Cholinergic REM induction test: Muscarinic supersensitivity underlies polysomnographic findings in both depression and Schizophrenia

Riemann, Dieter; Hohagen, Fritz; Krieger, Stefan H.; Gann, Horst; Müller, Wernér E.G.; Olbrich, Robert; Wark, Hans-Jörg; Bohus, Martin; Löw, H.; Berger, Thomas

doi:10.1016/0022-3956(94)90006-x

Cited by 68 publications

(31 citation statements)

References 45 publications

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“…For example, in addition to the recent demonstration that this antimuscarinic agent has rapid antidepressant effects, several types of evidence suggest that muscarinic cholinergic receptor sensitivity is increased in the depressed phases of MDD and BD (Janowsky and Overstreet, 1990;Janowsky et al, 1994;Riemann et al, 1994b). Compatible with the findings of the current study, functional sex differences have been reported in baseline and cholinergically stimulated plasma hormone measures between major depressives and matched controls that suggest that heightened cholinergic sensitivity exists in premenopausal female, but not in male, patients with MDD (Riemann et al, 1994a;Rubin et al, 1999Rubin et al, , 2003.…”

Section: Discussionmentioning

confidence: 99%

Scopolamine Produces Larger Antidepressant and Antianxiety Effects in Women Than in Men

Furey

Khanna

Hoffman

et al. 2010

Neuropsychopharmacol

102

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Some antidepressant agents generate differential benefit based on gender. Blocking cholinergic muscarinic receptors using scopolamine produces robust and rapid antidepressant effects in males and females combined. This study evaluated if males and females differ in the antidepressant response magnitude following scopolamine administration. A total of 52 male and female outpatients meeting criteria for recurrent major depressive or bipolar disorder participated in a double-blind, randomized, placebo-controlled, crossover clinical trial involving seven i.v. infusions of placebo or scopolamine (4 mg/kg). Following a single-blind placebo lead-in, participants entered either a placebo-block/scopolamine-block or a scopolamine-block/placebo-block sequence. Each block included three sessions. Clinical ratings were acquired before each infusion and included the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A). A treatment group Â block interaction (F ¼ 21.0, po0.001) was observed in MADRS scores across gender, and the reduction was significant by the evaluation following the first scopolamine administration (F ¼ 8.4, p ¼ 0.006). The treatment group Â block interaction was also significant in males (F ¼ 3.8, p ¼ 0.043) and females (F ¼ 35.6, po0.001) separately. A block Â gender interaction (F ¼ 7.4, p ¼ 0.009) indicated that the response magnitude was larger in women. The treatment Â block interaction was significant for the HAM-A across gender (F ¼ 12.0, po0.001), and was significant for females (F ¼ 24.9, po0.001) but not for males (F ¼ 1.3, p ¼ 0.30). When comparing the baseline block to study end, the block Â gender interaction (F ¼ 12.6, p ¼ 0.001) showed that the antianxiety response was greater in women. Men and women show a rapid antidepressant response following scopolamine, but the magnitude of response is larger in women than in men.

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Section: Discussionmentioning

confidence: 99%

Scopolamine Produces Larger Antidepressant and Antianxiety Effects in Women Than in Men

Furey

Khanna

Hoffman

et al. 2010

Neuropsychopharmacol

102

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“…Specifically, inspection time, a measure of speed of information processing that does not require a speeded motor response, has been found to be slower in subjects with unipolar major depression than in age-, sex-, and IQ-matched controls independent of current mood (Tsourtos et al, 2002). The cholinergic basis of inspection time (Nathan and Stough, 2001) paralleling the hypothesis of a cholinergic dysfunction in major depression (Riemann et al, 1994) lends biological plausibility to this putative endophenotype. Twin studies demonstrated heritability for inspection time, sharing a substantial genetic relationship with performance IQ (Luciano et al, 2003).…”

Section: Impaired Executive Cognitive Function (Response Speed)mentioning

confidence: 91%

Discovering Endophenotypes for Major Depression

Hasler

Drevets

Manji

et al. 2004

Neuropsychopharmacol

1,020

739

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The limited success of genetic studies of major depression has raised questions concerning the definition of genetically relevant phenotypes. This paper presents strategies to improve the phenotypic definition of major depression by proposing endophenotypes at two levels: First, dissecting the depressive phenotype into key components results in narrow definitions of putative psychopathological endophenotypes: mood bias toward negative emotions, impaired reward function, impaired learning and memory, neurovegetative signs, impaired diurnal variation, impaired executive cognitive function, psychomotor change, and increased stress sensitivity. A review of the recent literature on neurobiological and genetic findings associated with these components is given. Second, the most consistent heritable biological markers of major depression are proposed as biological endophenotypes for genetic studies: REM sleep abnormalities, functional and structural brain abnormalities, dysfunctions in serotonergic, catecholaminergic, hypothalamic-pituitary-adrenocortical axis, and CRH systems, and intracellular signal transduction endophenotypes. The associations among the psychopathological and biological endophenotypes are discussed with respect to specificity, temporal stability, heritability, familiality, and clinical and biological plausibility. Finally, the case is made for the development of a new classification system in order to reduce the heterogeneity of depression representing a major impediment to elucidating the genetic and neurobiological basis of this common, severe, and often life-threatening illness.

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“…Increasing cholinergic activity using physostigmine (an anticholinesterase inhibitor) provides a challenge uniquely capable of exacerbating depressive symptoms in currently depressed patients with MDD and inducing depressive symptoms in currently manic patients with BD. [4][5][6][7][8][9] The cholinergic system also is implicated in depression by evidence showing that polysomnographic responses to muscarinic receptor agonists [10][11][12] and neuroendocrine and pupillary responses to cholinomimetics [13][14][15][16] are exaggerated in depressed patients and that some muscarinic receptor gene polymorphisms are associated with an elevated incidence of depression. 17,18 Elevated cholinergic function thus was hypothesized to participate in the pathogenesis of mood disorders.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Antidepressant Efficacy of the Antimuscarinic Drug Scopolamine

Furey¹,

Drevets²

2006

Arch Gen Psychiatry

370

292

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Context-The need for improved therapeutic agents that more quickly and effectively treat depression is critical. In a pilot study we evaluated the role of the cholinergic system in cognitive symptoms of depression and unexpectedly observed rapid reductions in depression severity following the administration of the antimuscarinic drug scopolamine hydrobromide (4 μg/kg intravenously) compared with placebo (P=.002). Subsequently a clinical trial was designed to assess more specifically the antidepressant efficacy of scopolamine.Objective-To evaluate scopolamine as a potential antidepressant agent.Design-Two studies were conducted: a double-blind, placebo-controlled, dose-finding study followed by a double-blind, placebo-controlled, crossover clinical trial. Setting-The National Institute of Mental Health.Patients-Currently depressed outpatients aged 18 to 50 years meeting DSM-IV criteria for recurrent major depressive disorder or bipolar disorder. Of 39 eligible patients, 19 were randomized and 18 completed the trial.Interventions-Multiple sessions including intravenous infusions of placebo or scopolamine hydrobromide (4 μg/kg). Individuals were randomized to a placebo/ scopolamine or scopolamine/ placebo sequence (series of 3 placebo sessions and series of 3 scopolamine sessions). Sessions occurred 3 to 5 days apart.Main Outcome Measures-Psychiatric evaluations using the Montgomery-Asberg Depression Rating Scale and the Hamilton Anxiety Rating Scale were performed to assess antidepressant and antianxiety responses to scopolamine.Results-The placebo/scopolamine group showed no significant change during placebo infusion vs baseline; reductions in depression and anxiety rating scale scores (P<.001 for both) were observed after the administration of scopolamine compared with placebo. The scopolamine/ placebo group also showed reductions in depression and anxiety rating scale scores (P<.001 for both) after the administration of scopolamine, relative to baseline, and these effects persisted as they received placebo. In both groups, improvement was significant at the first evaluation after scopolamine administration (P≤.002).Conclusion-Rapid, robust antidepressant responses to the antimuscarinic scopolamine occurred in currently depressed patients who predominantly had poor prognoses.Correspondence: Maura L. Furey, PhD, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, 15K North Dr, Bldg 15K, Room 115B, Bethesda, MD 20892 (mfurey@mail.nih.gov). Additional Information: A use-patent application for the use of scopolamine as an antidepressant agent has been filed. NIH Public Access Author ManuscriptArch Gen Psychiatry. Author manuscript; available in PMC 2012 January 3. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMajor depression is the leading cause of years lived with disability. 1 A range of antidepressant agents is available, but 30% to 40% of patients with major depressive disorder (MDD) do not respond to initial treatment, 2 an...

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Cholinergic REM induction test: Muscarinic supersensitivity underlies polysomnographic findings in both depression and Schizophrenia

Cited by 68 publications

References 45 publications

Scopolamine Produces Larger Antidepressant and Antianxiety Effects in Women Than in Men

Scopolamine Produces Larger Antidepressant and Antianxiety Effects in Women Than in Men

Discovering Endophenotypes for Major Depression

Antidepressant Efficacy of the Antimuscarinic Drug Scopolamine

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