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 

Психостимуляторы для пожилых больных

Psychostimulants are recognized for their role in managing attention-deficit/hyperactivity disorder
(ADHD), but also have found a treatment niche in conditions such as apathy, fatigue, and depression.

Psychostimulants for older adult

Фармакотерапия когнитивных нарушений при травмах головного мозга

Recommended treatments for mild TBI-related cognitive deficits

Deficit	First-line medication	Side effects	Contraindications	Other treatments
Memory	Donepezil (5 to 10 mg/d)	Diarrhea, nausea, vomiting, muscle cramps, fatigue, anorexia	Hypersensitivity to donepezil or piperidine derivatives	Rivastigmine, galantamine, physostigmine, CDP-choline
Speed of processing	Methylphenidate (0.3 mg/kg twice daily)	Headache, insomnia, decreased appetite, nausea, vomiting, anxiety, irritability	Hypersensitivity to methylphenidate, glaucoma, history of Tourette syndrome or tics, use of MAOI within 14 days	Dextroamphetamine
Executive function	Amantadine (200 to 400 mg/d)	CNS depression, orthostatic hypotension, peripheral edema, agitation, nausea, anorexia	Hypersensitivity to amantadine	Bromocriptine, pramipexole, carbidopa/levodopa
CDP-choline: cytidinediphosphocholine; MAOI: monoamine oxidase inhibitor
Source:Reference 8

Executive function responds to non-stimulant catecholaminergics. In a review, Writer and Schillerstrom5 found that TBI patients who received catecholaminergic augmentation showed improved function in 6 of 7 studies. In 2 randomized controlled trials (RCTs) and 4 nonrandomized, placebo-controlled trials, patients with mild to severe TBI showed improved executive function, attention, global cognitive function, memory, language, and/ or arousal with use of bromocriptine, pramipexole, carbidopa/levodopa, or amantadine.5 The greatest improvements were found in executive function. In 1 RCT, 10 patients with mild to severe TBI showed no functional improvement after 2 weeks of treatment.

Amantadine, 200 to 400 mg/d, has been shown to safely improve arousal and cognitive function in patients with moderate to severe TBI when started 3 days to 5 months after injury.9 Amantadine, 400 mg/d, also improves executive function measures without significant benefit in attention or memory in patients with mild to severe TBI 6 months post-injury.10

Memory responds to cholinesterase inhibitors. Memory deficits secondary to TBI affect immediate and delayed memory. The cholinesterase inhibitor donepezil is approved for treating Alzheimer’s disease (AD) in the United States and Canada, and research suggests memory deficits after TBI may be similar to those seen in AD.11 This includes deficits in long-term memory storage, which likely is associated with the cholinergic system.11 Post-mortem studies have found similarities in traumatically injured brains and those of AD patients.11

Three small prospective studies of done-pezil have shown improved memory and attention in TBI patients when cognition is the primary outcome, with 1 small negative open-label trial.7 In a study of 53 patients, Whelan et al12 found that donepezil improved patients’ intelligence quotient and clinician-based assessment of cognition over 2 years. Taverni et al13 found memory improvement in 2 TBI patients within 3 weeks of starting donepezil. These results suggest that donepezil may be used in acute and late phases of memory deficits following mild, moderate, or severe TBI.6 All studies titrated donepezil from 5 to 10 mg/d over several weeks. Dosing guidelines for donepezil in AD suggest 5 mg/d for 4 to 6 weeks, which may be increased to 10 mg/d if needed.8

Rivastigmine (3 to 6 mg/d) has been shown to be effective in mild TBI when started 1 year after injury and safe for 12 to 38 weeks of treatment.14,15 One retrospective cohort study of 111 patients with chronic TBI found no difference among donepezil, rivastigmine, or galantamine, with mean doses of 7.2 mg/d, 10 mg/d, and 2.3 mg/d, respectively.16 Sixty-one percent of patients showed improvement and the remainder had modest or no response. This study suggests that positive response on cognition may be similar among cholinesterase inhibitors. In case reports, physostigmine has offered some benefit17,18; however, cardiovascular and autonomic side effects restrict its use.11 Tacrine is associated with problematic gastrointestinal and hepatic side effects.

Processing speed responds to stimulant catecholaminergics. Although the incidence of psychiatric illness is not correlated with TBI severity, evidence suggests that speed of processing mediates the relationship between injury severity and functional decline.19 Therefore, aggressively treating these deficits may help improve function.

Methylphenidate improves attention and processing speed after TBI. A review of 7 randomized trials and 2 nonrandomized trials indicated that patients with mild to severe, chronic TBI experienced significantly improved cognitive function after methylphenidate treatment.5 Willmott and Ponsford20 found significant enhancement in information processing speed within 2 weeks of methylphenidate treatment in 40 patients with moderate or severe TBI. Methylphenidate increased the rate of recovery and led to improvement in acute21 and post-acute phases.22 In addition, methylphenidate may improve processing speed even in the absence of significant changes in attention.23

The standard methylphenidate dose used in most studies, 0.3 mg/kg twice daily, is safe and effective. Dosing usually is started at 5 mg/d and titrated to symptomatic relief. Because methylphenidate does not lower the seizure threshold, it is safe for patients at high risk for seizure.24 Methylphenidate also significantly improves attention and speed of processing in pediatric head trauma.25,26

Dextroamphetamine also is used to treat speed of processing dysfunction after TBI, but is less studied than methylphenidate. Dextroamphetamine, 5 to 30 mg/d, was found to effectively treat attention problems that interfered with rehabilitation in patients with severe TBI.

Traumatic brain injury: Pharmacotherapy options for cognitive deficits

Шизофреноподобный психоз при болезни Альцгеймера с ранним началом

Our patient was a 65-year-old right-handed woman. In August 2003, her family noticed her mild memory disturbance, and she developed delusions that someone intruded into her house, always watched her, and stole her bankbook. In March 2005, she developed auditory hallucinations that someone told her bad things. She also insisted that someone let snakes loose in her house and that someone hid himself under the stool and watched her. She was first diagnosed with schizophrenia and prescribed risperidone. At the next visit, the Mini-Mental Status Examination was administered and she scored 21/30. MRI showed mild diffuse brain atrophy, and SPECT showed right-dominant decreased rCBF in the temporoparietal lobe. Considering these results, her diagnosis was changed to early-onset Alzheimer’s disease. Donepezil was prescribed, and her psychoses were improved.

Schizophrenia-Like Psychosis and Dysfunction of the Right-Dominant Temporoparietal Lobe in Early-Onset Alzheimer’s Disease

Сосудистая деменция: фармакотерапия

Vascular dementia is a common condition for which there are no effective approved pharmacological treatments available. Absence of effective treatments creates a difficult situation for those suffering from the disease, their caregivers, and healthcare providers. This review will address our current understanding of the mechanisms of nerve cell damage due to ischemia and summarize available clinical trial data on several commonly used compounds including memantine, donepezil, galantamine, rivastigmine, nimodipine, hydergine, nicergoline, CDP-choline, folic acid, as well as such nonpharmacological approaches as validation therapy.

From the studies reviewed here, one may draw several conclusions. First, there are relatively few studies on vascular dementia treatment and no compound has been approved by any regulatory body for treatment of vascular dementia. Second, it appears that there are several compounds with different mechanisms of action that show mild efficacy in improving cognition and even ADLs in patients with vascular dementia. Third, there is one compound (memantine) that has been suggested to act within the confines of the current excitotoxic cell death model, although direct evidence confirming this hypothesis is still lacking. Overall, one could easily conclude that a number of different mechanisms may be at play in ethiopathogenesis of vascular dementia. Vascular conditions aside, nerve cell resistance to injury and our efforts to manipulate it still remains a conundrum, which will require new technologies to solve.

Vascular dementia: Pharmacological treatment approaches and perspectives