desensitization and down-regulation of postsynaptic receptors. Another way to increase monoamines involves blocking the process of reuptake. Blocking reuptake prevents the presynaptic neuron from reclaiming neurotransmitter, which increases the amount of neurotransmitter in the synaptic cleft.
Drugs were developed in the 1950s that blocked reuptake in just this way. These drugs - still widely used today - are called tricyclic antidepressants or TCAs. The Biogenic Amine Hypothesis has been the cornerstone of research on depression for more than 30 years. However, an important fact cannot be explained by the Biogenic Amine Hypothesis. Laboratory tests indicate that antidepressants such as TCAs and MAOIs increase available neurotransmitters quite rapidly - within a matter of hours. Yet, typically, clinical relief takes much longer. A person suffering from depression may not experience significant relief for as long as 6 to 8 weeks. The Receptor Sensitivity Hypothesis The Biogenic Amine Hypothesis alone cannot explain the delay in time of onset of clinical relief of depression of up to 6-8 weeks. Recall how the body compensates for a deficit or excess of neurotransmitter.
Supersensitivity is a compensatory response of the postsynaptic neuron when it receives too little stimulation. The neuron tries to make up for a lack of stimulation by increasing receptor responsiveness. Over time, the postsynaptic neuron may also compensate for lack of stimulation by synthesizing additional receptor sites. This process is known as up-regulation. By increasing the amount of neurotransmitter in the cleft, you can normalize responsiveness. Increased neurotransmitter increases stimulation of receptor sites, which prompts the postsynaptic neuron to compensate by decreasing receptor sensitivity, a process known as desensitization. The postsynaptic neuron is also thought to compensate for increasing stimulation by decreasing the number of receptor sites, a process known as down-regulation. As you know, antidepressant drugs are thought to work by increasing the amount of neurotransmitter in the cleft. They do this by blocking metabolism of monoamines - the MAOIs - or by blocking reuptake - the TCAs. Most TCAs are more effective in blocking noradrenaline reuptake than serotonin reuptake.
Chronic administration of TCAs or MAOIs is thought to alter the responsiveness and/or the number of postsynaptic receptor sites. Observation of this long-term effect of antidepressants led to the Receptor Sensitivity Hypothesis. This hypothesis proposes that depression is the result of a pathological alteration (supersensitivity and up-regulation) in receptor sites, which results from too little stimulation by monoamines, i.e., a deficiency of noradrenaline and serotonin in the cleft. Chronic administration of TCAs or MAOIs results in increased availability of noradrenaline and serotonin. This causes desensitization (the uncoupling of receptor sites) and possibly down-regulation (a decrease in the number of receptor sites). According to this hypothesis, relief from depression symptoms comes from a normalization of receptor sensitivity. According to the Receptor Sensitivity Hypothesis, antidepressant drugs achieve their clinical effect by reducing receptor supersensitivity. This theory is an important step toward understanding the long delay between administration of TCAs and MAOIs and clinical response. While TCAs are effective in blocking the reuptake of noradrenaline and serotonin into the presynaptic neuron, they are non-selective: they also block postsynaptic receptor sites, including cholinergic (muscarinic), histaminergic, and adrenergic receptor sites. Blockade of histaminergic receptors can lead to sedation, weight gain, and hypotension. In the elderly, this is a particular problem, since it can result in fainting or falls. TCAs also block muscarinic receptors, which can lead to blurred vision, dry mouth, constipation, urinary retention, confusion, and delirium.
The Serotonin-only Hypothesis. Early in the 1980s, drugs were introduced that selectively blocked serotonin reuptake, resulting in more serotonin available in the cleft. These drugs were known as selective serotonin reuptake inhibitors, or SSRIs. Unlike the TCAs, which are non-selective, the SSRIs may have fewer serious side effects and are therefore easier for patients to tolerate. This has led to the Serotonin-only Hypothesis which emphasizes the role of serotonin in depression and downplays noradrenaline.
But the serotonin-only theory has shortcomings:
A study at Yale tested the serotonin-only hypothesis and demonstrated the importance of noradrenaline. The test group consisted of depressed patients who were being treated successfully with either selective serotonin reuptake inhibitors (SSRIs) or a non-selective TCA. All these patients were placed on a tryptophan-free diet. (Remember, tryptophan is the precursor of serotonin.) Researchers reasoned that is serotonin alone were responsible for depression, all patients should relapse when the tryptophan-free diet caused their serotonin levels to fall. In fact, only those patients taking SSRIs relapsed, while those on TCAs did not. This suggested that both noradrenaline and serotonin play a critical role in depression. Another key observation came from laboratory studies. When noradrenergic neurons are destroyed in laboratory animals, drugs that affect serotonin do not have their usual effects. Likewise, when serotonergic neurons are destroyed, drugs that affect noradrenaline do not have their usual effects. Current research suggests that mood is controlled by a balance of noradrenaline and serotonin, not by absolute levels of these neurotransmitters or their receptors. According to this hypothesis - the Permissive Hypothesis - the control of emotional behavior results from a balance between noradrenaline and serotonin. According to this theory, both the manic phase and the depressive phase of bipolar disorder are characterized by low central serotonin function. Evidence suggests that brain serotonin systems dampen or inhibit a range of functions involving other neurotransmitters. Mood disorders result from the removal of the serotonin damper. The Permissive Hypothesis postulates that low levels of serotonin permit abnormal levels of noradrenaline to cause depression or mania. If serotonin cannot control noradrenaline, and noradrenaline falls to abnormally low levels, the patient becomes depressed. On the other hand, if the level of serotonin falls and the level of noradrenaline becomes abnormally high, the patient becomes manic.
According to this hypothesis, antidepressant drugs are effective to the degree that they reinstate the ability of serotonin to control noradrenaline, thus restoring the critical balance that controls emotional behavior. A new class of antidepressant drugs, serotonin-noradrenaline reuptake inhibitors (SNRIs) work to selectively block reuptake of both noradrenaline and serotonin, thereby increasing levels of both monoamines. The SNRIs have very little affinity for other postsynaptic receptor sites and are therefore less likely to produce some of the side effects associated with TCAs. The Electrolyte Membrane Hypothesis This theory is largely based on studies in the 1960s of state related fluctuations in manic depressive illness such as urine volume and body weight. This hypothesis largely died out after the 1960s but may be reemerging with the resurgence in the literature in the biochemistry and biophysics of membrane functions. For example, the lithium-sodium counterflow mechanism in red cells has been described and protein structural differences between patients with bipolar-polar disorder and controls have been revealed. The mechanism of action of lithium in bipolar disorder is still not understood. The Neuroendocrine Hypothesis. According to this hypothesis, pathological mood states are explained or contributed to by altered endocrine function. This theory historically grew out of observations that altered mood states were associated with thyroid or Cushings disease. Current explorations of pathophysiology using neuroendocrine theories have tended to result in research tools such as the dexamethasone suppression test becoming diagnostic tools, perhaps prematurely.
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