The effects of acute scopolamine in geriatric depression. Scopolamine alone or combined with ephedrine in seasickness: a double-blind, placebo-controlled study. Scopolamine Produces Larger Antidepressant and Antianxiety Effects in Women Than in Men Drug treatment of motion sickness: scopolamine alone and combined with ephedrine in real and simulated situations. Sleep electroencephalographic abnormalities in adolescent depressives: Effects of scopolamine Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, placebo-controlled clinical trial. Modulation by muscarinic antagonists of the response to carbon dioxide challenge in panic disorder. Estrogen Treatment Effects on Anticholinergic-Induced Cognitive Dysfunction in Normal Postmenopausal Women The role of cholinergic systems in visuospatial processing and memory. Hypothalamo–pituitary–adrenal cortical responses to low-dose physostigmine and arginine vasopressin administration: sex differences between major depressives and matched control subjects Modulation of Mood and Cognitive Performance Following Acute Administration of Single Doses of Melissa Officinalis (Lemon Balm) with Human CNS Nicotinic and Muscarinic Receptor-Binding Properties A randomised placebo controlled study to assess the effects of cholinergic treatment on muscarinic receptors in Alzheimer’s disease A strategy of "combination chemotherapy" in Alzheimer's disease: rationale and preliminary results with physostigmine plus deprenyl. Comparative Efficacy of Yohimbine Against Pyridostigmine for the Treatment of Orthostatic Hypotension in Autonomic Failure Estradiol interacts with the cholinergic system to affect verbal memory in postmenopausal women: Evidence for the critical period hypothesis Postoperative nausea and vomiting: a comparison of anti-emetic drugs used alone or in combination. Glycopyrrolate abolishes the exercise-induced increase in cerebral perfusion in humans. Estrogen Therapy and brain muscarinic receptor density in healthy females: A SPET study Bilateral skin conductance and the pupillary light-dark reflex: Manipulation by chlorpromazine, haloperidol, scopolamine, and placebo Effects of scopolamine on autonomic profiles underlying motion sickness susceptibility. (S)-(+)-mecamylamine (TC-5214): a neuronal nicotinic receptor modulator enters phase III trials as an adjunct treatment for Major Depressive Disorder (MDD). Replication of Scopolamine's Antidepressant Efficacy in Major Depressive Disorder: A Randomized, Placebo-Controlled Clinical Trial Controlled trials of inositol in psychiatry
In an intensive multidrug , multidose study , nine elderly depressed patients were administered 0.1 , 0.25 , and 0.5 mg of scopolamine hydrobromide , 1 mg of oral lorazepam , and placebo in a double-blind investigation aim ed at assessing the status of the central cholinergic nervous system in geriatric depression . Significant cognitive and behavioral effects of scopolamine were observed only at the high dose ( 0.5 mg ) , while lower doses and lorazepam showed no significant differences from placebo .  Cognitive deficits caused by scopolamine were in the areas of new learning , access to semantic memory , vigilance , and continuous performance . Behavioral effects consisted of activation , restlessness , and anxiety , but there was no significant effect on depressed mood . These results suggest that elderly depressed patients with mild to moderate cognitive impairment seem to be more similar to previously studied elderly controls rather than to patients with Alzheimer 's disease in their reaction to short-term cholinergic blockade , and suggest that the cognitive and mood changes often seen in geriatric depression may involve factors other than disturbed muscarinic cholinergic mechanisms In seasickness , the central cholinergic-noradrenergic balance is disturbed . Capsules of identical appearance -- containing scopolamine hydrobromide 0.3 mg , scopolamine hydrobromide 0.3 mg + ephedrine hydrochloride 25 mg , or placebo -- were given prophylactically three times daily to 30 naval cadets during a crossing . In this r and omized , double-blind trial the superiority of scopolamine and scopolamine + ephedrine over placebo was confirmed . Ephedrine did not clearly increase the effectiveness of scopolamine .  One subject in the scopolamine group and one in the placebo group interrupted the treatment . The symptoms of seasickness as well as the number of side-effects of the drugs decreased on the third day of the study . Scopolamine alone or in combination with ephedrine proved useful in the prevention of seasickness in young healthy male volunteers 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 out patients meeting criteria for recurrent major depressive or bipolar disorder participated in a double-blind , r and omized , placebo-controlled , crossover clinical trial involving seven i.v . infusions of placebo or scopolamine ( 4 μg/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 × block interaction ( F=21.0 , p<0.001 ) was observed in MADRS scores across gender , and the reduction was significant by the evaluation following the first scopolamine administration ( F=8.4 , p=0.006 ) . The treatment group × block interaction was also significant in males ( F=3.8 , p=0.043 ) and females ( F=35.6 , p<0.001 ) separately . A block × gender interaction ( F=7.4 , p=0.009 ) indicated that the response magnitude was larger in women . The treatment × block interaction was significant for the HAM-A across gender ( F=12.0 , p<0.001 ) , and was significant for females ( F=24.9 , p<0.001 ) but not for males ( F=1.3 , p=0.30 ) . When comparing the baseline block to study end , the block × gender interaction ( F=12.6 , p=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 In two placebo-controlled , double-blind , r and omized trials scopolamine ( 0.3 mg ) alone or combined with ephedrine ( 25 mg ) was tested for its effectiveness in the prevention of seasickness during 24 h at sea and of motion sickness in rotating chair tests in a laboratory . Scopolamine was effective both alone and in combination with ephedrine , which supports the hypothesis on central cholinergic overactivity in the pathogenesis of motion sickness . Ephedrine did not markedly increase the effectiveness of scopolamine . Side-effects were slight and did not disturb the operating ability of the volunteers In contrast to sleep studies of adult depressives that have consistently demonstrated abnormalities of sleep continuity , slow-wave sleep , and REM sleep , existing studies of depressed children and adolescents have been conflicting . Furthermore , only one study has explored the cholinergic regulation of sleep in early-onset depressives . In the present study , the electroencephalographic sleep of 20 adolescent out patients with major depressive episodes and 13 normal control adolescents was obtained on two separate 2-night sessions , 1 night incorporating challenge with scopolamine .  Depressed adolescents showed increased baseline phasic REM sleep measures , increased arousals , a trend toward reduced slow-wave sleep , and a greater difference in the change of first REM period density on the scopolamine night versus placebo night compared to controls . These findings support the continuity of some sleep abnormalities of depression into adolescence , and suggest that adolescent depression may be associated with alterations of cholinergic neurotransmission in some patients 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 microg/kg intravenously ) compared with placebo ( P = .002 ) . Subsequently a clinical trial was design ed 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 out patients aged 18 to 50 years meeting DSM-IV criteria for recurrent major depressive disorder or bipolar disorder . Of 39 eligible patients , 19 were r and omized and 18 completed the trial . INTERVENTIONS Multiple sessions including intravenous infusions of placebo or scopolamine hydrobromide ( 4 microg/kg ) . Individuals were r and omized 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 < or = .002 ) . CONCLUSION Rapid , robust antidepressant responses to the antimuscarinic scopolamine occurred in currently depressed patients who predominantly had poor prognoses BACKGROUND Panic attacks can be induced in persons with panic disorder by inhalation of carbon dioxide . Hypercapnia also elicits a reflex hyperventilation , which is controlled in part by cholinergic mechanisms . This study investigated whether the exaggerated response to carbon dioxide in panic disorder ( PD ) can be modulated by antagonists of muscarinic cholinergic receptors . METHODS Twelve patients with PD received biperiden hydrochloride ( a muscarinic antagonist that crosses the blood-brain barrier ) , pirenzepine hydrochloride ( a muscarinic antagonist that does not cross the blood-brain barrier ) , or placebo 2 hours before a 35 % carbon dioxide-65 % oxygen respiratory challenge ( vs air as a placebo ) on 3 separate days , in a double-blind , r and om crossover design . RESULTS According to patients ' self-ratings of subjective anxiety , inhalation of the carbon dioxide/oxygen mixture provoked a significant and intense response after treatment with pirenzepine and placebo . After biperiden treatment , however , hypercapnia elicited a response profile similar to that elicited by air , whereby subjective anxiety remained similar to preinhalation levels . CONCLUSIONS Consistent with the hypothesis of the study , a central ly active muscarinic antagonist can block the response to carbon dioxide commonly observed in subjects with PD Estrogen has been shown to interact with the cholinergic system and influence cognition in animal models . This study investigated the interaction of estrogen and cholinergic system functioning and the effects of this interaction on cognitive task performance in healthy older women . Fifteen post-menopausal women were r and omly and blindly placed on 1 mg of 17-β estradiol or placebo for 3 months after which they participated in five anticholinergic challenge sessions , where they were administered one of two doses of the antimuscarinic drug scopolamine ( SCOP ) or the antinicotinic drug mecamylamine ( MECA ) or placebo . After the first challenge phase , they were crossed over to the other hormone treatment for another 3 months and repeated the challenges . Performance in multiple domains of cognition was assessed during anticholinergic drug challenge , including attention and verbal and nonverbal learning and memory . Results showed that estrogen pretreatment attenuated the anticholinergic drug-induced impairments on tests of attention and tasks with speed components . This study is the first to demonstrate the interaction of estrogen and the cholinergic system and the effects on cognitive performance in humans . The results suggest that estrogen status may affect cholinergic system tone and may be important for cholinergic system integrity Few studies have specifically addressed the cholinergic role in visuospatial memory . In the present study , we employed a r and omized double-blind repeated measures design to investigate the effects of scopolamine on Judgement of Line Orientation ( JLO ) and two distinct visuospatial memory tasks . Complex Figures ( CF ) is a test of drawn reproduction similar to the Rey complex figure . The Spatial Array Memory Test ( SAMT ) is a two-dimensional free-recall visuospatial test which minimizes constructive skills and allows sensitive measurement of placement errors . Scopolamine impaired performance on JLO and CF . However , no effects of scopolamine on SAMT were apparent even though the SAMT is sensitive to aging and right temporal-lobe lesions . Selective effects of scopolamine on focused versus distributed attention may account for these differential results Of heuristic value in underst and ing the neurochemistry of major depression is whether the hypothalamo-pituitary-adrenocortical ( HPA ) axis hyperactivity that occurs in this illness can be related to putative neurotransmitter dysfunction(s ) . Cholinergic neurotransmission stimulates hypothalamic corticotropin releasing hormone ( CRH ) and arginine vasopressin ( AVP ) secretion , both of which stimulate pituitary corticotropin ( ACTH ) secretion , but whether the HPA axis in humans is activated only by doses of cholinergic agonists that produce noxious side effects remains controversial . To test the hypothesis of increased cholinergic sensitivity in major depression , physostigmine ( PHYSO ) , a reversible cholinesterase inhibitor , was administered to patients and control subjects at a dose that elevated plasma ACTH , cortisol , and AVP concentrations but produced few or no side effects . Exogenous AVP also was administered to determine if it would augment the effect of low-dose PHYSO on the HPA axis . Twelve premenopausal or estrogen-replaced female major depressives , 12 individually matched female control subjects , eight male major depressives , and eight matched male control subjects underwent four test sessions 5 - 7 days apart : PHYSO ( 8 microg/kg IV ) , AVP ( 0.08 U/kg IM ) , PHYSO + AVP , and saline control . Serial blood sample s were taken before and after pharmacologic challenge and analyzed for ACTH1 - 39 , cortisol , and AVP . Estradiol and testosterone were also measured at each test session . PHYSO ( 8 microg/kg ) significantly increased plasma ACTH , cortisol , and AVP , while producing no side effects in approximately half the subjects and predominantly mild side effects in the other half . These hormone increases following PHYSO occurred primarily in the female depressives and the male control subjects and were not significantly related to the presence or absence of side effects . The greater the ACTH and AVP responses to PHYSO , the stronger their correlation , suggesting that AVP may have been acting as a secretagogue for ACTH . Administered AVP significantly increased the secretion of ACTH in the patients and control subjects to a similar degree , and AVP given after PHYSO did not augment the HPA axis response to a greater degree in the depressives than in the control subjects . Plasma estradiol and testosterone were within the normal range for all four groups of subjects and were not significantly related to their HPA axis hormone responses . The study results support the hypothesis of heightened cholinergic sensitivity in premenopausal female , but not in male , patients with major depression . The low dose of PHYSO used may represent a useful paradigm for central cholinergic stimulation of the HPA axis Melissa officinalis ( Lemon balm ) is a herbal medicine that has traditionally been attributed with memory-enhancing properties , but which is currently more widely used as a mild sedative and sleep aid . In a previous study it was demonstrated that a commercial Melissa extract led to dose-specific increases in calmness , and dose-dependent decrements in timed memory task performance . However , the extract utilized in that study did not exhibit in vitro cholinergic receptor-binding properties . The current study involved an initial screening of sample s of M. officinalis for human acetylcholinesterase inhibition and cholinergic receptor-binding properties . The cognitive and mood effects of single doses of the most cholinergically active dried leaf were then assessed in a r and omized , placebo-controlled , double-blind , balanced crossover study . Following the in vitro analysis , 20 healthy , young participants received single doses of 600 , 1000 , and 1600 mg of encapsulated dried leaf , or a matching placebo , at 7-day intervals . Cognitive performance and mood were assessed predose and at 1 , 3 , and 6 h postdose using the Cognitive Drug Research computerized assessment battery and Bond – Lader visual analog scales , respectively . In vitro analysis of the chosen extract established IC50 concentrations of 0.18 and 3.47 mg ml−1 , respectively , for the displacement of [3H]-(N)-nicotine and [3H]-(N)-scopolamine from nicotinic and muscarinic receptors in the human cerebral cortex tissue . However , no cholinesterase inhibitory properties were detected . The most notable cognitive and mood effects were improved memory performance and increased ‘ calmness ’ at all postdose time points for the highest ( 1600 mg ) dose . However , while the profile of results was overwhelmingly favorable for the highest dose , decrements in the speed of timed memory task performance and on a rapid visual information-processing task increased with decreasing dose . These results suggest that doses of Melissa officinalis at or above the maximum employed here can improve cognitive performance and mood and may therefore be a valuable adjunct in the treatment of Alzheimer 's disease . The results also suggest that different preparations derived from the same plant species may exhibit different properties depending on the process used for the sample preparation Objective : To determine the effects of cholinergic treatment on the muscarinic receptor in patients with Alzheimer ’s disease . Methods : 12 patients with mild to moderate Alzheimer ’s disease and six controls were studied . The patients underwent ADAS-COG psychometric assessment and SPECT brain imaging with 123I quinuclidinyl benzilate ( QNB ) , to demonstrate the postsynaptic muscarinic M1 receptor , before being r and omised in a double blind study to receive either an acetylcholinesterase inhibitor ( donepezil ) or placebo for four months . Following this , the ADAS-COG and the 123I-QNB receptor scan were repeated . The controls were imaged on one occasion only . All image analyses were undertaken using SPM99 . Results : 123I-QNB imaging showed a significant relation between baseline psychometric impairment and deficits on scanning . Both placebo and actively treated groups had reductions in 123I-QNB uptake . Greater reductions in receptor binding were demonstrated in the placebo group than in those receiving active treatment . Intraindividual reproducibility of the 123I-QNB imaging technique appeared highly robust . Conclusions : The results suggest that 123I-QNB uptake is better preserved in Alzheimer ’s disease patients on cholinergic treatment than on placebo . Cholinergic treatment may play a neuroprotective role . Sequential 123I-QNB imaging seems to be a powerful tool in monitoring the response of these receptors to disease modifying treatments Although the central cholinergic deficits are still considered to be of primary importance in Alzheimer 's disease , there is great need for an expansion of the pharmacological approach in this illness beyond the simple cholinergic replacement hypothesis . This report focuses on the concept of " combination chemotherapy " in Alzheimer 's disease as the next generation of therapeutic strategies . Based on earlier positive findings in Alzheimer patients with the monoamine oxidase B inhibitor , 1-deprenyl  , the authors speculate that a combination of physostigmine , the short-acting cholinesterase inhibitor , and 1-deprenyl might be more beneficial than either agent alone . The authors outline a sample paradigm for such combination studies , report preliminary data on the first 16 Alzheimer subjects to have received an initial combination of physostigmine and deprenyl , and point to other possible " combination chemotherapy " strategies for future study Orthostatic hypotension affects patients with autonomic failure producing considerable disability because of presyncopal symptoms . Severely affected patients may have residual sympathetic tone that can be engaged to increase blood pressure ( BP ) with the & agr;-2 adrenergic antagonist yohimbine . This medication activates sympathetic outflow central ly and unrestrains norepinephrine release from noradrenergic neurons . Alternatively , the acetylcholinesterase inhibitor , pyridostigmine , can increase sympathetic tone by improving ganglionic cholinergic neurotransmission . Our purpose was to compare these complementary approaches and to explore whether the combination would lead to synergistic increases in BP . We compared the effects of 60 mg of pyridostigmine and 5.4 mg of yohimbine in a single-blind , r and omized , placebo-controlled , crossover fashion . In a subset of patients we tested the combination of pyridostigmine and yohimbine . Our primary outcome was the change in st and ing diastolic BP 60 minutes after drug administration from baseline . We studied a total of 31 patients with severe autonomic failure .  Yohimbine significantly improved st and ing diastolic BP as compared with placebo ( 11±3 mm Hg [ 95 % CI : 6 to 16 mm Hg ] ; P<0.001 ) . On the contrary , pyridostigmine did not increase the st and ing diastolic BP ( 0.6±3 mm Hg [ 95 % CI : −5 to 5 mm Hg ] ; P=0.823 ) . Only yohimbine showed a significant improvement in presyncopal symptoms .  Sixteen patients received the combination of pyridostigmine and yohimbine , but no evidence of synergistic pressor effect was found . Engaging residual sympathetic tone with yohimbine is a more effective approach to improve orthostatic hypotension as compared with pyridostigmine in patients with severe orthostatic hypotension Estradiol has been shown to interact with the cholinergic system to affect cognition in postmenopausal women . This study further investigated the interaction of estradiol and cholinergic system functioning on verbal memory and attention in two groups of healthy younger ( ages 50 - 62 ) and older ( ages 70 - 81 ) postmenopausal women . Twenty-two postmenopausal women were r and omly and blindly placed on 1 mg of 17-beta estradiol orally for 1 month then 2 mg for 2 months or matching placebo pills after which they participated in three anticholinergic challenge sessions when verbal memory and attention were assessed . Subjects were administered either the antimuscarinic drug scopolamine ( SCOP ) , the antinicotinic drug mecamylamine ( MECA ) , or placebo . After the first challenge phase , they were crossed over to the other hormone treatment for another 3 months and repeated the challenges . Results showed that estradiol pretreatment significantly attenuated the anticholinergic drug-induced impairments on a test of episodic memory ( the Buschke Selective Reminding Task ) for the younger group only , while estradiol treatment impaired performance of the older group . The results suggest that younger subjects may experience more cholinergic benefit from estradiol treatment than older subjects , supporting the concept of a critical period for postmenopausal estrogen use Drugs with anti-emetic properties can exert their actions at more than one receptor site , histamine H1 , muscarinic cholinergic or dopaminergic D2 receptors . This study was design ed to test the hypothesis that a combination of drugs acting at different receptor sites in lower than st and ard doses would be at least as effective as a st and ard therapeutic dose of a single anti-emetic agent . A combination of droperidol , hyoscine and metoclopramide in subtherapeutic doses has been shown to be at least as effective as droperidol ( 1.25 mg ) alone . In both groups there was a low incidence of emetic sequelae in the first 3 hours postoperatively Brain blood vessels contain muscarinic receptors that are important for cerebral blood flow ( CBF ) regulation , but whether a cholinergic receptor mechanism is involved in the exercise-induced increase in cerebral perfusion or affects cerebral metabolism remains unknown . We evaluated CBF and cerebral metabolism ( from arterial and internal jugular venous O(2 ) , glucose and lactate differences ) , as well as the middle cerebral artery mean blood velocity ( MCA V(mean ) ; transcranial Doppler ultrasound ) during a sustained static h and grip contraction at 40 % of maximal voluntary contraction ( n = 9 ) and the MCA V(mean ) during ergometer cycling ( n = 8) . Separate , r and omized and counterbalanced trials were performed in control ( no drug ) conditions and following muscarinic cholinergic receptor blockade by glycopyrrolate . Glycopyrrolate increased resting heart rate from approximately 60 to approximately 110 beats min(-1 ) ( P < 0.01 ) and cardiac output by approximately 40 % ( P < 0.05 ) , but did not affect mean arterial pressure . The central cardiovascular responses to exercise with glycopyrrolate were similar to the control responses , except that cardiac output did not increase during static h and grip with glycopyrrolate . Glycopyrrolate did not significantly affect cerebral metabolism during static h and grip , but a parallel increase in MCA V(mean ) ( approximately 16 % ; P < 0.01 ) and CBF ( approximately 12 % ; P < 0.01 ) during static h and grip , as well as the increase in MCA V(mean ) during cycling ( approximately 15 % ; P < 0.01 ) , were abolished by glycopyrrolate ( P < 0.05 ) . Thus , during both cycling and static h and grip , a cholinergic receptor mechanism is important for the exercise-induced increase in cerebral perfusion without affecting the cerebral metabolic rate for oxygen Estrogen Therapy ( ET ) may protect against age-related cognitive decline and neuropsychiatric disorders ( e.g. Alzheimer 's disease ) . The biological basis for this putative neuroprotective effect is not fully understood , but may include modulation of cholinergic systems . Cholinergic dysfunction has been implicated in age-related memory impairment and Alzheimer 's disease . However , to date no one has investigated the effect of long-term ET on brain cholinergic muscarinic receptor aging , and related this to cognitive function . We used Single Photon Emission Tomography ( SPET ) and (R , R)[(123)I]-I-QNB , a novel lig and with high affinity for m(1)/m(4 ) muscarinic receptors , to examine the effect of long-term ET and age on brain m(1)/m(4 ) receptors in healthy females . We included 10 younger premenopausal subjects and 22 postmenopausal women ; 11 long-term ET users ( all treated following surgical menopause ) and 11 ET never-users ( surgical menopause , n=2 ) . Also , verbal memory and executive function was assessed in all postmenopausal subjects . Compared to young women , postmenopausal women ( ET users and never-users combined ) had significantly lower muscarinic receptor density in all brain regions examined . ET users also had higher muscarinic receptor density than ET never-users in all the brain regions , and this reached statistical significance in left striatum and hippocampus , lateral frontal cortex and thalamus . Moreover , in ET users , (R , R)[(123)I]-I-QNB binding in left hippocampus and temporal cortex was significantly positively correlated with plasma estradiol levels . We also found evidence for improved executive function in ET users as compared to ET never-users . However , there was no significant relationship between receptor binding and cognitive function within any of the groups . In healthy postmenopausal women use of long-term ET is associated with reduced age-related differences in muscarinic receptor binding , and this may be related to serum estradiol levels Cholinergic blocking with scopolamine produces skin conductance orientating response ( SCOR ) nonresponding in normal subjects . This may be one of a number of causes for nonresponding in schizophrenic subjects . Blockade of dopamine with haloperidol produces an increase in amplitude and shortening of recovery time in the SCOR of normal subjects . This result closely resembles that of Nielsen and Petersen ( 1976 ) who found a similar pattern of responding in normal subjects who scored high on a scale of schizophrenism . These results , along with those for chlorpromazine and the pupillographic effects of the three drugs are discussed in terms of biochemical working hypotheses of schizophrenic subclassification The purpose of this study was to examine the effects of scopolamine on the physiological patterns occurring prior to and during motion sickness stimulation . In addition , the use of physiological profiles in the prediction of motion sickness was evaluated . Sixty subjects ingested either 0.6 mg scopolamine , 2.5 mg  methscopolamine  ,  or a placebo .  Heart rate ( HR ) , respiratory sinus arrhythmia ( an index of vagal tone ) , and electrogastrograms were measured prior to and during the exposure to a rotating optokinetic drum . Compared to the other groups , the scopolamine group reported fewer motion sickness symptoms , and displayed lower HR , higher vagal tone , enhanced normal gastric myoelectric activity , and depressed gastric dysrhythmias before and during motion sickness induction . Distinct physiological profiles prior to drum rotation could reliably differentiate individuals who would develop gastric discomfort from those who would not . Symptom-free subjects were characterized by high levels of vagal tone and low HR across conditions , and by maintaining normal ( 3 cpm ) electrogastrographic activity during drum rotation . It was concluded that scopolamine offered motion sickness protection by initiating a pattern of increased vagal tone and gastric myoelectric stability Major Depressive Disorder ( MDD ) is a common illness that affects > 40 million people worldwide , and antidepressants are one of the top 5 leading classes of pharmaceuticals with annual sales in excess of $ 20 billion ( 1,2 ) . The current st and ard of care focuses on serotonin−norepinephrine reuptake inhibitors ( SNRI ) and selective serotonin reuptake inhibitors ( SSRI ) ; however , patients often respond poorly . In fact , the National Institute of Mental Health conducted a large-scale STAR*D study and found that 63 % of patients did not achieve remission with the SSRI Citalopram ( 1,3−5 ) . Citalopram was originally developed in Lundbeck in the late 1980s and sold as a racemate . Lundbeck , in collaboration with Forest Laboratories , has recently released an up date d version called Escitalopram ( also known as Lexapro ) , which is the single (S)-enantiomer of the racemic Citalopram , which provided new patent life . In 2009 , Lexapro garnered ∼$2.7 billion in sales in the US ( Figure ​(Figure1)1 ) ( 2 ) . Figure 1 Structures of Citalopram , Escitalopram , and TC-5214 . An alternative hypothesis for depression emerged over 30 years ago and suggests that a cholinergic imbalance ( hypercholinergic tone ) is a major factor in depression , and both clinical and pre clinical studies have implicated neuronal nicotinic cholinergic receptors ( NNRs ) rather than muscarinic receptors ( 5 ) . On the basis of these data , AstraZeneca and Targacept have explored the role of NNR antagonism in depressive disorders and recently announced the initiation of a phase III trial of TC-5214 , (S)-(+)-mecamylamine , as an adjunct therapy with Citalopram . TC-5214 is a low molecular weight ( 167.3 as free base , 203.8 as the HCl salt ) , basic ( pKa = 11.5 ) compound , freely soluble in water . While TC-5214 displays modest selectivity among the NNRs , its antidepressive properties are presumed to be the result of inhibition of the α4β2 NNRs . Pre clinical ly , TC-5214 demonstrated robust efficacy in rodent models of depression ( forced swim and behavioral despair ) and anxiety ( social interaction and light/dark chamber ) . The (S)-enantiomer showed a superior preclincial safety profile compared to that of either the racemic compound or the (R)-enantiomer . Furthermore , TC-5214 was well tolerated in both acute and chronic toxicity tests , displayed no mutagenic potential , and possessed pharmacokinetic properties suitable for development ( 3−5 ) . In 2009 , Targacept conducted a double blind , placebo controlled phase IIb trial in MMD patients with TC-5214  , as an adjunct treatment with Citalopram demonstrated superiority to placebo in both primary and secondary outcome measures ( 3−5 ) . This positive outcome led to a license agreement in December of 2009 with AstraZeneca for the global development and commercialization of TC-5214 . On June 23 , 2010 , AstraZeneca and Targacept announced the enrollment of the first patients in the phase III trial of TC-4214 . Coined the Renaissance Program , the trial will include two fixed dose and two flexible dose phase III studies of TC-5214 as an adjunct treatment for patients with poor response to st and ard SSRI or SNRI therapy . Each fixed dose and flexible dose phase III study will employ an initial open label phase wherein patients diagnosed with MDD receive one of seven marketed SSRIs or SNRIs for eight weeks to assess therapeutic response . Patients that respond poorly will then be r and omized into a double blind , placebo controlled second phase to receive a fixed or a flexible dose of TC-5214 or placebo , twice daily , while continuing the SSRI or SNRI therapy . A change from double blind baseline for TC-5214 on the Montgomery−Asberg Depression Rating Scale ( MADRS ) as compared to placebo is the primary outcome measure . The program will also include a double blind , placebo controlled study for long-term safety . The companies plan completion of the trial in time to file an IND with the FDA in late 2012 ( 3−5 ) . MMD is the leading cause of disability in the US for people 15−44 , and the burden for MDD in the US in 2000 was in excess of $ 83 billion ( 6 ) . When broken down , the workplace burden for lost time is ∼62 % , treatment costs account for ∼31 % , and suicide related costs average 7 % ( 6 ) . For those suffering from MDD with poor response to SSRIs and SNRIs , the phase III data is anxiously awaited BACKGROUND We previously reported that intravenous ( IV ) scopolamine administration produced rapid and robust antidepressant effects in a sample consisting of both unipolar and bipolar depressives . The present study aim ed to replicate this finding in an independent sample limited to unipolar depressives . METHODS Out patients with major depressive disorder ( MDD ; n = 23 ; 22 were included in analyses ) participated in a double-blind , placebo-controlled , crossover trial . Subjects were r and omized into either a P/S or S/P sequence ( P = block of three placebo sessions ; S = block of three scopolamine sessions ; [ 4.0 microg/kg IV ] ) . Sessions occurred 3 to 5 days apart , such that time spent in each block lasted 1.5 to 2 weeks and the interval between blocks was 3 to 5 days . The Montgomery-Asberg Depression Rating Scale ( MADRS ) served as the primary outcome measure . RESULTS Following the initial block , the group receiving scopolamine first ( S/P ) showed a 32 % reduction in MADRS scores ( p < .001 ) , which exceeded the corresponding change of 6.5 % under placebo ( P/S ; p = .009 ) , confirming the a-priori hypothesis . Improvement was significant at the first evaluation that followed scopolamine administration ( p = .011 ) . In Block 2 , the P/S group showed a 53 % reduction in MADRS scores ( p = .001 ) following scopolamine versus placebo , whereas the reduction seen in S/P subjects who received scopolamine during Block 1 persisted as they received placebo during Block 2 . Scopolamine induced drowsiness , blurred vision , dry mouth , light-headedness , and reduced blood pressure , which were sufficiently well tolerated that no subject dropped out because of side effects . CONCLUSIONS These results replicate previous finding that scopolamine produces a rapid and robust antidepressant response Inositol is a simple polyol precursor in a second messenger system important in the brain . Cerebrospinal fluid inositol has been reported as decreased in depression . A double-blind controlled trial of 12 g daily of inositol in 28 depressed patients for four weeks was performed . Significant overall benefit for inositol compared to placebo was found at week 4 on the Hamilton Depression Scale . No changes were noted in hematology , kidney or liver function . Since many antidepressants are effective in panic disorder , twenty-one patients with panic disorder with or without agoraphobia completed a double-blind , placebo-controlled , four week , r and om-assignment crossover treatment trial of inositol 12 g per day . Frequency and severity of panic attacks and severity of agoraphobia declined significantly with inositol compared to placebo .  Side-effects were minimal . Since serotonin re-uptake inhibitors benefit obsessive compulsive disorder ( OCD ) and inositol is reported to reverse desensitization of serotonin receptors , thirteen patients with OCD completed a double-blind controlled crossover trial of 18 g inositol or placebo for six weeks each . Inositol significantly reduced scores of OCD symptoms compared with placebo . A controlled double-blind crossover trial of 12 g daily of inositol for a month in twelve anergic schizophrenic patients , did not show any beneficial effects . A double-blind controlled crossover trial of 6 g of inositol daily vs. glucose for one month each was carried out in eleven Alzheimer patients , with on clearly significant therapeutic effects . Antidepressant drugs have been reported to improve attention deficit disorder ( ADDH ) with hyperactivity symptomatology . We studied oral inositol in children with ADDH in a double-blind , crossover , placebo-controlled manner . Eleven children , mean age 8.9 + /- 3.6 years were enrolled in an eight week trial of inositol or placebo at a dose of 200 mg/kg body weight . Results show a trend for aggravation of the syndrome with myo-inositol as compared to placebo . Recent studies suggest that serotonin re-uptake inhibitors are helpful in at least some symptoms of autism . However a controlled double-blind crossover trial of inositol 200 mg/kg per day showed no benefit in nine children with autism . Cholinergic agonists have been reported to ameliorate electroconvulsive therapy (ECT)-induced memory impairment . Inositol metabolism is involved in the second messenger system for several muscarinic cholinergic receptors . Inositol 6 g daily was given in a crossover-double-blind manner for five days before the fifth or sixth ECT to a series of twelve patients , without effect . These results suggest that inositol has therapeutic effects in the spectrum of illness responsive to serotonin selective re-uptake inhibitors , including depression , panic and OCD , and is not beneficial in schizophrenia , Alzheimer 's ADDH , autism or ECT-induced cognitive impairment
Scopolamine is an effective and rapid antidepressant in both unipolar and bipolar depression , working as quickly as 3 days after initial infusion .
OBJECTIVES The cholinergic-adrenergic hypothesis of mania and depression states that depression is characterized by an increase in central cholinergic activity relative to noradrenergic tone .
Scopolamine is a central ly acting competitive inhibitor of the muscarinic cholinergic receptor site .
This review seeks to find all available data investigating scopolamine as an antidepressant .