The Cholinergic Hypothesis of Affective Disorders.
A MEDLINE Search by, Ivan Goldberg, MD
Prog Neuropsychopharmacol Biol Psychiatry 1983;7(2-3):297-307
Adrenergic-cholinergic balance and the treatment of affective disorders.
Janowsky DS, Risch SC, Gillin JC
Centrally acting cholinomimetic drugs cause anergia, behavioral inhibition and
depression. Centrally acting cholinomimetic drugs have antimanic properties.
Combinations of acetylcholine precursors and centrally active cholinomimetic
agents may cause augmented muscarinic effects, as may a combination of an
antiadrenergic and cholinomimetic drugs. Centrally active anticholinergic
agents may exert antidepressant effects. Affective disorder patients may show
hyperreactivity to cholinomimetic agents, a phenomena which may have diagnostic
significance.
J Neural Transm 1987;70(3-4):295-312
Acetylcholine and affective disorder.
Leong SS, Brown WA
Department of Psychiatry, Providence Veterans Administration Medical Center,
Rhode Island.
We reviewed the evidence for involvement of central cholinergic neurons in
affective disorder. Cholinomimetics inhibit speech, thought, and activity in
most subjects, decrease manic symptoms and, in some affective disorder
patients, produce depressive symptoms. Cholinomimetics also cause ACTH and
cortisol secretion and decrease latency to REM sleep. It is unclear whether
cholinomimetics are specifically "antimanic" or "depressogenic" or whether
their fundamental effect is nonspecific behavioral inhibition; whether the
observed effects of cholinomimetics are mediated largely through cholinergic
pathways, are secondary to changes in other neurotransmitters or are part of a
nonspecific stress response. The suggestion that anticholinergic agents have
mood elevating properties has not yet been subjected to controlled
investigation. Although the proposal that affective disorders involve
cholinergic neurons has received some support from clinical investigation
further research is required to substantiate the intriguing observations to
date and to clarify the physiologic and psychologic processes mediating them.
Fortschr Neurol Psychiatr 1988 Jan;56(1):8-21
[The cholinergic-adrenergic equilibrium hypothesis of affective psychoses].
[Article in German]
Fritze J, Beckmann H
Psychiatrische Klinik und Poliklinik, Universitat Wurzburg.
The biochemical effects of antidepressant drugs generated the hypothesis of
disturbances in the noradrenergic system in the pathogenesis of affective
disorders. However, interference with the cholinergic system also yields
psychotropic sequelae. Central cholinomimetics revealed antimanic properties as
opposed to antidepressant effects of anticholinergics. Therefore, in extension
of the catecholamine hypothesis and again based on the paradigm of
pharmacological isomorphism, a cholinergic-adrenergic balance hypothesis has
been suggested for affective disorders. This postulates a cholinergic
predominance relative to noradrenergic activity in depression and the converse
in mania. Although there are indications of inverse behavioral effects of
cholinergic as opposed to catecholaminergic stimulation in man and animal,
there is only few evidence at the neurophysiological and biochemical level in
favor of the net effects depending on such a balance. However, only the direct
demonstration of a biochemical defect can prove the balance hypothesis. More
probably, interindividually different defects must be expected. They need not
necessarily involve the synaptic signal transduction directly. Strategies and
findings which might demonstrate biochemical disturbances are presented and
discussed.
Acta Psychiatr Scand Suppl 1991;366:52-60
Cholinergic drugs as diagnostic and therapeutic tools in affective disorders.
Berger M, Riemann D, Krieg C
Central Institute of Mental Health, Mannheim, Federal Republic of Germany.
The hypothesis of a significant involvement of the cholinergic system in the
pathogenesis of affective disorders still lacks strong experimental support.
This is mainly because of missing specific peripheral markers of the central
nervous activity of the cholinergic system and the lack of specific cholinergic
agonists and antagonists without severe peripheral side effects. As the direct
cholinergic agonist RS 86 seems to be more suitable because of its minor side
effects, long half-life and oral applicability, it was tested for its antimanic
property and its effect on the hypothalamo-pituitary adrenal system and the
rapid eye movement (REM) sleep-generating system. RS 86 exhibited antimanic and
REM sleep-inducing properties, but failed to stimulate the cortisol system.
Acta Psychiatr Scand Suppl 1991;366:66-69
Cholinergic drugs, affective disorders and dementia: problems of clinical research.
Spiegel R
Clinical Research, Sandoz Pharma Ltd., Basel, Switzerland.
Rev Neurosci 1993 Jan;4(1):63-93
The adrenergic-cholinergic imbalance hypothesis of depression: a review and a perspective.
Fritze J
Department of Psychiatry, University of Wurzburg, Germany.
The catecholamine deficiency hypothesis of depression was essentially based on
the incidental detection of iproniazide and imipramine. However, current
findings favor noradrenergic overactivity, at least in the periphery. The
incidental observation of acute behavioral inhibition by centrally active
cholinomimetics like physostigmine suggested a cholinergic-adrenergic balance
involved in the regulation of drive and mood. Indeed, cholinomimetics seem to
have acute depressiogenic and antimanic properties and, conversely,
anticholinergics some acute euphoriant activity. However, time course and
dose-response relationships of drugs influencing mood and drive do not favor
simple concepts of too much or too little activity of one or the other
transmitter system. Cholinomimetics and psychostimulants show an acute mutual
antagonism, the mechanism of which is obscure. In healthy volunteers clonidine
and the putative antidepressant brofaromine did not influence the effects of
physostigmine. Patients with mood disorders respond supersensitively to a
cholinergic challenge in terms of behavior, neuroendocrine regulation and REM
sleep induction. Thus, the anticholinergic properties of tricyclics might be
relevant to their antidepressant activity. However, adjunctive treatment with
the cholinolytic biperiden as compared to placebo did not enhance the
antidepressant efficacy of mianserin or viloxazine. This is incompatible with
cholinergic overactivity contributing to the depressive state. Physostigmine
induces autonomous and endocrine responses reminiscent of stress reactions.
Findings in healthy volunteers suggest relationships between the sensitivity to
physostigmine and personality traits like irritability and emotional lability
and passive stress coping strategies. Thus, the cholinergic supersensitivity in
mood disorders might be related to some personality dimension like stress
intolerance rather than the depressive state itself.
Psychiatry Res 1981 Aug;5(1):108-109
Central cholinergic-adrenergic imbalance in the regulation of affective state.
Siever LJ, Risch SC, Murphy DL
J Clin Psychopharmacol 1981 Jul;1(4):186-192
Cholinergic challenges in affective illness: behavioral and neuroendocrine correlates.
Risch SC, Kalin NH, Janowsky DS
The cholinergic-adrenergic balance hypothesis of affective disorders suggests
that, in the areas of the brain that regulate mood, depression may represent a
relative predominance of central cholinergic tone over adrenergic tone and that
mania may represent the converse. Currently, converging lines of investigation
from a number of independent groups suggest that affective disorder patients
may have a central cholinergic receptor hypersensitivity that induces a
vulnerability to affective and neuroendocrine disturbances. This article
reviews the evidence for cholinergic mechanisms in the regulation of affective
state and describes current research strategies using centrally active
cholinomimetic agents to explore disturbances in affective disorder subjects.
AANA J 1976 Jun;44(3):272-280
Current concepts on the pharmacodynamics of adrenergic and cholinergic receptors.
Drain CB
Lancet 1976 Dec 18;2(7999):1342-1343
Adrenergic-cholinergic imbalance in affective disorders [editorial].
Psychiatry Res 1990 Dec;34(3):271-279
Cholinergic-adrenergic balance: Part 2. Relationship between drug sensitivity and personality.
Fritze J, Sofic E, Muller T, Pfuller H, Lanczik M, Riederer P
Department of Psychiatry, School of Medicine, University of Wurzburg, Germany.
Sensitivity to the centrally active cholinomimetic physostigmine varies
dramatically among healthy individuals. The elucidation of the reasons for this
variability could contribute to the understanding of the pathophysiology of
affective disorders where a cholinergic supersensitivity has been demonstrated.
Therefore, personality characteristics and habitual stress-coping strategies
were related to sensitivity to physostigmine in eight healthy male volunteers.
Cardiovascular and behavioral responses tended to be positively correlated with
irritability and emotional liability. Passive, "helpless" strategies for coping
with stress were positively related to these responses. The metabolic and
neuroendocrine responses to physostigmine were generally unrelated to
personality. In view of putative beta-adrenergic disturbances in depression,
the responses to the peripheral beta 2-adrenergic agonist reproterol were
studied. Irritability and emotionality tended to be positively correlated with
cardiovascular responses to reproterol as well as with reductions of heart rate
by the peripheral cholinomimetic neostigmine.
Psychopharmacol Bull 1978 Oct;14(4):58-60
Adrenergic-cholinergic balance in affective disorders.
Janowsky DS, Davis JM
Pharmacopsychiatria 1981 Mar;14(2):71-73
Clinical notes on the possible anticholinergic reversal of depressive syndromes.
Ungvari G, Karczag I, Gerevich J, Petho B
The authors report on the effects of acute confusional states and deliria
(pharmacogenic confusional syndromes - PCS), occurring under the influence of
psychotropic drugs on the depressive syndrome of three patients. The favorable
influence of PCS on the depressive syndrome is considered to be largely linked
to the anticholinergic effect of the drugs. The observations made in these
three patients may give support to the hypothesis that cholinergic activity has
pathogenic significance in depressive syndromes.
J Clin Psychopharmacol 1986 Apr;6(2):65-74
Pharmacologic induction of cholinergic system up-regulation and
supersensitivity in affective disorders research.
Dilsaver SC
Phenomenological, physiological, biochemical, and receptor binding measures are
useful as dependent variables in affective disorders research. Abnormalities of
these measures can result from up-regulation and supersensitivity of
cholinergic systems and disturbances of cholinergic-monoaminergic interaction.
These deviations are safely and inexpensively produced by pharmacologic
induction of up-regulation and supersensitivity of central muscarinic
cholinergic systems. Techniques for inducing these changes in cholinergic
systems are reviewed, and principles governing their application to specific
problems are illustrated.
Am J Med Genet 1994 Dec 15;54(4):335-344
Is cholinergic sensitivity a genetic marker for the affective disorders?
Janowsky DS, Overstreet DH, Nurnberger JI Jr
Center for Alcohol Studies, University of North Carolina School of Medicine,
Chapel Hill 27599-7160, USA.
The recent literature on the involvement of cholinergic muscarinic mechanisms
and adrenergic/cholinergic balance in affective disorders is reviewed and
integrated with the older literature. There is strong evidence supporting the
presence of exaggerated responses (behavioral, neuroendocrine, sleep) to
cholinergic agents in affective disorder patients relative to normal controls
and certain other psychiatric patients. There is also some, albeit less,
conclusive evidence that these exaggerated responses may occur in euthymic
individuals with a history of affective disorders, or in children at risk for
development of affective disorders. Despite these promising results, suggesting
a role for acetylcholine in the genetics of the affective disorders, further
work in biochemistry and genetics is needed to link specific muscarinic
receptors or other cholinergic variables to affective illness.
Hillside J Clin Psychiatry 1988;10(1):38-54
Pharmacological perturbation of cholinergic systems: applications to the study
of pathophysiological mechanisms in affective disorders.
Dilsaver SC
Neuroscience Program, Ohio State University, Columbus, Ohio
Clinical, behavioral, physiological, biochemical and receptor binding
parameters are useful as dependent measures in studies into the pathophysiology
of affective disorders. Pharmacological perturbation of cholinergic mechanisms
and modification of cholinergic-monoaminergic interaction mimics aspects of the
neurobiology of affective disorders. The effects of these pharmacological
manipulations can be quantitatively assessed by measuring their impact on
variables in each of these classes. These deviations are easily and safely
produced by several classes of drugs which directly or indirectly modify the
function of central muscarinic cholinergic networks. Methods for inducing these
changes in cholinergic systems and their application to clinical and basic
research in the field of affective disorders are highlighted.
N Engl J Med 1984 Jul 26;311(4):254-255
Cholinergic mechanisms in affective disorders.
Snyder SH
Encephale 1985 Nov;11(6):229-234
[Cholinergic hypothesis of depression].
[Article in French]
Leboyer M, Plaisant O
Is acetylcholine implicated in depressive disorders? Biochemical methods
studying the cholinergic system are not well set up. Only indirect elements
could confirm the cholinergic hypothesis of affective disorders. Cholinergic
agonists induce depressive symptomatology. Moreover, a central, cholinergic
dysfunction could be an explanation of sleep disturbances and of neuroendocrine
abnormalities seen in affective disorders. These observations could be applied
in two ways: a more precise choice of antidepressive drugs, and the use of new
tests developed to detect population with high depression risk.
Acta Psychiatr Scand 1986 Oct;74(4):312-334
Cholinergic mechanisms in affective disorders. Future directions for investigation.
Dilsaver SC
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: roles of cholinergic mechanisms in mediating effects of stress
and cholinergic mechanisms linking the pathophysiologies of affective and panic
disorders, use of pharmacologic agents to produce cholinergic system
supersensitivity in modeling biologic aspects of affective illness, use of
multigenerational intrapedigree studies of cholinergic markers associated with
affective disease, research into the neurobiology of lithium and ECT as they
pertain to muscarinic cholinergic mechanisms, study of the interrelationship of
sodium, calcium and lithium ion metabolism and their relationship to
cholinergic-monoaminergic interaction, 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, identification and validation of a peripheral model of the central
muscarinic receptor, 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 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.
Biol Psychiatry 1991 Jan 15;29(2):127-138
The cholinergic-adrenergic hypothesis of depression reexamined using clonidine, metoprolol, and physostigmine in an animal model.
Hasey G, Hanin I
Department of Psychiatry, Faculty of Medicine, University of Toronto, Ontario, Canada.
The role of central nervous system (CNS) cholinergic and noradrenergic
mechanisms in the pathogenesis of depression and hypothalamic-pituitary-adrenal
(HPA) axis hyperactivity is examined using the Behavioral Despair rat model of
depression. Immobility (IM), the analog of depression in this model, and plasma
corticosterone (C) were increased by physostigmine (PHYSO). Neostigmine (NEO),
which does not cross the blood-brain barrier, produced the same peripheral
cholinomimetic effects and motor inhibition as PHYSO, but did not change IM.
PHYSO's effects on C and IM were blocked by metoprolol pretreatment and
partially blocked by clonidine pretreatment. PHYSO increased acetylcholine in
the striatum. In this animal model of depression, cholinergic and noradrenergic
mechanisms are interactively involved in the regulation of behavioral
depression and the HPA axis.
J Psychiatry Neurosci 1995 Jan;20(1):39-48
Cholinergic neurotransmission seems not to be involved in depression but possibly in personality.
Fritze J, Lanczik M, Sofic E, Struck M, Riederer P
Department of Psychiatry, University of Wurzburg, Germany.
Concordant with the adrenergic-cholinergic imbalance hypothesis of affective
psychosis, there is a cholinergic supersensitivity in depression. Thus, the
anticholinergic properties of some antidepressants might contribute to their
efficacy. However, in the present double-blind studies (n = 20) with mianserin
and viloxazine, respectively, which lack anticholinergic properties, adjunctive
treatment with the anticholinergic biperiden versus placebo did not enhance the
antidepressive efficacy. Therefore, we hypothesized that cholinergic
supersensitivity might be linked to some possibly predisposing dimension of
personality. Indeed, in healthy male volunteers (n = 11) the behavioral and
cardiovascular sensitivity to physostigmine correlated significantly with
"irritability" and "emotional lability" as well as with habitually passive
strategies in stress coping. The rise in plasma cortisol and norepinephrine
correlated with "retardation"; that of epinephrine with active coping. Thus,
the cholinergic supersensitivity in affective psychoses might be linked to a
personality dimension like stress sensitivity rather than to the diagnostic
category itself.
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