The Role of Neurotransmitters and Inflammatory Cytokines in Depression

Question:

Discuss about the Chronic Alcohol Disrupts Dopamine.

Signs and symptoms of severe depressive episodes: David Wilson, a 38 year old man working as a mechanical fitter for mining company has been diagnosed with Major Depression (ICD10 diagnosis F32.2 severe depressive episode without psychotic symptoms). In the category of depressive episodes, his condition comes under F32.2. A severe depressive episode without psychotic symptoms is one where symptoms like fatigue, tiredness, lowering of mood, decreased concentration, low capacity for enjoyment, decreased appetite and sleep disturbance are present at extreme level and patient develop distressing experiences in life. In patients with F32.2 severe depressive episodes, the continuous presence of such symptoms results in loss of self-esteem and feeling of worthlessness (ICD-10 Version: 2016, 2017).  This was also seen in case of David, as his performance at workplace decreased due to poor concentration and he kept ruminating over negative events resulting in poor self-esteem. Such patients generally have suicidal feelings and somatic symptoms like unusual waking hours, weight loss, loss of appetite, psychomotor and loss of libido. As majority of these symptoms were present in Mr. David Wilson, he has been diagnosed with Major Depression.

Pathophysiology of depression: The difficulty faced by Mr. David Wilson is clearly an indication of severe depression. Major depressive disorder is medical condition in which feeling, thinking and activities of a person is negatively affected. This leads to feelings of sadness, loss of interest in activities, guilty feeling, loss of energy, change in appetite and sleeping patterns and difficulty in concentration. People may experience single or multiple episodes of depression. The examination of neurobiological theories elucidating the pathophysiology of depression suggest that depletion of neurotransmitters like dopamine and serotonin in the central nervous system results is the underlying factor behind the pathophysiology of depression (Hasler, 2010).

While considering the pathophysiology behind the condition, it can be said that neurotransmitters, the brain chemicals plays a major role in depression. Sperner-Unterweger, Kohl, & Fuchs, (2014) has shown that changes in function of neurotransmitters affect their interaction with neurocircuits and this in turns results in development of depression as neurocircuits are mainly involved in maintaining mood stability. Hence, mood stability is severely affected by the biological changes in neurotransmitters. Links has been found between inflammatory pathways and neurocircuits in the brain as the mechanism of interactions of the immune system with the neurotransmitters and neurocircuits affects the risk for depression. The activation of inflammasome results in release of stress induced inflammatory signals such as increased expression of pro-inflammatory cytokines. The inflammatory cytokines consequently has an impact on monoamines, noradrenaline and dopamine. Neurotransmission plays a role in mood regulation and through several mechanism, inflammatory cytokines reduces the availability of monoamines which contributes to the pathophysiology of depression. In case of dopamine, they play a role in motivation and motor activity and cytokines decreases the release of dopamine leading to poor mood and depression (Miller & Raison, 2016). Hence, activation of inflammasome leads to release of inflammatory cytokines and this affects the function of neurotransmitters and neurocircuits resulting to unsuitable behavior in affected person.

Genetic Predisposition and Work Environment as Contributing Factors

There is ambiguous evidence on the specific causes of depression. However, a combination of biological factors as well as environmental stressors might play a role in the onset and diagnosis of depression (Uher, 2014).. While reviewing the case of David Wilson, it has been found that his mother, Michelle, 69 years old had a history of depression and currently she was also suffering from early onset of Alzheimer’s dementia. This is an indication that David may have hereditary links to depression as blood relatives with history of depression are known to increase the risk of developing depression. Research has shown that genetics has a role in the development of depression and as it mainly runs in families, it is highly regarded as hereditary (Flint & Kendler, 2014). In case of David, his mother has been found to have a history of depression and in such case he is 1.5 to three times more likely to suffer from the condition. Hence, hereditary factors may have contributed to David’s depression.

Other biological factors that might be the cause of depression in David include the abnormal brain structure and brain chemistry. For instance, the parts of brain involved in regulating mood, thinking and behavior might be affected and the imbalance in neurotransmitters leads to the progression of depression (Kemp, Lickel & Deacon, 2014). Due to such imbalance, David might be suffering from low moods and other symptoms of depression.

As David has been working as a mechanical fitter on the Pilmara mines since the last 7 years, it is also possible that his work environment might have increased the risk of depression in him. This is said because research has pointed out that mining industry workers often develops mental health problems like depression and anxiety. The lifestyles, work characteristics and attitudes influences the mental and psychological health and well-being of workers (Liu,Wang, & Chen, 2014). Hence, work environment and occupational factors might be cause of depression in David.

For patients like David, who is suffering from major depressive disorder, two types of medications can be given to treat him. The first is the selective serotonin reuptake inhibitors (SSRIs) like Fluoxetine (Prozac) and this is the first medication which is initially started in patients. However, medications needs to be taken with caution as Prozac may result in common side effects of skin rashes, restlessness, fever as well as severe side effects of anxiety, joint pain, seizures and diarrhea. The main cause side effects in Prozac is that the drug has long half life and this results in slow processing of drugs in the body (Prozac Oral: WebMD 2017).  The function of SSRIs is to prevent the serotonin neurotransmitter from being reabsorbed into the nerve cells. This results in lightening of mood effect. Antidepressants are often linked to severe side effects of first time seizures and SSRIs was found to be associated with the worse odds of having first time seizures. This was seen mainly because overdose of the drug and timing of taking medicines (Schloesser et al., 2015).

Treating Depression with Selective Serotonin Reuptake Inhibitors and Tricyclic Antidepressants

Another medication that can be given to Mr. David Wilson for treating depression is tricyclic antidepressants like Clomipramine (Anafranil) if the above medication does not work on the patient. The drug acts by increasing the level of norepinephrine and serotonins and blocking the action of acetylcholine. This helps to restore the balance in neurotransmitters and it alleviates depressive symptoms in patient. However, the consumption of the medication is associated with many side-effects. Common side effects include dry mouth, fatigue and constipation whereas serious side effects include low blood pressure, seizures and irregular heart rate in patients (Annette (Gbemudu) Ogbru, 2017). The heart rate variability is mostly seen during treatment of patients with tricyclic antidepressants because of dose variability and abrupt discontinuation of drugs. Evidence by van Zyl, Hasegawa & Nagata, (2008) also proved that tricyclic antidepressants lead to the increase in heart rate of patients.

When David’s employer presented him to the local hospital, he was found in an intoxicated state. His employer also reported that he is not able to work due to increased consumptions of alcohol and poor concentration in work. Increased consumption of alcohol might also be a reason for depressive symptom in patients because alcohol is found to have an impact on adult brain. Evidence has mainly showed that alcohol has damaging effects on the brain. Consumption of alcohol results in blurred vision, impaired memory and slow reaction time. The PET imaging of brains in people with heavy alcohol consumption has indicated that alcohol influences the function of the neurotransmitter system, the brain cell mechanism as well as the blood flow within the brains. The changes in function have been found mainly in frontal lobes which is involved with learning and memory and the cerebellums involved in controlling movements and coordination (Hermens et al., 2013). This discussion clearly explains why alcohol consumption results in impaired memory, difficulty in walking and concentrating. The dependence and overuse of alcohol can also be regarded as a pathway to depression in Mr. David because of its link with neuropsychological impairment. The controlled process of attention and memory and mental flexibility of student is affected by the overuse of alcohol.

Alcohol has been found to influence neurotransmitter pathway too as evidence has shown that it activates neuro-immune signaling and persistent neuoroimmune-gene induction leads to continuous neurodegeneration and loss of behavioral flexibility in person (Crews et al., 2015). This has been also support by another research study which has explained that the effect of alcohol on disrupting dopamine receptor activity. The dopamine receptors in the medial prefrontal cortex control the cognition process by balancing the excitatory and inhibitory transmission. The impact of alcohol on dopamine mediated neurotransmission in rats has shown that behavioral flexibility decreased in rats with alcohol exposure. This confirms that cognitive function is seriously affected by alcohol exposure due to its impact on dopamine receptor signaling (Trantham-Davidson et al., 2014). For this reason, cognitive disruption has been seen in David as he has isolated him from others and shows poor concentration.

The Impact of Alcohol Consumption on the Brain and Cognitive Function

Pathophysiology of alcohol withdrawal: During admission to the hospital, David came in an intoxicated state. While staying at the hospital, he is likely to go into alcohol withdrawal state. Going into the phase of sudden reduction in alcohol use following a period of excessive consumption may result in alcohol withdrawal symptoms like vomiting, fever, and increase in heart rate, anxiety and shakiness. In severe cases, people may also suffer from seizures (Mirijello et al., 2015). In case of people consuming excess alcohol, ethanol interacts with gamma-aminobutyric acid (GABA) type A receptor and the N-methyl-D-aspartate (NMDA) receptor. Ethanol targets GABA type A leading to the downregulation of GABA type A receptors. However, in contrast to the stimulation of GABA type A receptor, ethanol inhibits function of NMDA receptor and causes compensatory upregulation of NMDA receptor. Hence, adaptive mechanism in neurotransmitter-receptor interaction promotes development of alcohol tolerance in people. In case of alcohol withdrawal in the alcohol-dependent patient, sudden reduction in alcohol use results in imbalance between the GABA receptor Type A function and the NMDA receptor. Due to the decrease in the alcohol level in blood, the inhibitory activity of GABA is reduced and symptoms of hallucination seizures, tremors and hyperactivity is seen in affected person (Yanta, Swartzentruber, & Pizon, 2015).

The severity of symptoms in alcohol withdrawal increases because of kindling phenomena. This is a process where low electrical stimulus leads to changes in behavioral response and symptoms of seizures. Evidence proves that this phenomena deteriorates the withdrawal symptoms (Mainerova et al., 2015).

In patients with alcohol withdrawal syndrome, many mild to severe symptoms can be seen which can be mistaken for other clinical condition. It is critical that nurses effectively manage alcohol withdrawal patients in hospital setting. Common withdrawal symptoms may include nausea, vomiting and insomnia, whereas severe symptoms include hallucination, disorientation and agitation. While caring for alcohol withdrawal patients, the nurse must understand the time at which the symptoms manifest in patients and the time at which the symptoms must terminate. Alcohol withdrawal patients are often very agitate and they show behaviors of violent outburst and verbal abuse. In such situation, the nurse needs to prioritize patient safety and injury. As family members are going to face problem due to abusive behavior of patient, the role of nurse is to educate family members regarding withdrawal symptoms and being empathetic and non-judgmental with patient during this period. Providing relaxing environment to patient is also important (Mirijello et al., 2015). The nurse must also take caution while interacting with patients and if they become extremely aggressive, then visitors or nurse must stay away from them. Observing facial signs and body language of patient can also support a nurse in keeping patient calm and compliant with treatment process. In case of severe withdrawal symptoms, nurse can also provide medications like Benzodiazepines to control agitation and treat such behavior of patients. Meeting their nutritional needs will also be important in such situation (Jarvis & Blad, 2010).

Pathophysiology of Alcohol Withdrawal Syndrome

Mr. David Wilson has been diagnosed with Major Depression and considering the impact of alcohol on neurotransmitter pathways, it can said that his condition has deteriorate even more by excessive use of alcohol. This explanation points out to the facts that there is biological link between alcohol and depression. This link is described in detail by the use of different biological factors which are as follows:

Genetics: The study by Mayfield, Harris & Schuckit, (2008) gives the implication that alcohol abuse and alcohol independence has relation with genetics and gene expression. For instance, genetic predisposition and genes increase the impaired controls towards many behavior such as alcohol use or drug use. This is also proved by the facts that relatives of alcoholics and twins of alcohol dependent person have fourfold higher risk of alcohol dependence. Secondly, specific genes like GABA A receptor, alpha 2 gene on chromosome 4 has been found to influence phenotypes of impulsivity and disinhibition (Dick et al., 2008). A study investigating about genetic relationship between alcoholism and depression has shown that combination of both alcoholism and depression run in families and this is most common in first degree relatives. The study showed that both alcoholism and depression were linked to specific chromosome region of chromosome 1. Hence, genes present on this region may predispose or increase risk of alcoholism and depression in different people. The importance of the research was that it reinforced the idea that heavy drinkers are genetically vulnerable to depression and antidepressant treatment on alcoholic depressed patients improves both depression as well as alcohol consumption symptoms (Nurnberger et al., 2002).

Changes in neurotransmitter pathways: The biological link between alcohol and depression is also proved in many research as both the condition has been found to lead to changes in neurotransmitter pathways. This is also evident from the above discussion regarding the pathophysiology of depression and alcohol withdrawal. A recent study highlighted the fact that various neurotransmitters are involved in the pathway towards alcohol addiction. This is said because alcohol exposure has an impact on function and balance of various neurotransmitters in the brain (Banerjee, 2014). Many studies done in patients with alcohol dependence has shown that the brain’s neurobiology is permanently changed by effect of alcohol. Alcohol has been found to particularly influence many neurobiological pathways like dopaminergic, GABA, serotoninergic and glutamate pathway (Yanta, Swartzentruber, & Pizon, 2015). Alcohol interact with these transmitters and produce reinforcing affects resultsing in changes in neuronal function and development of alcoholism. The research by Zuo et al., (2017) investigated particularly about the effect of ethanol on dopamine and glutamate receptors. The study gave the insight that ethanol stimulates the release of presynaptic glutamate mediated by the activation of dopamine subtype receptors and the cAMP dependent metabolic pathways. Hence, this evidence is useful to manipulate glutamate receptor while planning treatment of alcohol abuse.  

Managing Alcohol Withdrawal Patients in the Hospital Setting

The impact of alcohol and depression on neurotransmitter pathway is again understood from the research by Heberlein et al., (2014) and this again established the biological link between alcohol and depression. Both depression and alcoholism are associated with morbidity, impact on quality of living and mortality. While discussing the physiological impact of alcoholism and depressions, the researcher showed that chronic alcohol consumption reduces the availability of dopamine and influences mood and memory of affected person Similarly, Yin et al., (2016) showed changes in GABA and neurotransmitter system resulting in suicide behavior and major depressive order. Both GABA and glutamate are major inhibitory and excitatory neurotransmitters and they are associated with suicidal behavior and major depressive disorder too. They have the capability to changes the normal function of brain in the area of cognition, mood regulation, memory and learning. This is reason for manifestation of symptoms like poor concentration, low esteem, feelings of guilt and social isolation. As GABA affects the concentration of monoamines in brain which reduced stress, this mechanism is often exploited for the delivery antidepressant therapy too. Hence, biological link between alcoholism and depression is proved through the changes in neurotransmitter system.

Brain dysfunction: Alcoholism and depression is also found to have association with brain and neurobehavioral functions. For instance, excessive alcohol use has been found to lead to brain damage and this has been mainly proved by neuro-imaging studies in animals or deceased patients. The alcohol related brain damage is also affected by age, history of drinking and risk to specific regions of brain. The regions that are most likely to be damaged by alcohol exposure includes neurotransmitter system, entire brain, frontal lobe system, limbic system, thalamus and hypothalamus (Shokri-Kojori et al., 2016). The study regarding brain development in heavy drinking adolescents have also showed that trajectory of normal brain development is altered due to excessive consumption of alcohol. The specific brain region that is affected includes regional cortical volumes and white matter structures. The longitudinal analysis of brain structure in adolescents mainly showed heavy decline in frontal and temporal cortical volumes (Squeglia et al., 2015).

Just like the connection between brain damage and alcoholism, the connection between depression and brain dysfunction has also been established. The biological link is close because alcoholism itself is known trigger depression and deteriorates symptoms of depression. They intensify the effects of GABA leading to sedative effects and this result in poor concentration in people with depression. Similarly, imbalance in function of neurotransmitters in both conditions results in depressive symptoms in people.  In addition, the dopamine and the endorphin pathway is also affected by the conditions. Alcohol also damages the area of brain involved in non-verbal emotional stimuli thus resulting in social withdrawal and inappropriate behavior in patients (Joseph, 2017).

Vitamin deficiency: The study also showed that vitamin deficiency in people also contributes to brain damage and results in severe cognitive deficits in person with alcohol use and those with Major depression (Shokri-Kojori et al., 2016). Nutritional deficiencies are also known to cause depression and anxiety in people. Certain vitamins like Vitamin B12, B-complex and Folate are known to delay depression (Rao, et al., 2008).

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