Frequency And Assessment Of Fatigue In Pd Patients
Among the 518 PD patients, 250 cases were male and 268 were female. The average score of mental fatigue in fatigue and non-fatigue groups was 7.00 and 4.00 points, respectively. The disease duration varied from 3 month to 33 years, with a median of 2.5 years . The demographic characteristics were listed in Table , Supplemental Table and Supplemental Table .
Table 1 Demographics information, motor and non-motor symptoms in non-fatigue and fatigue groups.
Relationship between mental fatigue score and the levels of iron and related proteins in serum in PD with fatigue group
The levels of iron, transferrin, ferritin and lactoferrin in serum were compared among control, fatigue and non-fatigue groups . The data revealed that transferrin level in serum in fatigue group was prominently decreased comparing with non-fatigue and control groups. Further analyses implied no relationship between mental fatigue score and the levels of iron and related proteins in serum.
Relationship between 5-HT level and the levels of iron and related proteins in serum in PD with fatigue group
Correlation analyses were made between 5-HT level and the levels of iron and related proteins in serum. The data did not indicate any correlation among them .
Dopamine Hypothesis Of Depression
Dopamine is produced in the substantia nigra pars compacta in the midbrain. Dopaminergic projections in both the mesocortical and the mesolimbic systems are known to be disturbed by stress . Dopaminergic pathways are part of the reward system and the effects of chronic stress on reward perception that lead to depression can occur because of the interaction between the dopaminergic system and the HPA axis and between the dopaminergic system and the serotonergic system . Studies have demonstrated that early psychological stress that activates the HPA axis, exacerbates DA depletion and is associated with a decrease in DA synthesis in the brain . Auffret et al. and Leentjens, have shown that symptoms of depression can be improved by administration of DA agonists highlighting the possibility of antidepressant drugs to have an affinity to DA receptors. Since DA depletion may accompany depression, some antidepressant drugs may act on both dopaminergic and serotonergic systems to exert their antidepressant effect . Therefore, DA deficiency resulting from early life stress may in some instances predispose an individual to depression and eventually to neurodegenerative diseases such as PD.
Treatment Of Depression/anxiety Associated With Parkinsons Disease
Antidepressants are a popular treatment for moderate to severe forms of depression in PD . Several classes of antidepressants are available and they work in a slightly different way with different side-effects. Neurotransmitters are associated with the pathogenesis of depression in PD . Antidepressants relieve the symptoms of depression by targeting these neurotransmitters . Tricyclic, monoamine oxidase inhibitors and newer selective antidepressants including serotonin and noradrenaline reuptake inhibitors are classes of antidepressants known to be effective in treating depression .
Tricyclic drugs are the older version of antidepressants . This class of antidepressant includes drugs such as desipramine, doxepin, imipramine, trimipramine . Although tricyclic antidepressant drugs are effective in treating depression, they have several side effects such as dry mouth, constipation, difficulty urinating, sedation, weight gain or sexual problems . Also, tricyclic drugs can be fatal in overdosing .
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A New Treatment For Tremor Based On Serotonin Increase
In this section, we show that it is possible to build on the neural mechanisms underlying the physiological influence of 5-HT on DA release , to test a new treatment for tremor based on a 5-HT increase. Figure 6 shows the effects of this treatment at the level of neural activity, whereas Figure 7 shows the effects on tremor.
Figure 6. Relationship between activities of model components and changes in DA and 5-HT concentrations after SNc damage and selective serotonin inhibitors simulated treatment. The first dotted vertical line represents the timing of the lesion in the dopaminergic circuits . The other three dotted vertical lines indicate the beginning of different serotonin-based drug treatment periods with different doses of the treatment . Color code and graphs displacement as Figure 3.
Figure 7. Oscillation amplitude of the bio-mimetic arm before and after the DA impairment and following SSRIs treatment .
Starting from a healthy model, after 75s we introduced an SNc impairment by increasing the value of ÏSNc and by increasing the value of αIP . Since these impairments are stronger than those produced in section 3.1, they produce a stronger DA loss . In this case, the physiological compensatory mechanisms involving 5-HT in between 75 and 125s only allow to partially recover the DA loss, and it is not strong enough to avoid tremor .
Mechanism Of Drug Interaction
MAO exists as 2 isoforms, MAO-A and MAO-B. Inhibition of MAO-A reduces the metabolism of both serotonin and noradrenaline, whereas inhibition of MAO-B does not affect the metabolism of these neurotransmitters, unless sufficient doses are used.15 Inhibition of MAO-B, the major isoform in the human brain, prevents the breakdown of extracellular levels of dopamine in the striatum. The resulting increase in dopaminergic activity in the striatum may explain the mechanism by which MAO-B inhibitors exert their beneficial effects in Parkinson disease.16,17 Inhibition of MAO can also be reversible or irreversible irreversible inhibitors can lead to longer-lasting toxic reactions caused by MAO inhibition, including serotonin syndrome.15 Selegiline and rasagiline, both irreversible MAO-B inhibitors, are selective for MAO-B at therapeutic doses of 10 mg daily and 1 mg daily, respectively, for patients with Parkinson disease. At higher doses, they lose selectivity and inhibit both MAO-B and MAO-A.15 Higher doses of MAO-B inhibitors alone have resulted in serotonin syndrome.17,18
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Detection Of The Levels Of Iron And Related Proteins In Csf And Serum
The levels of iron and related proteins, including iron, transferrin, ferritin and lactoferrin in CSF and serum from PD patients were detected by Enzyme Linked Immunosorbent Assay . CSB-E08831h kit for lactoferrin was from Wuhan Huamei Biological Limited Company . Ab83366 kit for iron, Ab108837 kit for ferritin and Ab108911 kit for transferrin were from Abcam Company .
Serotonin Hypothesis Of Depression
Serotonin is mainly produced in the dorsal raphe nucleus . Serotonin transporters take up released serotonin from the synaptic cleft into serotonergic neurons in a manner that helps to modulate various functions in the brain including mood and emotion . The striatum, the amygdala, and the prefrontal cortex are regions of the brain that are innervated by serotonergic neurons . These brain regions including the dorsal raphe nucleus which is part of the brains serotonergic system, are activated during early maternal stress . Abnormal 5-HT levels in these brain areas have been associated with depression . Pre-clinical and clinical studies have demonstrated that early life stress affects 5-HT levels in the brain and this may lead to depression . Selective serotonin re-uptake inhibitors are a class of antidepressant drugs commonly used to treat depression . SSRIs work by blocking 5-HT re-uptake thus increasing the availability of 5-HT in the synaptic cleft as well as its chance to bind to receptors in the post-synaptic membrane . Therefore, by restoring the levels of monoamines and their transporters in the brain, SSRIs drugs are appropriate treatments to address early life stress dysfunction that predisposes to depression later in life.
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Pharmacologic Mechanism Of Action Of 5ht2a Antagonism In Pdp: No Longer Between A Rock And A Hard Place
Traditional treatments for PDP included dose reduction of dopaminergic therapy if that was a contributing factor, or administration of antipsychotics, especially quetiapine or clozapine, assumed initially to work by blocking D2 dopamine receptors just as they do in schizophrenia.Reference Vaillancourt, Schonfeld, Kwak, Bohnen and Seidler18Reference MacDonald and Monchi21,Reference Zahodne and Fernandez38,Reference Desmarais, Massoud, Filion, Nguyen and Bajsarowicz39 However, this often put both PDP patients and their clinicians between a rock and a hard place when trying to balance simultaneously the treatment of both PDP and motor symptoms of Parkinsons disease, since what was good for psychotic symptoms was generally bad for motor symptoms.
Oxidative Stress Neuroinflammation And Parkinsons Disease
Oxidative stress is the result of an imbalance between the production of reactive oxygen species and the body capacity to counteract their harmful effects through neutralization by antioxidant defenses . Brain neurons are constantly exposed to reactive oxygen species and reactive nitrogen species as a result of endogenous or exogenous exposure to oxidative stress . Chronic psychological stress increases neuroinflammation which may facilitate nigral cell death in PD . For instance, under stress conditions, there is evidence that dysfunction of inflammatory markers such as tumor necrosis factor -, interleukin -1, IL-6, IL-10, transforming growth factor – in microglia of patients with depression participates in worsening PD symptoms .
PD research is often directed towards the prevention of DA neuron degeneration . However, all current treatments only address the symptomatic effects of the disease, none of which neither halt nor retard DA neuron degeneration . About 95% of PD cases are sporadic hence caused by environmental factors versus 5% that are inherited . The point of view in favor of exposure to stressful events early in life predisposing an individual to develop neurodegenerative disorders later in life seems to emphasize that PD is much more than just a DA-dependent motor deficit.
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The Case Of Fluvoxamine Maleate
The role of serotonergic drugs in PD associated with depression has been receiving considerable attention amongst the research community . As a link between DA and the development of depression in patients with PD has been suggested, the pathophysiological features of both PD and depression have in common DA pathway dysfunction and depletion and/or 5-HT deficit . It has been suggested that an increase in serotonergic tone may indirectly influence DA function and may contribute to increased motor activity which is partially blocked by DA antagonists . Studies have shown that depression may be associated with an abnormal level of DA . As studies have also shown that brain regions affected by abnormal DA processing may also be affected when 5-HT is abnormally processed, we hypothesize that Fluvoxamine maleate treatment may play a role in improving the chemical imbalance caused by low levels of DA in the brain .
Diagnostic Criteria For Serotonin Syndrome
Serotonin syndrome is a measure of central nervous system hyperexcitability in relation to an excess of serotonin. This hyperexcitability can manifest in multiple ways, and ultimately there is no true gold standard for the diagnosis of serotonin syndrome. Published diagnostic criteria have attempted to identify symptoms or symptom combinations that best capture the nature of CNS hyperexcitability related to an excess of serotonin.9
Serotonin syndrome can manifest as symptoms that range from mild to life-threatening. Initially, the patient may present with akathisia and tremor, followed by mental status changes and inducible clonus. The clonus can become sustained, and may then evolve to muscular rigidity or hypertonicity. Hyperthermia is a symptom that manifests later it can be life-threatening.10 Most cases of serotonin syndrome present within 24 h of a dose increase or initiation of a new serotonergic agent.11
In 2003, Dunkley and others13 undertook to improve the Sternbach criteria, and developed the Hunter serotonin toxicity criteria . According to these criteria, a diagnosis of serotonin syndrome requires the presence of a serotonergic agent and one of the following conditions:
-
clonus
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inducible clonus AND agitation or diaphoresis
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ocular clonus AND agitation or diaphoresis
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tremor AND hyperreflexia
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hypertonicity AND temperature > 38°C AND ocular clonus or inducible clonus
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Noradrenaline Hypothesis Of Depression
Noradrenaline is known to play a role in the regulation of emotions . The deficiency of noradrenaline/norepinephrine mainly produced in the locus coeruleus and affecting certain brain areas such as the prefrontal cortex, the hippocampus or the hypothalamus has been associated with depression . Studies have shown that exposure to chronic stress including early maternal separation decreases noradrenaline levels within the brain leading to depression . This explains why selective norepinephrine re-uptake inhibitors , a new class of antidepressants that work by increasing norepinephrine levels in the brain, have been used to treat depression .
How Is Depression Treated In People With Parkinsons Disease
Depression must be treated differently in people who have Parkinsons disease. Many people can be treated with a type of antidepressant called serotonin reuptake inhibitors . However, some other Parkinsons symptoms may worsen from SSRI use in a very small number of people.
SSRIs shouldnt be taken if youre currently taking selegiline . This is a commonly prescribed medication to control other symptoms of Parkinsons.
If both are taken at once, it could cause serotonin syndrome. Serotonin syndrome occurs when theres excessive nerve cell activity, and it can be fatal. Symptoms can include:
- confusion, disorientation, or hallucinations
- digestive issues like diarrhea or nausea
- rapid heartbeat, or tachycardia
- overactive reflexes, or hyperreflexia
- dilated pupils
Some medications used to treat other symptoms of Parkinsons, like dopamine agonists, may have an antidepressant effect. These appear to be particularly helpful in those who experience periods when their medication isnt effective. This is also known as on-off motor fluctuation.
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Serotonin Dysfunctions Produce Dopamine Loss
Starting from a healthy system, we produced a 5-HT impairment by gradually increasing the ÏDRN parameter, approximating the effects of a DRN neural loss . Figure 4 shows that as we increase the degree of the simulated 5-HT impairment, the DA concentration in the striatum drops down. As a result, the oscillatory component of IP increase , feeding the emergence of an overt tremor . This outcome supports the hypothesis that 5-HT dysfunctions might indirectly contribute to the emergence of tremor.
Figure 4. Dopamine concentration vs. 5-HT release impairments. DAMAGE1 = ÏDRN+ 40% DAMAGE2 = ÏDRN+ 60% DAMAGE3 = ÏDRN+ 80%.
Figure 5. Oscillation induced by 5-HT release impairments. DAMAGE1 = ÏDRN+ 40% DAMAGE2 = ÏDRN+ 60% DAMAGE3 = ÏDRN+ 80%.
Recommendations From Tertiary References
The product monographs for escitalopram, paroxetine, fluoxetine, sertraline, citalopram, and fluvoxamine all recommend avoiding their concurrent use with selective and nonselective MAO inhibitors and separating administration of these drugs by a washout period ranging from 2 to 5 weeks.2126 The product monograph for sertraline reports serious, sometimes fatal reactions with concomitant use of selegiline.24 Various drug interaction references and the product monographs and labels for selegiline and rasagiline reiterate these recommendations.2,4,68,16,17,20,27,28
Table 1Recommendations for Management of the Interaction between MAO-B Inhibitors and SSRIs from Tertiary Sources
Based on the Canadian Network for Mood and Anxiety Treatments 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder,39 SSRIs vary in their overall potential for drugdrug interactions: citalopram and escitalopram have minimal or low potential sertraline has moderate potential and fluoxetine, fluvoxamine, and paroxetine have high potential. Selegiline is also classified as having a higher potential for drugdrug interactions relative to other antidepressants rasagiline is not classified.39 Selegiline is metabolized primarily via the cytochrome P450 isozymes CYP2B6, CYP2C9, CYP3A4, and CYP2A6, whereas rasagiline is metabolized via CYP1A2.40,41
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Environmental Toxins And Parkinsons Disease
Neuronal cell death in PD may also be triggered by exposure to toxic substances or environmental factors which precipitate the symptoms of the disease as they render the brain vulnerable to subsequent physiological chronic stress . The environmental cause of PD mainly refers to exposure to dopaminergic toxins 6-hydroxydopamine , 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine , paraquat and rotenone as these toxins are known to induce formation of reactive oxygen species and oxidative stress which may result in neuronal cell death .
DA is one of the common neurotransmitters present in most parts of the central nervous system . The mesocortical, mesolimbic, nigrostriatal and tubero-infundibular pathways are the four main pathways that play a key role in dopaminergic signaling . DA cannot cross the blood brain barrier, therefore, it is synthesized from tyrosine which is carried into the brain via amino acid transporters . At the dopaminergic neuron level, tyrosine is then converted into dihydroxyphenylalanine by tyrosine hydroxylase then finally into DA by aromatic L-amino acid decarboxylase . DA is then stored in the vesicle until an action potential allows the vesicle to be discharged into the synapse . Monoamine oxidase is the enzyme that is responsible for breaking down excess DA and is known to similarly act on 6-OHDA inducing oxidative stress resulting in apoptosis .
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New Research Puts Serotonin At The Heart Of Parkinsons
In a seminal research paper, published in Lancet Neurology, researchers from King’s College London have used brain scans to uncover early changes in the brain that may happen years before the symptoms of Parkinson’s appear.
The study looked at serotonin signalling in the brains of people with extremely rare genetic mutations that meant they had a very high risk of developing Parkinson’s in the future.
They showed that changes in serotonin signalling may happen in the earliest stages of Parkinson’s – before significant loss of dopamine-producing cells. The changes could also be found ahead of dopamine cell loss in other areas of the brain, as the condition progressed.