Citicholine And Bipolar. Cognitive Impairment.
Over the last decade, there has been a growing appreciation of the importance of identifying and treating cognitive impairment associated with bipolar disorder, since it persists in remission periods. Evidence indicates that neurocognitive dysfunction may significantly influence patients’ psychosocial outcomes. An ever-increasing body of research seeks to achieve a better understanding of potential moderators contributing to cognitive impairment in bipolar disorder in order to develop prevention strategies and effective treatments.
Data from different meta-analyses confirm that most patients with bipolar disorder show neurocognitive dysfunction, even during euthymia. Some of these neurocognitive deficits seem to be present not only in the early course of the illness but also in premorbid stages before illness onset. According to the most recent meta-analyses, the most affected domains, with effect sizes ranging from moderate to high, are attention, verbal learning and memory, and executive functions, whereas premorbid intelligence appears to be preserved.
Although cognitive abnormalities are present across all illness phases, they are usually more notable during acute episodes. Because BD has a high heritability, it is not surprising that unaffected first-degree relatives and offspring of patients with BD present mild cognitive dysfunctions. In this sense, some authors have suggested that neurocognitive deficits could be considered as putative endophenotypes of BD.
In the last 10 years, there is also growing evidence for impairment in some social cognition domains even during periods of remission. In general, evidence supports a theory of mind deficit in euthymic bipolar patients, whereas it remains unclear whether substantial deficits in other social cognition dimensions could persist in euthymic patients with BD. Importantly, 2 points need to be kept in mind regarding social cognition: first, there is a large number of available tasks that evaluate social cognition domains with different levels of complexity and quality; second, some findings point out that other neurocognitive deficits may influence social cognitive performance and this issue deserves further exploration.
Evidence points out that the neurocognitive impairment profile observed in patients with BD is similar to that shown in patients with schizophrenia although in a lesser extent; therefore, differences between the two disorders seem to be predominantly quantitative rather than qualitative. Patients with schizophrenia also significantly underperform bipolar patients in social cognitive tasks, such as emotion recognition and theory of mind similarly to findings for other neurocognitive tasks.
Nevertheless, an important matter is that studies comparing both psychiatric disorders have not taken into consideration the potential effect of the extant cognitive variability in both disorders. Overall, approximately 40% to 60% of patients with BD exhibit neurocognitive impairment, with a large heterogeneity among them. It seems that several clinical (e.g., number of episodes, psychotic symptoms, etc.) or sociodemographic variables (e.g., schooling, premorbid intelligence quotient, etc.) would be associated with the neurocognitive variability, although we cannot dismiss methodological issues as well as other intrinsic individual factors (e.g., motivation, self-esteem, etc.) as potential factors.
Pharmacotherapy.
From a pharmacologically therapeutic perspective, different drugs with potential beneficial effects for the treatment of neurocognitive impairment have been examined (e.g., some cholinesterase inhibitors, glutamate receptor antagonists, glucocorticoid receptor antagonists, dopaminergic agonists, intranasal insulin, some antioxidants, erythropoietin, etc.). Unfortunately, there is no well-established pharmacological treatment for cognitive impairment, since studies have yielded mixed results with no convincing effects.
Citicholine.
Citicoline is the name for cytidine 5′-diphosphocholine (CDP-choline) when this is used as an exogenous sodium salt. In fact, CDP-choline is an endogenous nucleotide naturally found in the body where it is an essential intermediate in the synthesis of the major phospholipid of the cell membranes, phosphatidylcholine (PtdCho). This type of synthesis is called the Kennedy pathway.
As a drug, citicoline has been proposed for use in traumatic brain injures, stroke, vascular dementia, Parkinson’s disease, and brain aging where it has the function of stabilizer of cell membranes and reduces the presence of free radicals. In particular, there is some evidence of a stimulating role of citicoline for the release of dopamine neurotransmitters in the brain.
Citicoline, by activating the central cholinergic system, also increases plasma adrenocorticotropic hormone (ACTH) levels and potentiates serum thyrotrophin (TSH) levels. The stimulation of central nicotinic and muscarinic receptors also increases growth hormone (GH) and luteinizing hormone (LH) serum levels. This activity on the cholinergic system is of high therapeutic usefulness in those clinical conditions where alterations of acetylcholine metabolism are considered one of the primary causes of disease, eg, Alzheimers Disease (AD).
The biological activity attributed to citicoline has suggested a possible role of citicoline on improving memory.
Citicoline is able to potentiate neuroplasticity and is a natural precursor of phospholipid synthesis, or rather serves as a choline source in the metabolic pathways for biosynthesis of acetylcholine. Several studies have shown that it can have beneficial effects both in degenerative and in vascular cognitive decline.
Citicoline inhibits apoptosis associated with cerebral ischemia and several models of neurodegeneration. It is also able to potentiate neuroplasticity and is a natural precursor of phospholipid synthesis, chiefly phosphatidylcholine, or rather serves as a choline source in the metabolic pathways for biosynthesis of acetylcholine. On a molecular basis, CDP-choline activates the biosynthesis of structural phospholipids in the neuronal membranes and increases cerebral metabolism, noradrenaline, and dopamine levels in the central nervous system (CNS). Furthermore, it is able to prevent the loss of cardiolipin, an exclusive inner mitochondrial phospholipid enriched with unsaturated fatty acids, which is essential for mitochondrial electron transport. All these evidences can explain why this drug can show neuroprotective effects in situations of hypoxia and ischemia through the restoration of mitochondrial ATPase and membrane Na+/K+ ATPase activity and the inhibition of phospholipase A2 activity. It also accelerates the reabsorption of cerebral edema in various experimental models, and since many years, it has been shown to improve learning and memory performances in animal models of brain aging (old rats with long-term memory impairment due to selective hippocampal damage, proved benefits from a dietary supplementation of CDP-choline). In particular, animal studies suggest that exogenously administered CDP-choline may protect cell membranes by accelerating resynthesis of phospholipids, thus resulting in rapid repair of injured cell surface and mitochondrial membranes. CDP-choline may also attenuate the progression of ischemic cell damage by suppressing the release of free fatty acids. Several studies have shown that it can have beneficial effects both in degenerative and in vascular cognitive decline.
Other studies have clearly demonstrated citicoline’s effects on several cognitive domains. Indeed:
it improves both the immediate and the delayed recall of words and objects;
it ameliorates short- and long-term memory, attention, and perceptual-motor ability, as well as behavioral and emotional control;
it improves verbal memory functioning in older individuals with relatively inefficient memory.