Biogenic amines have been important in hypotheses of mood disorders

The catecholamine hypothesis of depression was an important organizing step that helped to define modern biological research in psychiatry [22–24]. It states that depression is caused by a functional deficiency of catecholamines, particularly norepinephrine (NE), whereas mania is caused by a functional excess of catecholamines at critical synapses in the brain. This hypothesis was based on a correlation of the psychological and cellular actions of a variety of psychotropic agents. Other biogenic amines in the brain have also been linked to depression and mania with the development of monoamine or biogenic amine hypotheses. These amines have included the indolamine serotonin (5-hydroxytryptamine [5-HT]) and two catecholamines in addition to NE, dopamine (DA) and epinephrine.

A number of strategies are used to investigate neuroregulators in mood disorders

Several strategies have been used to examine the role of monoamines in the mood disorders. Precursor loading entails administering precursors of biogenic amines to subjects to raise monoamine concentrations in the brain. The serotonin precursors l-tryptophan and 5-hydroxytryptophan (5-HTP), with or without concomitant antidepressant medication, and the catecholamine precursors tyrosine and levodopa have been attempted as therapeutic regimens. None of these compounds is in routine clinical use for mood disorders. Blockers of neurotransmitter degradation, such as monoamine oxidase (MAO) inhibitors, have also been employed, as described below. See Chapters 12 and 13 regarding the metabolism and synaptic effects of these amines.

Another approach has been to deplete amines by dietary means or by administering inhibitors of enzymes involved in the formation of biogenic amines. Although dietary depletion of tryptophan, the serotonin precursor amino acid, does not change mood in unmedicated depressed subjects, this procedure produces a relapse of depression in recovered subjects who have been treated with antidepressant medication or light therapy. Dietary tryptophan depletion also can induce depressive symptoms in subjects with a family history of depression but not in control subjects. Similarly, para-chlorophenylalanine (PCPA), an inhibitor of tryptophan hydroxylase, lowers levels of 5-HT and has been found to reverse the antidepressant effects of imipramine but to have no effect on mania. A competitive inhibitor of tyrosine hydroxylase, α-methyl-para-tyrosine (AMPT), which lowers levels of catecholamines, also has been reported to worsen depression in some previously depressed patients treated with antidepressant medication. In addition, AMPT appears to improve mania in some patients. These intriguing findings are the subject of ongoing research.

Another important strategy has involved studies of the metabolites of the neuroregulators by determination of their concentrations in cerebrospinal fluid (CSF), blood or urine. There has generally been considerable inconsistency in such studies, but this may reflect not only the fact that such methods involve a summation of many events in many areas of the brain but also that the bulk of monoamine transmitters released at synapses does not spill over into the CSF or peripheral circulation. Techniques have been developed, based on radiolabeled tracers, to more accurately estimate synaptic spillover of catecholamines under different conditions. These studies have shown enhanced plasma noradrenergic activity in patients with severe agitated depression. Additional difficulties arise from the necessarily small number of subjects in these sampling studies and the likelihood of substantial clinical heterogeneity with possibly multiple disorders presenting as common syndromes.

Catecholamine hypotheses remain important for depression and mania

The norepinephrine-deficiency hypothesis of depression had several roots: one observation concerned the natural alkaloid reserpine. Treatments involving reserpine had been used in India for centuries as a treatment for mental illness. Beginning in the 1950s, reserpine was used more widely for the treatment of hypertension and schizophrenia. It was noted that, in some patients, reserpine caused a syndrome resembling depression. Animals given reserpine also developed a depression-like syndrome, consisting of sedation and motor retardation. Subsequently, it was demonstrated that reserpine caused the depletion of presynaptic stores of NE, 5-HT and DA. While it is now recognized that depression is relatively uncommon following reserpine administration, the drug had a key role in the development of psychopharmacology and was a powerful impetus to the study of the biochemistry of neuroregulators in the brain.

In contrast to reserpine, iproniazid, a compound synthesized in the 1950s for the treatment of tuberculosis, was reported to produce euphoria and hyperactive behavior in some patients. It was found to increase brain concentrations of NE and 5-HT by inhibiting the metabolic enzyme MAO. Iproniazid as well as other MAO inhibitors were soon shown to be effective in alleviating depression.

The clinical and cellular actions of tricyclic antidepressants, such as amitriptyline, were considered to support the monoamine hypothesis of mood disorders. These drugs, resulting from a modification of the phenothiazine nucleus, were found to alleviate depression consistently, as did the MAO inhibitors. Their major cellular action is to block the reuptake by presynaptic terminals of monoamine transmitters, thereby, presumably, increasing the concentration of monoamines available to interact with synaptic receptors. Thus, the actions of reserpine, MAO inhibitors and tricyclics were initially thought to be consistent in supporting the monoamine hypothesis.

Inconsistencies arose, however. The pharmacological activities of several other clinically effective compounds are difficult to reconcile with the monoamine hypothesis. Several antidepressant agents do not significantly inhibit MAO or block the reuptake of monoamines. The antimanic agent lithium (discussed below) can also be used to treat depression, yet it does not chronically increase synaptic concentrations of monoamines. Conversely, cocaine, a potent inhibitor of monoamine reuptake, has no antidepressant activity.

More detailed examination of the actions of reserpine, MAO inhibitors and tricyclics also reveals inconsistencies among their actions. Reserpine induces depression in only about 6% of patients, an incidence quite similar to the estimated incidence of depression in the general population. More importantly, the cellular effects of MAO inhibitors and tricyclic antidepressants on catecholamines are immediate, yet their clinical antidepressant effects develop quite slowly, generally over 2 to 6 weeks.

Attempts to directly measure changes in brain monoamine concentrations in the mood disorders have provided intriguing but inconsistent results. Initially, investigators concentrated on measuring the catecholamine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), in urine and CSF. Early evidence suggested that there were decreased urinary MHPG concentrations in depressed patients and increased levels in manic patients but later reports did not bear this out. This is not entirely surprising as it is now known that urinary MHPG is a poor indicator of CNS NE turnover because the CNS contributes as little as 20% of urinary MHPG content. In addition, MHPG concentrations are substantially affected by physical activity, which was often not well controlled in research studies. Concentrations of MHPG in the CSF, which may represent a more direct measure of brain NE function, have generally been found to be unaltered in mood disorders, although this remains a controversial area (see Chap. 12).

Dopamine mechanisms may be important in some forms of depression and mania

DA may also be involved in depression, and a body of literature suggests that there may be a subgroup of mood disorders in which the neuroregulator is altered [18–21]. DA receptor agonists have been reported to have some antidepressant effects in at least subgroups of patients. A number of antidepressant drugs also have DA agonist activities. Furthermore, patients in the DA-depleted state of Parkinson's disease (see Chap. 45) often develop a concomitant depression, although that may be for other reasons. Conversely, there is evidence linking DA to mania in certain patients. Several drugs that increase available amounts of DA produce behaviors that simulate some aspects of mania. Administration of levodopa (l-DOPA), the metabolic precursor of DA, can induce hypomania in some patients, a finding particularly noted in persons with bipolar disorder. In addition, DA antagonists are useful pharmacological treatments for mania, and there is evidence that DA synthesis inhibitors may also be effective. Neuroleptic drugs are also important agents for resolution of psychotic symptoms that occur in severe cases of both mania and depression [18]. However, there are problems with postulating a primary role for DA in the mood disorders. Most notably, neuroleptic medications that are known to block DA receptors and used to treat psychosis (Chap. 51) are not generally associated with the induction of depression. It is more likely that other, primary pathophysiological processes impact on dopaminergic systems, especially in more severe, psychotic forms of affective illness.

Studies of the major metabolite of DA in CSF, homovanillic acid (HVA), have been somewhat inconsistent, suggesting decreased concentrations in at least some patients with depression. Comparison between studies has been difficult due to small sample size and differences among clinical populations, including age differences. A number of studies have suggested elevated concentrations of the metabolite in the CSF of manic individuals. However, metabolites for other transmitters were also elevated in some of these studies.

Serotonin has a role in some forms of depression

A major hypothesis is that some forms of mood disorder may be due to a relative deficiency of serotonin [18–21,25]. The efficacy of several new antidepressant medications that have a high specificity as serotonin-reuptake blockers has been taken as a form of proof of the existence of such a subtype of patients. Preclinical studies indicate that chronic administration of these drugs increases the efficiency of serotonergic neurotransmission. Further support for this hypothesis comes from repeated findings of precipitation of depression during serotonin depletion in vulnerable individuals, as described above. In addition, cerebral metabolic responses to the 5-HT-releasing agent fenfluramine (see Chap. 13) are reduced in patients with depression.

One of the most consistent findings in biological research dealing with mental disorders has been that some patients with low CSF 5-hydroxyindoleacetic acid (5-HIAA) are prone to commit suicide [26]. The lower concentrations of 5-HIAA are not specific to depression; there has also been a correlation between decreased 5-HIAA and aggressive behavior in some individuals.