Cholinergic mechanisms in affective disorders.

Advances in clinical and basic research methodology combined with clearly articulated concepts create new opportunities for researching the roles of cholinergic mechanisms in the pathophysiology of affective disorders. Areas for study include: 1) roles of cholinergic mechanisms in mediating effects of stress and cholinergic mechanisms linking the pathophysiologies of affective and panic disorders, 2) use of pharmacologic agents to produce cholinergic system supersensitivity in modeling biologic aspects of affective illness, 3) use of multigenerational intra.. pedigree studies of cholinergic markers associated with affective disease, 4) research into the neurobiology of lithium and ECT as they pertain to muscarinic cholinergic mechanisms, 5 ) study of the interrelationship of sodium, calcium and lithium ion metabolism and their relationship to cholinergic-monoaminergic interaction, 6) the development of brain imaging strategies and techniques, e.g., positron emission tomography (PET), to measure changes in cholinergic receptor density and affinity as a function of clinical state, 7) identification and validation of a peripheral model of the central muscarinic receptor, 8) study of the pharmacology of abusable substances and its relationship to mechanisms regulating mood, affect, psychomotor function and other variables related to the affective disorders, and 9) development of in vitro and in vivo models useful in studying the physiology and biochemistry of the interaction of cholinergic and monoaminergic neurons. These models may allow us to bridge the traditional cholinergic and monoamine hypotheses of affective disorders. Received September 21, 1985; accepted for publication April 5, 1986 Research into the pathophysiology of affective disorders tends to focus on disturbances of cholinergic or monoaminergic mechanisms. “In the limit” investigations must consider interaction of these neurotransmitter systems but for practical and heuristic purposes it is possible to isolate them. This article highlights areas for future attention by those interested in cholinergic mechanisms involved in the pathophysiology of affective disorders. 1. Cholinergic mechanisms as mediators of the effects of stress and affective disorders The dichotomization of depression as biological or psychological is problematic. The stereotypical melancholic or endogenous episode can occur without situational provocation. However, subjects with affective disorders may have an unsituationally related episode of melancholia at CHOLINERGIC MECHANISMS IN AFFECTIVE DISORDERS 3 13 one point in life and another occurring in strong association with a major life event at another. Both can be biological and psychological events. Weiss et al. (1) reported that an uncontrollable stressor, a phenomenon often reductionistically conceived as being “psychological in nature,” produced a fall in the concentration of the brain biogenic amines. This is supposed to be a feature of a “biological” depression. Lloyd (2) reviewed studies examining the hypothesis: life events precipitate depressive disorders. He found that relative risk of illness is increased fiveto six-fold in the 6 months after a major life event. Kennedy et al. (3) found a two-fold increase in life events during the 4 months preceding hospitalization in a cohort of 20 manic patients. Events carrying a significant negative impact were more common among manic subjects independent of clinical status. Rasmussen et al. (4) observed a case of “loss-induced” depression in an adult Macaque monkey after a miscarriage. The animal developed anorexia, psychomotor retardation, weight loss and poor grooming. After several weeks without improvement, she was treated with amitriptyline, 5 mg/kg. Within a week she became active and resumed eating and grooming. The “stress” of reintroduction into her usual social environment was associated with a recurrence, but symptoms abated within 2 weeks. Her closest companion was then removed from the colony. Once again she developed features of melancholia (5). These points highlight the difficulty of categorically distinguishing the psychological and biological. What appears to have a psychological cause can have a biological basis. Further, published data and clinical experience both suggest that affective disorder subjects are at an increased risk for development of manic or depressive episodes in the face of stresses due to their neurobiological peculiarities. Janowsky and associates (6-8) proposed that effects of acute and chronic stress are partially mediated by central muscarinic systems with capacities to activate adrenergic networks. Acetylcholine is unique among known neurotransmitters in its ability to simultaneously produce behavioral, cardiovascular, neuroendocrine and noradrenergic effects typifying stress. Aberrant cholinergic mechanisms are also involved in the pathophysiology of the affectibe disorders and regulation of mood (9, 10). This includes genesis of the phenomenology and neuroendocrinology and polysomnographic abnormalities of these conditions. Secondly, central cholinergic sy5tems participate in regulation of blood pressure and heart rate (11-13). Thus, affective, neuroendocrine, sleep and autonomic changes following acute or chronic stress could have a cholinergic component. The reason stress increases the frequencies of depressive and manic episodes is unknown. However, this observation can be explained within the context of a cholinergic-monoaminergic interaction theory (9). This model predisposes that an abiding supersensitivity of cholinergic systems renders affective disorders subjects liable to developing depressive and manic episodes. Primary components in this account are an inhibitory cholinergic system and activatory monoaminergic network. Depressive phases are marked by “cholinergic overdrive” and mania by a hypocholinergic-hypermonoaminergic state. However, cholinergic systems are unusually perturbable in every phase in bipolar subjects. During depressed phases, there is a drive toward compensatory down-regulation and subsensitivity of cholinergic and up-regulation and supersensitivity of monoaminergic systems. The reverse characterizes the switch from mania to depression. This model emphasizes dysfunction of homeostatic mechanisms and imbalance between the cholinergic and monoaminergic systems as pathogenic forces. Stressors further activating overly driven cholinergic systems can incline the organism to development of mania due to dysfunction of these homeostatic mechanisms. That is, the more effective cholinergic systems are in provoking compensatory or restorative responses in cholinergic systems (down-regulation and subsensitivity) the greater the probability of a “paradoxical” mania occurring. Aberrant cholinergic mechanisms, affective disorders and panic disorder may be related. Nearly 50 years ago, Lindemann & Finesinger (14) reported that norepinephrine and methacholine produced panic attacks. Thus, both cholinergic and aminergic drugs have been shown to produce panic. These observations are consis-