Biogenic Amine Hypothesis

Most of the evidence supporting the biogenic amine hypothesis is indirect. Specifically, deficits of norepinephrine and/or serotonin have been cUfficult to demonstrate. Considerable research into urinary levels of methoxy-hydroxy-phenylethanolamine glycol (MHPG), a norepinephrine metaboUte, in depressed 

Another test for the biogenic amine hypothesis w ould involve precursor loading sLategies. In other w ords, compounds w hich could increase brain levels of norepinephrine and/or serotonin should demonsLate antidepressant efficacy. Results of these studies have been mixed. Several positive findings w ere reported wdth Seating depression wdth the serotonin precursors tryptophan and 5-hydroxy tryptophan (5-HT) (Shaw et al., 2001), but these w ere not consistently replicated. Less posidve results w ere reported wdth attempts to increase brain norepinephrine levels wdth precursors. 

In adcUdon to the biogenic amines, the amino acid neurotransmitters are also implicated in the neurochemistry of major depressive disorder. Neurotransmitter y-aminobutyric acid (GABA) levels are low in brain, cerebrospinal fluid, and blood of padents w ith major depressive disorder (Petty, 1995 Brambilla et al., 2003). 

Possibly the best evidence suggesting involvement of norepinephrine and serotonin in major depressive disorder devolved from depletion studies (Delgado et al., 1990). In these stndies, patients who have responded to treatment for depression are given procedures, which deplete brain levels of serotonin or norepinephrine. Serotonin levels are decreased by nse of a low monoamine diet, followed by a drink which inclndes all the amino acids except the serotonin precnrsor tryptophan. Norepinephrine levels are depleted by administration of alpha-methylparatyrosine. In patients who had responded to treatment with a serotonergic antidepressant, depletion of serotonin cansed a prompt and dramatic, but brief reoccurrence of the symptoms of major depression. In patients who had responded to treatment with a noradrenergic antidepressant, depletion of norepinephrine caused a relapse into depression. The converse was not true in other words, serotonin depletion did not canse relapse in patients who responded to noradrenergic antidepressants, and vice versa. 

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Biogenic amine hypothesis. Depression may be caused by decreased brain levels of the neurotransmitters norepinephrine (NE), serotonin (5-HT), and dopamine (DA). 

As outlined previously, initial biological hypotheses of mood disorders were derived from the pharmacological actions of antidepressant drugs, which increase synaptic concentrations of noradrenaline (NA] and/or serotonin. Consequently, the biogenic amine hypothesis was formulated, but it lacks consistent proof that NA and/or serotonin release is indeed diminished. This failure is in part a result of the limited access to relevant brain areas. Measurements of NA and serotonin and their metabolites in blood, urine, and CSF... 

This phenomenon is one of the pillars of the biogenic amine hypothesis of depression (see Suicide later in this chapter). An intriguing finding with reserpine is that those susceptible to a depressive syndrome while on this agent also have an increased likelihood of a personal or family history of MDD, in comparison with those who are not susceptible. This finding suggests an interaction between a constitutional predisposition and the biochemical effects of this drug. Because depression is a... 

Depression. Depression is our most common mental problem. One in four women and one in ten men will have a major depression during their lifetime.1095 More than 15 million people in the United States are affected by severe depression in any given year and more than 30,000 may commit suicide.1096 1097 Worldwide psychiatric problems, mostly depression, account for 28% of all disabilities.1098 The biogenic amine hypothesis states that depression results from the depletion of neurotransmitters in the areas of the brain involved in sleep, arousal, appetite, sex drive, and psychomotor activity. An excess of transmitters is proposed to give rise to the manic phase of the bipolar (manic-depressive) cycle that is sometimes observed. In support of this hypothesis is the observation that administration of reserpine precipitates depression, which may be serious in 15-20% of hypertensive patients receiving the drug. Similar effects are observed with the dopa decarboxylase inhibitor a-methyldopa... 

Keywords Major depressive disorder Biopolar disorder Schizophrenia Mood disorders Biogenic amine hypothesis Learned helplessness Antidepressant drugs Mood stabilizers Dopamine hypothesis Antipsychotic drugs... 

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). 

Traditional explanations of the biologic basis of depressive disorders have focused largely on NE and 5-HT however, most of the evidence that coalesced into the biogenic amine hypothesis of depression does not clearly distinguish between NE and DA. ... 

Thus there appear to be significant mechanistic differences the hydrazines inhibit MAO, the tertiary amine tricyclics seem to inhibit the serotonin amine pump, whereas the secondary amine ones seem better in switching off the NE reuptake mechanism. Table 12-18, however, shows that there is some overlap. Nevertheless, there is a thread of commonality—the net increase of amine neurotransmitters in the synaptic area—yet all these drugs require several weeks of treatment before objective results are noted. The biogenic amine hypothesis does not satisfactorily explain this. It is even more difficult to explain the antidepressant action of some of the second-generation drugs, such as mianserin (Fig. 12-26), that seem to have no significant effect on amine reuptake mechanism of either... 

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