There’s no doubt that 2020 was difficult for everyone and tragic for many.
But now vaccines against COVID-19 are finally being administered – giving a much needed hope of a return to normality and a happy 2021.
However, months of anxiety, grief and loneliness can easily create a spiral of negativity that is hard to break out of. That’s because chronic stress changes the brain. And sometimes when we’re low we have no interest in doing the things that could actually make us feel better.
To enjoy our lives in 2021, we need to snap out of destructive habits and get our energy levels back. In some cases, that may initially mean forcing yourself to do the things that will gradually make you feel better. If you are experiencing more severe symptoms, however, you may want to speak to a professional about therapy or medication.
Here are six evidenced-based ways to change our brains for the better.
1. Be kind and helpful
Kindness, altruism and empathy can affect the brain. One study showed that making a charitable donation activated the brain’s reward system in a similar way to actually receiving money. This also applies to helping others who have been wronged.
Volunteering can also give a sense of meaning in life, promoting happiness, health and wellbeing. Older adults who volunteer regularly also exhibit greater life satisfaction and reduced depression and anxiety. In short, making others happy is a great way to make yourself happy.
2. Exercise
Exercise has been linked with both better physical and mental health, including improved cardiovascular health and reduced depression.
In childhood, exercise is associated with better school performance, while it promotes better cognition and job performance in young adults. In older adults, exercise maintains cognitive performance and provides resilience against neurodegenerative disorders, such as dementia.
What’s more, studies have shown that individuals with higher levels of fitness have increased brain volume, which is associated with better cognitive performance in older adults. People who exercise also live longer.
One of the very best things that you can do to reboot your brain is in fact to go out and get some fresh air during a brisk walk, run or cycling session. Do make sure to pick something you actually enjoy to ensure you keep doing it though.
3. Eat well
Nutrition can substantially influence the development and health of brain structure and function. It provides the proper building blocks for the brain to create and maintain connections, which is critical for improved cognition and academic performance. Previous evidence has shown that long-term lack of nutrients can lead to structural and functional damage to the brain, while a good quality diet is related to larger brain volume.
One study of 20,000 participants from the UK-Biobank showed that a higher intake of cereal was associated with the long-term beneficial effects of increased volume of grey matter (a key component of the central nervous system), which is linked to improved cognition. However, diets rich in sugar, saturated fats or calories can damage neural function. They can also reduce the brain’s ability to make new neural connections, which negatively affects cognition.
Therefore, whatever your age, remember to eat a well-balanced diet, including fruits, vegetables and cereal.
4. Keep socially connected
Loneliness and social isolation is prevalent across all ages, genders and cultures – further elevated by the COVID-19 pandemic. Robust scientific evidence has indicated that social isolation is detrimental to physical, cognitive and mental health.
One recent study showed that there were negative effects of COVID-19 isolation on emotional cognition, but that this effect was smaller in those that stayed connected with others during lockdown. Developing social connections and alleviating loneliness is also associated with decreased risk of mortality as well as a range of illnesses.
Therefore, loneliness and social isolation are increasingly recognised as critical public health issues, which require effective interventions. And social interaction is associated with positive feelings and increased activation in the brain’s reward system.
In 2021, be sure to keep up with family and friends, but also expand your horizons and make some new connections.
5. Learn something new
The brain changes during critical periods of development, but is also a lifelong process. Novel experiences, such as learning new skills, can modify both brain function and the underlying brain structure. For example juggling has been shown to increase white matter (tissue composed of nerve fibers) structures in the brain associated with visuo-motor performance.
Similarly, musicians have been shown to have increased grey matter in the parts of the brain that process auditory information. Learning a new language can also change the structure of the human brain.
A large review of the literature suggested that mentally stimulating leisure activities increase brain-reserve, which can instil resilience and be protective of cognitive decline in older adults – be it chess or cognitive games.
6. Sleep properly
Sleep is an essential component of human life, yet many people do not understand the relationship between good brain health and the process of sleeping. During sleep, the brain reorganises and recharges itself and removes toxic waste byproducts, which helps to maintain normal brain functioning.
Sleep is very important for transforming experiences into our long-term memory, maintaining cognitive and emotional function and reducing mental fatigue. Studies of sleep deprivation have demonstrated deficits in memory and attention as well as changes in the reward system, which often disrupts emotional functioning.
Sleep also exerts a strong regulatory influence on the immune system. If you have the optimal quantity and quality of sleep, you will find that you have more energy, better wellbeing and are able to develop your creativity and thinking.
So have a Happy New Year! And let’s make the most of ourselves in 2021 and help others to do the same.
In the context of the ongoing pandemic of CoronaVirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2), there are already a lot of available research data considering the stressful impact of “social distancing”, but also difficulties that medical professionals experience, dealing with long shifts and frequent death witnessing, possible viruses exposure and above all stigmatization (1).
Working at the University hospital requires that we also need to organize psychiatric consultations in the so-called “COVID-19 units” on a daily basis.
There are some recently published clinical experiences in managing symptoms of anxiety, depression, and psychosis in patients with diagnosed COVID-19 (2). Considering the urge of these newly established assignments for psychiatrists, but also the need to resolve psychotic symptoms in the best manner, we were wondering if antipsychotic treatment could accomplish positive effects, not only on psychotic symptoms but also on somatic state in patients with COVID-19.
Therefore, we tried to find rational that the chlorpromazine (CPZ), a first-generation antipsychotic, could be useful in these purposes, considering its structure, and pharmacological origin, as well as anti-inflammatory potential and safety profile.
SARS-CoV-2 Impact on Central Nervous System (CNS) and Behavior
The etiopathogenesis of this worldwide spread virus is still unknown, while somatic complications are various and proposed therapeutical protocols are inconsistent (3). Important for our scope of interest is that the SARS-CoV-2 penetration route into the brain is still the subject of various discussions.
It has been proven that a virus enters the brain by migrating through the blood-brain barrier and interacts with the Angiotensin-Converting Enzyme 2 (ACE2) receptors, expressed by the brain tissue (4). Viral attachment to ACE2 receptors in the brain may cause arterial and venous thromboses, large-vessel ischemic strokes, intracerebral and subarachnoid hemorrhage widespread (5).
There are three proposed potential ways in which the SARS-CoV-2 affects a person’s behavior and mental functioning: above presented direct neuronal damage, but also by causing immune injury and hypoxia (5).
In a genetic review paper, Debnath et al. (6) tried to explain geographical discrepancies of SARS-CoV-2 by genetic variants of three gateways: ACE2, Human Leukocyte Antigen Locus, and Tool-like receptor and component pathways, leading to exaggerated immunity response.
Recent studies pointed out that the activation of the immune-inflammatory pathways, as well as the occurrence of “cytokine storm” caused by COVID-19, plays an important role in the development of neuropsychiatric symptoms in affected patients, but also exacerbation of pre-existing symptoms among affected patients with a history of mental illnesses.
Results based on computerized tomography and magnetic resonance imaging features presented by Poyiadji et al. (7) suggested the presence of COVID-19 associated acute necrotizing encephalopathy, indicating that it could be a potential consequence of a “cytokine storm” in the CNS of the patients with COVID-19.
The fulminant and possibly fatal hypercytokinemia in hospitalized COVID-19 patients, presented as elevated blood plasma levels of interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemo-attractant protein 1, macrophage inflammatory protein 1-α, and Tumor Necrosis Factor-alpha (TNF-α) (8), and IL-6 and ferritin were much more expressed among fatal COVID-19 cases (9).
SARS-CoV-2 attacks on hemoglobin, putting the lungs at the same time in a toxic and inflammatory state (10). It is well-known that serum levels of ferritin have been positively associated with inflammation, but opposite, hemoglobin showed a negative correlation (11).
These cytokine’s perturbations could lead to behavioral changes, the clinical presentation of delirium, and psychotic symptoms.
COVID-19 patients with no previous psychiatric history have developed psychotic symptoms, comorbid acute delirium, or psychosis conditions, characterized by thoughts of reference and structured delusional beliefs (12). The burden of long-term post-SARS-CoV-2 delirium may be significant, particularly for elderly patients who are more susceptible to post-infectious neurocognitive complications (13).
Most of the cytokines involved in this “cytokine storm” have been previously linked with mental disorders, such as schizophrenia and bipolar disorder (14).
And vice versa, influenza, SARS-CoV, and Middle East Respiratory Syndrome-related CoronaVirus (MERS-CoV) infections were shown to be associated with the onset of psychiatric symptoms (15, 16). Based on these understanding, neuropsychiatric consequences of “cytokine storm” seem highly likely in individuals with COVID-19 infection.
Possible Advantages of Chlorpromazine Application in COVID-19 Induced Psychosis
Antipsychotics are widely used in the treatment of acute and chronic psychotic disorders, but they also showed to be effective in the treatment of agitated states in delirium and dementia, bipolar mania, and other psychopathological conditions (17). Also, there is a division of antipsychotics according to the receptor system on which they perform their action, so it could differ into serotonin-dopamine antagonists, dopamine antagonists, multireceptor antagonists, and partial dopamine agonists (18).
Further, beyond the neurotransmitter’s hypothesis, antipsychotics showed to have additional ability to attenuate type-2 immune response, similarly seen in asthma (19) and the question is what could be the rational choice for treating these complexly compromised COVID-19 patients when its somatic state is complicated with psychosis.
Chinese clinical recommendations were to use atypical antipsychotics olanzapine or quetiapine in patients with COVID-19 (20). Some antipsychotics showed to be more efficient in lowering these specific cytokines that were measured to be elevated in COVID-19 patient’s serum, such as risperidone, olanzapine, and aripiprazole (21, 22), so maybe it could be more rational to use these antipsychotics in the first psychotic episode with possible secondary somatic benefits.
Interestingly, the search for an effective antimalarial drug led to the modification of phenothiazines and the consequent development of CPZ (23). CPZ belongs to the category of typical antipsychotics or neuroleptics, also known as first-generation antipsychotics, although the latest guidelines did not recommend it as a first line treatment.
Furthermore, other indications for the use of this drug are in the treatment of nausea and vomiting (24), chronic hiccups (25), anxiety before surgery, acute intermittent porphyria, and tetanus symptoms (26). CPZ achieves his effects by the postsynaptic blockade at the D2 receptors in the mesolimbic pathway (to treat psychotic disorders) and combined blockade at histamine (H1), dopamine (D2), and muscarinic (M1) receptors in the vomiting center (antiemetic effect).
CPZ has an excellent tolerance profile and it is easy to manage, but confirmed side effects are: sedation, dry mouth, hyperprolactinemia, and several endocrinal side effects, constipation and urinary retention, and in rare situations QT prolongation and potentially fatal malignant syndrome (26). On the other hand, apart from above-mentioned indications, where CPZ is widely used, less is known about its immunomodulatory and antiviral potential which may be useful during the COVID-19 pandemic.
Immunomodulatory and Antiviral Properties of Chlorpromazine
Lately, more attention is focused on the immunomodulatory effects of CPZ which are accomplished by increasing the human blood levels of IgM (27). Along with that, CPZ reduces the serum levels of multiple pro-inflammatory cytokines such as IL-2, IL-4, and TNF, while boosting the anti-inflammatory chemical IL-10 in stimulated blood cells culture (27–30).
Opposite to that, when different stimulants were used, Himmerich et al. (31) measured increased IL-4, IL-17, IL-2, and TNF-α levels, and Bertini et al. (32) suggested inhibitory effects of IL-1 in vivo. CPZ contributes to TNF production possibly due to more than one of its pharmacological activities and sufficiently protects against endotoxic shock simulated in vitro (28).
Besides that, CPZ significantly increased C-reactive protein levels in the blood culture samples (33), reduces the secretion of IL-1β and IL-2 in mixed cultures of rat glial and microglia cells (34). Furthermore, it was point out that physiological importance of CPZ binding with hemoglobin in positive co-operative mode (35).
CPZ can also inhibit phospholipase A2 and reduce the proinflammatory effects of platelet-activating factor, thromboxane (TxB2) (36) and leukotrienes (37), cascades that showed to be related into the progression of COVID-19 infection (38, 39).
Previously proven antiviral effects of CPZ indicate that its antiviral properties relevant to COVID-19 would be helpful. In vitro, antiviral properties of this molecule against various ribonucleic acid and deoxyribonucleic acid viruses were noted and can be very useful in the treatment of viral infections. CPZ has been reported to inhibit the replication of alphaviruses, hepatitis C virus, and coronaviruses: SARS-CoV, MERS-CoV, and Ebola virus (40–42).
An efficient target for CPZ antiviral action could be ACE2 receptors blockage in the brain (41). The usefulness of CPZ in the treatment of COVID-19 infection may be in its antiviral property due to the interaction with dynamin (cell membrane protein) to block clathrin-dependent endocytosis essential for coronavirus entry into the host cell.
CPZ has a long half-life and it has a good safety profile at the doses required to treat numerous viral infections (43). CPZ biodistribution has a favorable antiviral profile: 20–200 times higher concentrations in the lungs that is important for the respiratory tropism of SARS-CoV-2, it is highly concentrated in the saliva for reduction of SARS-CoV-2 contagiousness and bypassing the blood-brain barrier could prevent neurological complications of COVID-19 (44).
A search of the literature so far gives the impression that the adequate dose of this drug should be the subject of more detailed research in humans with COVID-19, but effective in vitro dosage for inhibiting viral replication of the MERS-CoV and SARS-CoV were non-toxic doses for cells (44, 45).
Some studies suggested that CPZ inhibits the replication of MERS-CoV, implying that an effect on clathrin-mediated endocytosis is probably not the only antiviral mechanism. In the “battle” against both MERS-CoV and SARS-CoV, CPZ was one of the four The United States Food and Drug Administration approved compounds that were identified as an inhibitor of MERS and SARS in cell culture (46).
CPZ and chloroquine, drug actively used in COVID-19 treatment, have similarities in the structure-activity characteristics. Both drugs are clathrin-dependent endocytosis inhibitor, which is an important mechanism in the treatment of viral infections. In vitro study of Ferraris et al. (47) highlighted chloroquine as the main drug having the potential for drug repurposing, but also suggested the need for a chemical improvement of CPZ, because of its low selectivity index.
Although CPZ was shown to be less efficient than chloroquine, it has much less pronounced adverse cardiological effects (48), and more prominent hepatotoxicity (49). Antipsychotics prescribed in COVID-19 could cause some adverse effects or interact with other drugs and possible interactions must be specially considered. In the simultaneous treatment of patients with antiviral medicines chloroquine and hydroxychloroquine, that showed shortening of the healing period and reduction of patient’s infectiousness, adjustment of the previously or acutely administered psychopharmacotherapy is required.
Interactions are possible at the level of amplification of dangerous side effects or effects on drug concentrations. In experimental models of malaria, it was shown that chlorpromazine was effective in potentiating chloroquine action (50).
These previous findings could possibly give the rational explanation for the simultaneous application of chlorpromazine and chloroquine in the COVID-19. Even though, more research is needed on the effects of CPZ on the SARS-CoV-2 virus itself. We believe that this drug, because of its similarity to chloroquine, may be a good choice in the treatment of acute psychotic conditions in patients diagnosed with SARS-CoV-2 infection.
reference link: https://www.frontiersin.org/articles/10.3389/fpsyt.2020.612347/full
Funding: Barbara Jacquelyn Sahakian has technology transferred through Cambridge Enterprise Wizard and Decoder to PEAK.
Jianfeng Feng receives funding from NSFC.
Christelle Langley does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.
