In addition to pervasive sadness, specific aspects of behavior and cognition are impaired in mood disorders, including selective attention, set-shifting and memory; and there also is evidence that depressed individuals exhibit a mood congruent processing bias whereby they more readily process negatively toned information as compared to positively toned information. This cognitive pattern lends itself to evaluation with functional brain imaging, both in terms of identifying the anatomical correlates of the specific behavioral and cognitive differences as well as characterizing the effects of pharmacological manipulation. Attention and memory functions are closely tied to the cholinergic neurotransmitter system whereby drugs that enhance cholinergic function are found to enhance memory and attention while agents that interfere with normal cholinergic function impair performance on attention and memory tasks. Moreover, the cholinergic system is one of the neurotransmitter systems implicated in the pathophysiology of mood disorders. Evidence suggests that during major depressive episodes, the cholinergic system is hypersensitive to acetylcholine. Agents that enhance muscarinic cholinergic receptor function increase depressive symptoms in depressed subjects, and can produce symptoms of depression in healthy subjects. The preclinical literature more specifically implicates the muscarinic receptors and indicates that the use of muscarinic antagonists, in the context of animal models of depression, results in improvement in the behavioral analogs of depression. ? ?This on-going project investigates the role of cholinergic neurotransmission in the mood, behavioral and cognitive symptoms observed in the depressed phase of both major depressive disorder (MDD) and bipolar disorder (BD). These studies will evaluate the effects of the cholinergic antagonist, scopolamine, on mood in patient populations, as well as performance effects and alterations in neural activity in brain regions recruited to perform cognitive tasks. This approach is expected to reveal how neuromodulators influence processing in brain structures recruited to perform these tasks, and are expected to elucidate the role of cholinergic muscarinic receptors in the mood and cognitive symptoms observed in depression. The combined use of functional brain imaging and pharmacological manipulation to evaluate the role of neurotransmitter dysfunction in depression may direct us to potential therapeutic approaches.? ? To date we have found that in healthy individuals, scopolamine modulates performance on attention tasks but does so differentially based on the emotional content of the task stimuli with greater effects associated with sad stimuli. This result suggests that manipulation of cholinergic function in healthy individuals has highly selective, stimulus dependent effects, and results in the modulation of the salience of stimuli, including emotional stimuli. Aspects of these findings recently were published in Neuropsychopharmacology.? ? We also are beginning to uncover baseline performance differences between the healthy controls and depressed patient groups that indicate differential processing of emotional stimuli in the context of attention tasks. Moreover, we have found evidence that cholinergic manipulation modulates performance differentially in healthy and depressed individuals based on the emotional content of the stimuli, supporting the hypothesis that acetylcholine is processing emotional stimuli differently in patients with mood disorders. This prediction was based on the hypothesis that the over-activity of the cholinergic system in depression results in an enhanced perceptual representation of negative stimuli that interfered with task performance, and that blocking overactive muscarinic receptors will diminish this effect. We also have preliminary findings showing both baseline performance differences and differential responses to scopolamine between the MDD and BD groups, differences that again are based on the emotional content of stimuli. As the identification of performance differences between these patient groups has been elusive, this finding also has the potential to be very revealing. ? ?The behavioral findings have guided functional imaging studies designed to elucidate the neurophysiological basis for observed differences between healthy individuals and patient groups, and for the differential responses to scopolamine. In healthy individuals, a response bias towards face stimuli (versus houses) that is evident during placebo is diminished during scopolamine. These behavioral effects are consistent differences in the effects of scopolamine on BOLD response to facial expressions in healthy individuals, and have observed selective effects on responses in lateral fusiform cortex and in amygdala as emotion is modulated in faces despite the fact that the emotional content is irrelevant to task performance requirements. These preliminary results may suggest that an inherent bias towards faces is cholinergically mediated, and that the cholinergic system differentially modulates stimuli based on the emotion content. We also are working with other tasks in the context of fMRI that are designed to assess the role of the cholinergic system in the emotional processing bias observed in mood disorders, including the affective shift task and a working memory task that requires matching face stimuli based on identify or emotion. We have observed preliminary data with the affective shift task that shows how task specific regions are altered by cholinergic modulation during task in brain areas important to emotional processing, including orbitofrontal cortex, insula and amygdala. The effects observed in these regions are consistent with changes in a behavioral emotional response bias, lending support to the hypothesis that acetylcholine has selective effects based on emotional valence of stimuli. ? ? The most important finding to date in the context of this project is that we have observed rapid and robust anti-depressant responses to scopolamine in our patient groups. Following a clinical observation (in the context of cognitive studies) that our patient groups showed antidepressant responses to scopolamine, we designed and completed a treatment study in a group of MDD and BD patients, the results of which have confirmed that scopolamine is having a dramatic antidepressant effect. We observed antidepressant responses that were clinically significant by the next clinic visit (generally 3 days later) following a single i.v. administration of scopolamine, and by patient report the effect actually was faster. Moreover, over 55% of our patients, the majority of whom were treatment resistant, experienced remission of symptoms. In our estimation, scopolamine has the potential to become a new option for the clinical treatment of depression in MDD and BD. To date we have observed antidepressant effects that are equally effective in depressed MDD and MD patients, and we also have observed larger effects in women than in men. These clinical findings have been published in Archives of General Psychiatry. Importantly, we have continued to collect data following the same protocol and have replicated these earlier findings in a new sample of 20 patients. ? ? Follow-up clinical studies have been initiated to evaluate the efficacy of scopolamine in patient groups when adminstered transdermally using a scopolamine patch. Although these studies are underway and on-going, few patients have completed the study to date and we do not have a sufficient amount of data to comment of the effectiveness of the scopolamine patch. ? ? Aspects of these results have been presented at Biological Psychiatry, International Biological Psychiatry, the American College of Neuropsychopharmacology and Human Brain Mapping.
