Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support.
Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.
Serotonin, norepinephrine, and dopamine, the chemical neurotransmitters with which most nurses are familiar, are relevant for understanding the mechanism of action of many psychotropic drugs, especially those used in the treatment of mood disorders. Acetylcholine (ACh) is a neurotransmitter that is important for communication between neurons and muscle (at the neuromuscular junction). It is involved in direct neurotransmission in the autonomic parasympathetic nervous system and has been implicated in cognitive processing, arousal, and attention in the brain (Picciotto, Alreja, & Jentsch, 2002). Cholinergic transmission can occur through muscarinic or nicotinic ACh receptors. The effects of ACh on cholinergic transmission are terminated by the action of cholinesterases (enzymes that degrade or break down ACh). Acetylcholinesterase inhibitors are drugs that block the effects of this enzyme, and they are used clinically to boost cholinergic function (i.e., for the treatment of Alzheimer’s disease). Seventeen different nicotinic ACh receptor subtypes and five different muscarinic ACh receptor subtypes are known to be expressed in the brain.
Cholinergic-Adrenergic Hypothesis of Mood Disorders
In 1972, Janowsky, el-Yousef, Davis, and Sekerke hypothesized that the cholinergic system plays a central role in the pathogenesis of mood disorders. This hypothesis stated that a given affective state (e.g., depression, mania) might represent a balance between central cholinergic and adrenergic neurotransmitter activity in those areas of the brain regulating moods. According to this hypothesis, depression would be the clinical manifestation of a state of cholinergic dominance, whereas mania would be the manifestation of a state of adrenergic dominance.
There is some support for this hypothesis from animal studies that demonstrate reciprocal and opposing cholinergic and adrenergic central nervous system behavioral effects. For example, reserpine, a drug causing depression, depletes the adrenergic neurotransmitters dopamine and norepinephrine but also has central cholinomimetic (cholinergic stimulating) properties. Tricyclic antidepressant drugs, which treat depression, boost the effects of serotonin, norepinephrine, and dopamine but also have central anticholinergic properties (Goldman & Erickson, 1983). In human beings, euphoria has been associated with the short-term administration of anticholinergic drugs.
Increasing cholinergic activity using physostigmine (an anticholinesterase inhibitor) may exacerbate depressive symptoms in currently depressed patients with major depression and may induce depressive symptoms in currently manic patients with bipolar disorder (Davis, Berger, Hollister, & Defraites, 1978; Janowsky, el-Yousef, Davis, Hubbard, & Sekerke, 1972). The cholinergic system is implicated in depression by evidence showing that sleep electroencephalography (EEG) responses to muscarinic receptor agonist drugs, as well as neuroendocrine and pupillary responses to cholinomimetic drugs, are exaggerated in depressed patients. Some muscarinic receptor gene polymorphisms are associated with an elevated incidence of depression. Altered muscarinic receptor transduction activity has also been found in manic patients (Richelson, 1995).
Antidepressant Efficacy Studies of Anticholinergic Drugs
In an open-label study, the anticholinergic drug biperiden (Akineton®), was administered to 10 severely depressed inpatients for 30 days (Kasper, Moises, & Beckmann, 1981). A significant improvement was demonstrated on a global depression measure, but biperiden treatment had to be discontinued after 3 weeks in 2 patients (paranoia in one case and inner restlessness in the other). Biperiden is still used today to treat extrapyramidal side effects of antipsychotic drugs.
In an acute double-blind study, infusions of biperiden or placebo were compared in 6 depressed women (Beckmann & Moises, 1982). There was an acute antidepressant effect during infusion of the active drug compared with placebo as assessed on some, but not all, of the global measures of depression.
The effects of biperiden and placebo were also compared in a randomized, double-blind, 6-week study (Gillin et al., 1995). All patients received placebo for the first week and then received either biperiden or glycopyrrolate (Robinul®), a peripherally acting anticholinergic drug, for 4 weeks. All patients received placebo during week 6. Both groups significantly improved; biperiden was not significantly better than glycopyrrolate.
The anticholinergic drug scopolamine hydrobromide (Scopace®) is a known depressant of the central nervous system and exhibits marked sedative and tranquilizing properties (Goldner, 1967). It exerts its effect most potently by blocking the action of ACh on M3 muscarinic receptors, and it has minimal activity on nicotinic receptors.
In a complex, crossover, multidrug, multidosage, double-blind study, 9 elderly depressed patients were administered three different dosages of scopolamine hydrobromide, lorazepam (Ativan®), and placebo (Newhouse et al., 1988). Significant cognitive and behavioral effects of scopolamine were observed only at the highest dosage. Both of the lower dosages of scopolamine and lorazepam showed no significant differences from placebo. Significant adverse cognitive deficits were caused by scopolamine. Behavioral effects of scopolamine consisted of activation, restlessness, and anxiety, but there was no significant effect on depressed mood.
In another study investigating the effect of scopolamine on mood and sleep, the drug was administered at bedtime for 3 consecutive nights to 10 depressed patients (8 with a history of alcohol abuse) and 10 normal comparison participants (Gillin et al., 1991). The depressed patients had a small, statistically significant antidepressant response on the second morning of treatment. Compared with the control group, depressed patients showed greater changes in various sleep EEG parameters on the first night of treatment.
In the most recent investigation of the potential antidepressant effects of scopolamine, Furey and Drevets (2006) reported on the results of two studies: an initial double-blind, placebo-controlled, dosage-finding study followed by a double-blind, placebo-controlled, crossover clinical trial. Eighteen currently depressed outpatients with recurrent major depressive disorder or bipolar disorder completed the trial. Multiple treatment sessions 3 to 5 days apart consisted of intravenous infusions of placebo or scopolamine hydrobromide. Individuals were randomized to a placebo/scopolamine or scopolamine/placebo sequence (a series of three placebo sessions and a series of three scopolamine sessions).
The placebo/scopolamine participants showed no significant change during placebo infusion compared with their baseline. Significant reductions in depression and anxiety ratings were observed after the administration of scopolamine compared with their baseline and with placebo. These scopolamine effects persisted when participants switched to the placebo sessions. Improvement was significant at the first evaluation after scopolamine administration, but patients continued to improve across the three active drug infusions, suggesting that repeated administrations provided more benefit than a single administration. The persistence of scopolamine’s antidepressant effect suggests a mechanism beyond the direct pharmacological actions on muscarinic receptors. Patients acutely experienced elevations in confusion during scopolamine administration, but it was otherwise well tolerated.
Sedation and tranquilization are prominent with other uses of scopolamine. Scopolamine transdermal patches are used for treating motion sickness, and the drug is still available for use in anesthesia.
Results from studies of several different anticholinergic drugs have not shown consistent antidepressant effects. The dosage dependency of scopolamine’s antidepressant effect across different studies and the lack of antidepressant effects with other anticholinergic drugs suggest that a specific muscarinic receptor subtype might be most relevant to the potential antidepressant mechanism of action of anticholinergic drugs. Biperiden and glycopyrrolate (the peripheral antimuscarinic agent) did not have significant antidepressant effects. Biperiden is relatively selective for M1-type muscarinic ACh receptors, whereas scopolamine is nearly 10 times more potent than biperiden at M3 receptors. In addition, similar to other antidepressant therapies (including many antidepressant drugs and electroconvulsive therapy), scopolamine also modulates the functional activity of glutamate receptors.
Compared with muscarinic anticholinergic drugs, the potential antidepressant effects of nicotinic anticholinergic drugs have not been as well studied. However, there is developing evidence from preclinical studies that mecamylamine (Inversine®), a nicotinic receptor anticholinergic drug, has positive effects in several kinds of animal models of depression and anxiety (Lippiello et al., 2008). Nurses should be familiar with the cholinergic-adrenergic hypothesis of mood disorders, as well as the potential use of novel anticholinergic drug therapies for the treatment of depression.
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