Reduced central serotonergic activity in mania: implications for the relationship between depression and mania

The hypothesized association between brain amine function and disturbance in mood postulates that clinical depression is associated with a decrease in aminergic function while mania is associated with increased activity of these amines. In a recent reevaluation of the behavioral changes associated with central aminergic depletion, the authors noted that the administration of parachlorophenylalanine (PCPA), which inhibits the synthesis of serotonin, did not produce a depressive syndrome. This observation led to the consideration that mania may be associated with a significant reduction in central serotonergic function, rather than with an excess of such function. It is noted that the data reviewed provide indirect rather than direct support to this hypothesis. CSF 5 HIAA (5 hydroxyindoleacetic acid), the primary metabolite of serotonia, is significantly reduced in depressed as well as manic patients. CSF concentration of tryptophan (the dietary precursor of serotonia) is low in both manic and depressed patients as compared with control subjects. If the lumbar spinal fluid tryptophan levels do reflect, in part, brain concentrations of the amino acid, then this might indicate a reduction in brain tryptophan levels. Dietary factors may influence brain serotonin concentration. Antidepressant and antimanic effects of tryptophan, alone or in combination, have been observed by some investigators, but not confirmed by others. Tryptophan has been reported to have some sedative properties, and this may have contributed to its therapeutic effect in manic patients. The role of imipramine in the treatment of depression is well established. It was therefore of interest to have noted that, in some cases, imipramine by itself has a significant anti manic effect. Methysergide has been reported as an effective anti manic agent, but this observation has not been confirmed by recent controlled investigations. PCPA in doses of up to 4 Gms. was given to healthy male volunteers, to several patients with migraine and to one addict receiving methadone. These subjects had a reduction in blood serotonin and/or urinary or CSF 5 HIAA concentrations of up to 80% of baseline values. These observations are sufficiently suggestive to warrant the hypothesis that there may be a reduction in central serotonergic activity in mania as well as in depression. Kety, in an effort to integrate the cathecholamine and indolamine hypotheses of affective illness, has postulated that there may be an insufficiency of serotonin associated with either a deficiency or an excess of catecholamines: i.e. excess catecholamines being associated with mania and deficient catecholamines with depression. The complex interactions between serotonin, norepinephrine and dopamine may account for the fact that an abnormality in one system does provide a basic vulnerability, so that an alteration in another system allows for the emergence of the clinical syndrome. In addition, it has been noted that there are a number of findings of similar biological changes in both mania and depression (reduction of CSF 5 HIAA concentrations; similar alterations in total body and intracellular water; similar changes in sleep patients; reduced transport of sodium into the CSF; effectiveness of ECT; response to treatment with lithium carbonate; and the high frequency of symptoms of depression in manic patients). These findings suggest the need to reconsider the biological relationship between mania and depression. (Scarcella - Washington, DC)