| NEUROSCIENCE | PEER-REVIEW 5-HTP (the rate-limiting step in serotonin synthesis)


can be inhibited by stress, insulin resistance, magnesium or vitamin B6 deficiency, or increasing age. The decarboxylation of 5-HTP to serotonin is dependent on the presence of P5P. P5P is also a cofactor in the synthesis of DOPA to dopamine, in the pathway converting tyrosine to adrenaline and noradrenaline.


Methylcobalamin (vitamin B12) Stress disrupts the circadian rhythmic secretion of cortisol. Methylcobalamin in conjunction with light helps to reset the circadian rhythm secondary to stress and its impact on cortisol. It does not impact total levels of cortisol, but evidence suggests it helps shift the cortisol secretion peak, and maintain the normal cortisol rhythm.


5-methyltetrahydrofolate (active folate) Tetrahydrobiopterin BH4 is a nutrient cofactor essential for the formation of the monoamine neurotransmitters serotonin, dopamine, noradrenaline, and adrenaline. BH4 acts as a rate-limiting enzyme cofactor to the hydroxylase enzymes that metabolise tryptophan to 5-hydroxytryptophan, phenylalanine to tyrosine, and tyrosine to dopa. Folate helps in regenerating (BH4), which is highly susceptible to oxidation.


Ascorbic acid (vitamin C) Ascorbic acid is another cofactor involved in monoamine neurotransmitter synthesis. It is also a cofactor and a stabiliser of BH4, so protects BH4 from oxidation as well as increasing the levels of BH4. Ascorbic acid can support adrenal function and decrease high cortisol levels. Administration of ascorbic acid improved the capacity of the adrenals to adapt to surgical stress by normalising cortisol and ACTH in patients with lung cancer. Ascorbic acid given orally (1 g three times per day) also buffered exogenous ACTH-induced increases in cortisol, although it had no significant effect on fasting cortisol levels.


Hormones Hydrocortisone/cortisol In some research35,36


Key points


■ Fatigue is commonly attributed to a variety of causes such as immunological, genetic, post-viral and even neuropsychological, but definitive evidence is still lacking


■ Acute stress or delayed effects of chronic stress and related conditions are significant reasons for patients ro visit primary care physicians. This can account for up to 75–90% of cases


■ As the majority of patients complain of fatigue, tiredness and inability to perform day-to-day activities, the management is targeted towards reducing the impact of stress, balancing the energy metabolism, and maintaining the normal levels of neurotransmitters and adrenal hormones


■ Stress is inevitable, but the consequences of stress are modifiable if the pathophysiologic basis of effects of stress and fatigue are well understood, and enough education and support is provided to the patient


it has been suggested that burnout


or chronic fatigue may be a mild form of AddisonÕs disease (adrenal insufficiency or hypoadrenalism). This is also favoured by the fact that fatigue improves with the supplementation of mineralocorticoids (fludrocortisone) or low-dose hydrocortisone (cortisol). Another study37–39 suggested that CFS may be associated with low serum cortisol and high 5-HT function. Hydrocortisone treatment in fatigue patients has


shown benefit in many studies. In one study, 1 month of low-dose hydrocortisone therapy significantly improved the fatigue of CFS patients (n=32)40


. In 28% (n=9) the score


became similar to the one of normal subjects. No adrenal suppression occurred in those low-dosed patients (at the insulin tolerance test). In another similar study41


hydrocortisone-treated


patients had a greater improvement in mean wellness score, a greater percentage recording an improvement of 5 or more points in wellness score, and a higher average


Ascorbic acid


is another cofactor involved in monoamine neurotransmitter synthesis.


improvement in wellness score in more days than placebo recipients. (Hydrocortisone 16 mg/m 2


= 20–30 mg


at 8am, 5 mg at 2pm over 12 weeks leading 30% net increase in daily cortisol exposure.)


DHEA In a study by Kuratsune et al42


, DHEA was shown to


improve energy levels in cases of chronic fatigue. Another study found that DHEA levels were lower in fatigue patients as compared with healthy control subjects. DHEA-S was found to be low in depressed patients. In a similar study43


have a blunted serum DHEA response curve after injecting ACTH. This suggests therapeutic as well as diagnostic use of DHEA in fatigue management.


Melatonin Melatonin, the primary hormone of the pineal gland, maintains normal circadian rhythms. In patients with sleep disorders and altered circadian rhythms, such as jet lag, night shift work, and a variety of neuropsychiatric disorders, oral administration of melatonin can provide the necessary resynchronisation of those cycles. When administered in pharmacological doses, melatonin maintains synchronicity. As the hours of highest melatonin secretion correlate with normal hours of sleep, it has been investigated for use in sleep disorders. Studies have demonstrated that patients with insomnia have decreased nocturnal melatonin secretion. In a placebo-controlled trial44


of eight subjects with


delayed sleep-phase insomnia, it was found that melatonin acts as a Ôphase-setterÕ for sleepÐ wake cycles. Subjects were given placebo or melatonin (5 mg nightly at 10pm) for 4 weeks with a 1-week washout period before crossing to the other treatment, and were allowed to wake naturally. In all subjects, the onset of sleep occurred earlier during melatonin treatment (mean change of 82 minutes; P<0.01); there was also a slight decrease in the total amount of time asleep. Similar results were obtained by another group of researchers who administered 5 mg of melatonin nightly to six subjects with delayed sleep-phase insomnia. The onset of sleep was an average of 115 minutes earlier when taking melatonin compared with pre-melatonin findings. Over the past 10 years, a number of randomised,


controlled trials support melatoninÕs effectiveness for improving aspects of normal sleep.


Management There are no standard guidelines or set treatment protocols for the management of fatigue. Once the provisional diagnosis is made on the basis of history and exclusion of other possible causes, the management should be started, and should include lifestyle management, cognitive behavioural therapy, sleep hygiene, supervised


exercise, and pharmacological support to balance the HPA axis. As the majority of patients complain of fatigue, tiredness and inability to perform day-to-day activities, the management is targeted


prime-journal.com | January/February 2013 ❚ 61


CFS patients were found to


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92