title: Hypothalamo–pituitary–adrenal cortical responses to low-dose physostigmine and arginine vasopressin administration: sex differences between major depressives and matched control subjects Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, placebo-controlled clinical trial. Baseline mood-state measures as predictors of antidepressant response to scopolamine Nicotine dependence, major depression, and anxiety in young adults. Scopolamine Produces Larger Antidepressant and Antianxiety Effects in Women Than in Men Replication of Scopolamine's Antidepressant Efficacy in Major Depressive Disorder: A Randomized, Placebo-Controlled Clinical Trial The effects of acute scopolamine in geriatric depression.
abstract: 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 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 Identifying predictors of antidepressant response will facilitate the successful treatment of patients suffering from depression .  Scopolamine produces robust antidepressant responses in unipolar and bipolar depression . Here we evaluate the potential for baseline self-ratings to predict treatment response to scopolamine .  Fifty-one unipolar and bipolar patients participated in a double-blind , placebo-controlled crossover trial . Following a single-blind placebo session , participants r and omly received P/S or S/P ( P=3 placebo ; S=3 scopolamine ( 4μg/kg ) sessions ) . Mood-state self-ratings ( Profile of Mood State ( POMS ) and Visual Analog Scales ( VAS ) ) and depression severity ( Montgomery-Åsberg Depression Rating Scale ( MADRS ) ) were obtained before each infusion . Day 1 ( baseline/placebo ) self-ratings were used in a discriminant function analysis to identify linear combinations of individual items that predict response . The discriminant analysis significantly separated responders from non-responders in both the unipolar and bipolar diagnostic subgroups . The discriminant functions accurately classified over 85 % of patients as responders/non-responders . The POMS depression subscale significantly correlated with clinical response , as did the VAS restlessness , sad , and irritated scales . These results indicate that self-report mood-ratings obtained before treatment can predict response outcome to scopolamine , and suggest that a constellation of mood-state features may be related to clinical response To determine whether nicotine dependence , classified by level of severity , was associated with other substance dependence , major depression , and anxiety disorders , we studied a r and om sample of 1007 young adults in the Detroit ( Mich ) area using the National Institute of Mental Health Diagnostic Interview Schedule , revised according to DSM-III-R. The systematic coverage of DSM-III-R criteria of nicotine dependence provides an unprecedented opportunity to separate persons with nicotine dependence from the larger class of persons with a history of smoking and to examine the prevalence of psychiatric disorders among persons with nicotine dependence and among nondependent smokers . The lifetime prevalence of nicotine dependence was 20 % . Nicotine dependence was associated with alcohol , cannabis , and cocaine dependence . Controlling for the effects of other substance dependencies , persons with nicotine dependence had higher rates of major depression and anxiety disorders . The strength of these associations varied by level of severity of nicotine dependence .  Nondependent smokers had higher rates of other substance dependencies , but not of major depression or anxiety disorders 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 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 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
target: Scopolamine is an effective and rapid antidepressant in both unipolar and bipolar depression , working as quickly as 3 days after initial infusion .
background: 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 .