Awakening from cognitively impaired states? "Health is infinite and expansive in mode, and reaches out to be filled with the fullness of the world; whereas disease is finite and reductive in mode, and endeavors to reduce the world to itself." - Oliver Sacks, Awakenings When you're old and dotty and losing your mind, how would you like it managed? Sure you can be thrown into a corner on some potent sedatives, but is that humane and what is the quality of life with such interventions? An interest has been in options for cognitive impairment that might promote some level of cognitive recovery to improve quality of life. Non-pharmacological strategies for improving cognitive domains eg diet, lifestyle, exercise,meditation and cognitive training are important but our current pharmacological interventions seem rather ineffective. "Cognitive impairment can directly affect QoL by impacting daily activities, interpersonal relationships, and leisure activities. Additionally, cognitive impairment can indirectly affect QoL through its influence on physical function and mental health. Factors such as physical function, depression, and activities of daily living (ADL) can mediate the relationship between cognitive impairment and QoL" One main approach currently is to palliate the symptoms with sedatives (antipsychotics and BZDs) but may they actually worsen subjective -particularly cognitive - complaints, decrease quality of life, whilst also increasing the mortality rate? Antipsychotics lead to a reduction of both pleasure and motivation and reductions in alertness and contentedness have been noted, increasing dopaminergic tone increased the hedonic experience, ↑ motivational responses, ↑ processing speed and ↓ depression. “Awakening , basically , is a reversal of this : the patient ceases to feel the presence of illness and the absence of the world , and comes to feel the absence of his illness and the full presence of the world ” — Oliver Sacks When healthy volunteers were administered an antipsychotic, up to 80% (at higher doses) experienced a dysphoria they said was sometimes 'very severe'and coincided with the maximal plasma drug concentrations. It was described as restlessness, irritability and tension, even in the absence of akathisia. Some have likened it to ‘‘feeling blah, listless, tired, and lacking interest and ambition.’’, "‘depressed and despondent’’ even becoming "tearful, clingy, whiny" It often had elements of anxiety, tension, depression, feelings of guilt and somatic concerns. In conditions that often have apathy as a feature, it may worsen such. It is ‘‘a generalized feeling of unwellness that the patient attributes to the neuroleptic’’. In other studies, the dysphoria induced by antipsychotics included subjective changes such as anger, depression, and hostility. Coupled with the affective changes induced by akathisia, it 1 can be severe. Motor symptoms may occur. Even in conditions where traditionally indicated, 23% had a ‘good’ response in the antipsychotic group vs 14% on placebos. Is the widespread prescription and use, even spreading to off-label use - of these in some cases instead worsening outcomes for the person involved and adding to the burden of disability and even reducing quality of life? Growing evidence also suggests antipsychotic medication may in fact worsen cognitive functioning, often with the effect of cognitive slowing. There have been attempts to promote different domains of cognition in impaired states such as dementias either through diet eg MCT supplementation or nutraceuticals, pharmacologically - through psychostimulants (normally modafinil and methylphenidate), nicotinic modulators, AChE inhibition, ampakines and positive allosteric AMPAR modulators, or through non-pharmacological means [1]. Another novel attempt to improve cognitive and behavioural outcomes is through 5-HT2A agonists to impact resting state functional connectivity in the ageing brain [2]. Other interventions have been studied with regard to managing other neuropsychiatric complications [3]. "Studies have shown that 5-HT2A agonists can enhance functional connectivity between hierarchical brain networks, effectively altering the influence of neural activity from lower- order to higher-order regions. This modulation can potentially disrupt abnormal neural dynamics associated with dementia, thereby improving cognitive function and reducing symptoms. Additionally, 5-HT2A receptor agonism has been found to change neuronal network activity and disrupt neurovascular coupling, which can influence resting state functional connectivity. These changes may help in rebalancing the excitatory and inhibitory signals in the brain, which are often disrupted in dementia. Overall, while more research is needed to fully understand the therapeutic potential and mechanisms, low-dose 5-HT2A agonism shows promise in altering resting state functional connectivity and improving cognitive outcomes in dementia patients". A decline in consciousness and arousal can be seen in cognitive impairment. As cognitive impairment worsens, levels of consciousness and arousal decrease. Higher levels of daytime sleepiness were associated with greater impairments in functional status [4, 5]. If the goal is maintaining some level of functional capacity and quality of life, should efforts not be directed at improving these domains through arousal-promoting interventions? Such interventions have been found to reduce apathy in humans [6], and in animal models, rescue cognitively impairment [7] Most neurotransmitter systems involved in arousal show significant decline in aging, which could lead to chronic underarousal. However, increased tonic levels of some arousal related neurotransmitters compensate for these declines [8]. 2 Loss of neurons, receptors, and other infrastructure involved in brain arousal systems threatens to create underarousal. Drowsy and confused is not a good cognitive state to try and manage independently, whereas alert and cognisant is much more conducive to maintaining some level of functional independence. The arousal-related neurotransmitter systems show decline in various aspects: Declines in the Dopamine System Declines inthe Serotonin System Declines in the Orexin System The Acetylcholine System Does Not Decline Much [1] https://doi.org/10.3389/fnsys.2014.00153 [2] https://doi.org/10.1007/7854_2021_267 [3] https://doi.org/10.1007/s40473-019-00181-6 [4] https://doi.org/10.1097/JGP.0b013e3180381521 [5] https://doi.org/10.1002/gps.6112 [6] https://doi.org/10.1002/trc2.12403 [7] https://doi.org/10.3390/biom13030467 [8] Mather, M. (2020). How Arousal-Related Neurotransmitter Systems Compensate for Age-Related Decline. The Cambridge Handbook of Cognitive Aging, 101–120. doi:10.1017/9781108552684.007 3