The Dopamine Hypothesis of Schizophrenia: A Review*

Neurobiological similarities in depression and drug dependence : A self-medication hypothesis

It is not “either/or”: Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood

Toward Constructing an Endophenotype Strategy for Bipolar Disorders

Major 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 and nonresponse rates are even higher in depressed patients with bipolar disorder (BD).3 Moreover, in patients who experience symptomatic relief after conventional antidepressant drug treatment, improvement generally is not evident for 3 to 4 weeks. The need for improved therapeutic agents that more quickly and effectively treat depression remains critical.

The cholinergic system is one of the neurotransmitter systems implicated in the pathophysiologic mechanism of mood disorders. 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.4–9 The cholinergic system also is implicated in depression by evidence showing that polysomnographic responses to muscarinic receptor agonists10–12 and neuroendocrine and pupillary responses to cholinomimetics13–16 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.15

Putative animal models of depression also have implicated the muscarinic system. The Porsolt “behavioral despair” model of depression19 that uses the forced swim test is used broadly to evaluate the effect of pharmacologic agents on depressive behaviors. In the context of this model, antimuscarinic agents produced antidepressant-like effects, although these findings were considered “false-positives” based on the assumption that these agents did not exert antidepressant effects in humans.20–22 Moreover, rats bred selectively for increased sensitivity of muscarinic receptors showed putative behavioral analogues of depression, such as lethargy, reductions in self-stimulation, and increased behavioral despair, in the forced swim test in response to cholinomimetic drugs.23,24

Some tricyclic antidepressant (TCA) agents exerted potent antimuscarinic actions,25–27 but these effects were thought primarily to produce adverse effects without contributing to therapeutic efficacy.28–30 As a result, during the past 2 decades, efforts to develop new antidepressant drug treatments emphasized the development of compounds that specifically lack antimuscarinic effects.31

Herein we report the results of 2 studies that each demonstrate rapid, potent antidepressant responses to the antimuscarinic agent scopolamine hydrobromide in depressed patients with MDD or BD. In a pilot study designed to evaluate the role of the cholinergic neurotransmitter system in the cognitive symptoms associated with depression, we unexpectedly observed an antidepressant response to scopolamine in depressed patients. We then designed a second study to more specifically establish the antidepressant effects of scopolamine, and we confirmed the findings of the first experiment by demonstrating antidepressant responses to scopolamine.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/209881/YOA60014.pdf

Antidepressant Efficacy of the Antimuscarinic Drug Scopolamine: A Randomized, Placebo-Controlled Clinical Trial

&NA; Physostigmine, a cholinesterase inhibitor which increases central acetylcholine levels, has been found in man to decrease manic symptoms, antagonize methylphenidate‐induced behavioral activation, and induce severe depression and psychomotor retardation in marijuana intoxicated normals. In the current study, physostigmine was found to increase depressed mood in patients with an affective component to their symptoms (manics, depressives, and schizoaffectives). Schizophrenics without an affective component did not become depressed. After physostigmine administration, all subject groups showed a significant increase in symptoms including lethargy, slowed thoughts, withdrawal, apathy, decreased energy, decreased thoughts, motor retardation, and feeling drained, indicating a state of psychomotor retardation; and all became less cheerful, friendly, and talkative. The above information is compatible with the hypothesis that acetylcholine may be involved in the etiology of affective disorders.

Acetylcholine and depression.

Three female schizophrenic patients receiving a combination of psychotropic agents, including the antiparkinsonian agent benztropine mesylate, developed the central anticholinergic syndrome, consisting of hallucinations, anxiety, short-term memory loss, disorientation, and agitation. These symptoms responded dramatically to physostigmine salicylate administered intramuscularly; they were unaffected by placebo injection given on a double-blind basis. In patients receiving multiple psychotropic drugs, evaluation of whether the patient is acting confused because of the combined central anticholinergic properties of these drugs is important. When identified, this syndrome can usually be treated by reduction of the dose of the anticholinergic agents or in special instances by the use of the cholinomimetic agent physostigmine.

el-Yousef Mk

Papers

Acetylcholine and depression.

Reversal of antiparkinsonian drug toxicity by physostigmine: a controlled study.

Amantadine hydrochloride treatment of tardive dyskinesia.

Effects of amantadine on tardive dyskinesia and pseudo-parkinsonism.

The augmentation of physostigmine toxicity in the rat by 9 -tetrahydrocannabinol.