Скополамин и циталопрам в терапии депрессии

Evidence is accumulating that cholinergic pathways in the brain help to regulate mood, and researchers have shown that intravenous scopolamine (an anticholinergic) is effective for moderate-to-severe depression (JW Psychiatry Mar 29 2010). This 6-week, Iranian, double-blind study tested whether oral scopolamine (0.5 mg twice daily), added to citalopram as an initial treatment produces greater antidepressant effects than citalopram plus placebo. Participants were 40 patients with moderate-to-severe major depression (baseline score on the 17-item Hamilton Rating Scale for Depression, 22).
At days 4, 28, and 42, patients receiving scopolamine augmentation had significantly greater reduction in symptoms than patients taking add-on placebo, with an overall large effect size (0.9). Response rates were higher with scopolamine than placebo at week 4 (65% vs. 30%) but not at week 6. Remission rates for scopolamine-treated patients were higher at week 6 (65% vs. 20%). Dry mouth, dizziness, and blurred vision were each noted by at least 40% of scopolamine recipients.
Comment: This study shows that scopolamine given orally (a much preferable route of administration for routine clinical practice) adds significantly to the effect of a selective serotonin reuptake inhibitor for initial treatment of moderate-to-severe depression, although whether it is worth the side effect burden is unclear. Unfortunately, we also do not know whether scopolamine would benefit patients with treatment-resistant depression, although this study's effects in relatively severe depression suggest that such a trial might be pursued. The study's high rate of placebo response (but not remission) and the absence of formal cognitive testing compromise the generalizability of the findings.

Oral Scopolamine Augmentation for Major Depression

Аугметация антидепрессантов ингибиторами холинэстеразы

STUDY SELECTION AND DATA EXTRACTION: English-language clinical trials were evaluated. Studies that included subjects with Alzheimer's disease, dementia, Parkinson disease, bipolar disorder, or schizophrenia were excluded. Four clinical studies met our criteria.
DATA SYNTHESIS: We identified 4 randomized, double-blind, placebo-controlled trials that ranged in sample size from 20 to 130. Galantamine 16 mg daily was evaluated in 2 trials lasting 8 and 24 weeks. Neither study found a statistically significant difference in measures of cognition or Hamilton Rating Scale for Depression scores. Donepezil augmentation was evaluated in a 1-year and a 2-year trial. Donepezil was found to improve global cognition at 1 year, but the benefit did not persist at year 2. Subjects with mild cognitive impairment at baseline who received donepezil experienced higher depression recurrence than did those who took placebo (p = 0.03); this effect was not observed in cognitively intact subjects (p = 0.39).
CONCLUSIONS: There is no clear benefit for ChEI therapy as an adjunct to antidepressant therapy for depressed older adults.

Cholinesterase Inhibitor Adjunctive Therapy for Cognitive Impairment and Depressive Symptoms in Older Adults with Depression 

Ещё одно неудачное исследование антидепрессанта нового механизма действия

On 8 November, Targacept, a drug company based in Winston-Salem, North Carolina, announced that TC-5214 had performed no better than placebo in one of four phase III trials. The results are a disappointment to clinicians eager for an innovative antidepressant.

TC-5214 is a form of mecamylamine, a blood-pressure drug introduced in the 1950s. It targets nicotinic α4β2 receptors (see ‘Mixed signals’), which normally receive chemical signals from the neurotransmitter acetylcholine. Because excess acetylcholine has been linked to major depression, blocking these signals might relieve the condition.

 Depression drug disappoints

ИАХЭ и холинолитики взаимно снижают эффективность друг друга

Many patients with Alzheimer's disease are simultaneously prescribed cholinesterase inhibitors (ChIs) and anticholinergics (AChs), 2 drug classes that have the potential to cancel each other out.

Meds Prescribed for Alzheimer's May Cancel Each Other Out

Аллостерическая регуляция мускариновых холинорецепторов как возможный механизм терапии шизофрении

Current antipsychotics provide symptomatic relief for patients suffering from schizophrenia and related psychoses; however, their effectiveness is variable and many patients discontinue treatment due to side effects. Although the etiology of schizophrenia is still unclear, a leading hypothesis implicates an imbalanced dopaminergic system. Muscarinic acetylcholine (ACh) receptors regulate dopamine levels in key areas of the brain involved in psychosis, with the M(4) subtype emerging as a key regulator of dopaminergic hyperactivity. Unfortunately, no selective small molecule tools exist to provide pharmacological validation of this hypothesis. Here, we describe the discovery of a small molecule modulator, LY2033298, that is highly selective for human M(4) receptors by virtue of targeting an allosteric site on this receptor. Pharmacological assays confirmed the selectivity of LY2033298 for the M(4) receptor and revealed the highest degree of positive allosteric enhancement of ACh potency thus far identified. Radioligand binding assays also show this compound to directly potentiate agonist binding while having minimal effects on antagonist binding. Mutational analysis identified a key amino acid (D(432)) in the third extracellular loop of the human M(4) receptor to be critical for selectivity and agonist potentiation by LY2033298. Importantly, LY2033298 was active in animal models predictive of clinical antipsychotic drug efficacy indicating its potential use as a first-in-class, selective, allosteric muscarinic antipsychotic agent.

Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia

холинергическая теория депрессии

Come the year 2012 there could be a new antidepressant with a novel mechanism of action on the market in these United States (1). As the drug is still in development, it is known as "TC-5214."

According the the press release, TC-5214 is a "nicotinic channel blocker that is thought to treat depression by acting on neuronal nicotinic receptors, or NNRs, according to Targacept. Targacept says NNRs are found on nerve cells throughout the nervous system and regulate nervous system activity."

The Cholinergic Hypothesis of Depression?