Thomas A. Ban: Depression and the Tricyclic Antidepressants
Chapter Four: Depression
Central Cholinergic Mechanisms

            Helmut Selbach (1961) described three successive stages of imipramine action. The first is characterized by trophotropic actions (e.g., feeling of tiredness, decrease of blood pressure), the second by lability (e.g., tremor, fluctuation in blood pressure) and the third by ergotropic effects (e.g., elation, increased interest). According to him, imipramine has an effect on autonomic regulation and produces an imbalance in which the parasympathetic (trophotropic) system is more strongly inhibited than the sympathetic (ergotropic) system as reflected in the prevalence of ergotropic manifestations.

            Since reserpine, a drug which causes depression, has central cholinomimetic properties, and imipramine, a drug which lifts depression, has anticholinergic properties, it was hypothesized that a given affective state may represent a balance between central cholinergic and adrenergic activity, with depression being a disease of cholinergic and mania of adrenergic dominance (Janowsky et al. 1972). In favor of this hypothesis are the findings that all presently available tricyclic antidepressants exert anticholinergic effects. This central anticholinergic effect may cause, in certain predisposed individuals, a toxic confusional state – similar to that seen with atropine or scopolamine poisoning – which can be reversed by the administration of physostigmine, a cholinesterase inhibitor substance. On the other hand, physostigmine administration rapidly controlled mania, at least in one clinical trial, and induced severe depression (in marijuana intoxicated patients) which could be reversed by the administration of atropine, the standard anticholinergic drug.

            It is known that anticholinergic drugs, e.g., atropine, block the circadian rise in plasma hydroxycorticosteroid levels in a dose-dependent manner (Krieger and Krieger 1967). Since an increase in plasma cortisol level is commonly seen in depression and since a fall in plasma cortisol level is a consistent finding with all forms of effective treatment of depressive states, the possibility was raised that in the therapeutic action of tricyclic antidepressants their plasma cortisol level lowering effect may play a role (Carroll 1972; Gibbons and McHugh 1962; Hullin et al. 1967; McLeod 1972; Suwa and Yamashita 1972).

            In a series of systematic studies, Bernard Carroll (1972) revealed that the administration of 2 mg of dexamethasone – a synthetic glucocorticoid – at midnight, clearly distinguished between two groups of depressed patients, i.e. “suppressors” and “nonsuppressors.” Subsequently, in a pilot study, a distinct difference was found between dexamethasone “suppressor” and “nonsuppressor” patients in terms of their response to antidepressant drugs. This was to the effect that after one month of treatment, all dexamethasone “suppressors” had a favorable therapeutic response to pharmacological treatment in contradistinction to the “non-suppressors” who remained refractory to tricyclic antidepressants (McLeod, Carroll and Davies 1970). Further substantiation of these findings was given by W.R. McLeod (1972).

            Findings in these two studies strongly suggest that the dexamethasone test may meaningfully differentiate therapeutically responsive from therapeutically unresponsive patients to tricyclic antidepressant drugs.

References:

Ban TA. Depression and the Tricyclic Antidepressants Montreal: Ronalds Federated; 1974, pp. 45-6.

Carroll BJ. Plasma cortisol levels in depression. In: Davies B, Carroll BJ, Mowbray RM, editors. Depressive Illness. Springfield: Charles C. Thomas; 1972.

Gibbons JL and McHugh PR. Plasma cortisol in depressive illness. J Psychiat Res 1962; 1: 162-71.

Hullin RP, Bailey AD, McDonald AD, McDonald R, Dransfiels GA and Milne HB. Variations in 17-hydroxycorticosteroids in depression and manic-depressive psychosis. Brit J Psychiat 1967; 113: 593-60.

Janowsky MK, El-Yousef MK, Davis JM, Sekerke HJ. A cholinergic – adrenergic hypothesis of depression and mania 1972; 2: 632 -5.

Krieger DT and Krieger HP. Circadian pattern of plasma 17-hydroxycorticosteroids: Alteration by anticholinergic agents. Science 1967; 155: 1421 -2.

McLeod WR. Poor response to antidepressants and dexamethasone non-suppression. In: Davies B, Carroll BJ, Mowbray RM, editors. Depressive Illness. Springfield: Charles C. Thomas; 1972

McLeod WR, Carroll BJ and Davies B. Hypothalamic depression and antidepressant drugs. Brit Med J 1970; 2: 480 -2

Selbach H. Ueber die vegetative Dynamik in der psychiatrischen Pharmakotherapie. Dtsch Med J 1961; 12: 511 – 7.

Suwa M, Yamashita L. Psychophysiological Studies of Emotional and Mental disorders. Sapporo: Hokkaido University School of Medicine; 1972.

January 10, 2019