Abstract
There is increasing interest in clinical psychiatry in those syndromes dominated by the symptom complex of chronic fatigue, neurocognitive disturbance, sleep disorder, musculoskeletal aches and pains, and affective symptoms [1, [2], [3], [4], [5], [6]]. Currently, the treatment of neurasthenia and/or chronic fatigue syndrome (CFS) remains controversial [3, [4], [5], [6], [7]]. Unfortunately, patients are often exposed to either unproven medical or alternative medicine interventions (see [6]). By contrast, systematic reviews highlight the potential benefits of cognitive-behavioural approaches and recommend more evaluation of relevant psychotropic agents [3, [4], [5], [6], [7]]. To date, selective serotonin re-uptake inhibitors (SSRIs) have not proved useful [8, [9]] but the reversible inhibitor of monoamine oxidase-A (moclobemide), appears to offer some benefits [8, [10], [11]]. Low doses of tricyclic antidepressants in combination with nonsteroidal anti-inflammatory agents have been shown to benefit patients with the closely related syndrome of fibromyalgia [12].
Nefazodone, a novel antidepressant agent which is a weak inhibitor of serotonin re-uptake and selectively antagonises the 5HT-2 receptor, has a number of clinical features which suggest it may provide some benefits to patients with CFS. First, patients with CFS report considerable sleep disturbance usually in the form of frequent awakenings [13]. It is thought that many of the mood, neurocognitive and musculoskeletal symptoms of CFS are secondary to sleep disturbance [13]. Interestingly, SSRIs, which have not been helpful in these patients, may result in increased awakenings in the early phase of treatment [14]. Nefazodone appears to have a rapid onset in terms of decreased awakening in patients with depressive disorders [15]. Second, patients with CFS have high rates of concurrent affective disturbance, usually in the form of irritable rather than depressed mood and associated generalized anxiety [1, [2], [3], [4], [5], [6]]. Nefazodone is an effective antidepressant with a rapid onset of anxiolysis [16, [17], [18]].
Therefore, an open evaluation of nefazodone in patients with CFS, particularly those who had failed to respond to moclobemide and/or reported significant sleep disturbance was undertaken within a specialist psychiatrist practice. Patients attending this practice are also instructed in the use of appropriate behavioural methods to gradually increase their level of physical and social activity and to help correct distortions of their sleep–wake cycle (see [3, [4], [5], [6]]).
Method
Patients are frequently referred to this specialist psychiatrist practice for evaluation of chronic fatigue states. Most have been assessed previously by a specialist immunology or infectious disease physician with experience in medical evaluation and treatment of these disorders. If patients do come direct from a family practitioner then they are further evaluated to ensure that no other medical disorder is likely to account for their condition (see [6]). Patients were included in this evaluation if they met international criteria for CFS [19] and had already failed to respond to moclobemide (or another appropriate antidepressant therapy) and/or reported marked sleep disturbance (particularly with frequent nocturnal awakenings). A past or current history of mood disorder was noted for each patient.
Nefazodone was introduced very slowly to these patients, typically commencing at 50 mg at night for three nights followed by 50 mg twice daily or 100 mg at night for 1 week. If patients did not experience an exacerbation of daytime somnolence then the dose was typically increased by 100 mg per week until they reached a total daily dose of at least 300 mg. If patients experienced increased daytime somnolence then they were continued on nocturnal dosing with dose increases generally limited to 50 mg per week. Outcome was then assessed after 6 weeks by means of clinical global ratings of key symptom dimensions of fatigue, sleep disturbance and mood disturbance (1, made worse; 2, no improvement; 3, mild improvement only; 4, moderate improvement; 5, marked improvement or complete recovery). The overall functional outcome was rated in a similar fashion.
Methods
Five males and five female patients with a mean age of 47.5 ± 15 (range == 28–82) years were treated with nefazodone for at least 6 weeks. Four patients had a clear past history of affective disorder, while six had sufficient symptoms to justify a concurrent diagnosis of major depression. Six of the patients reported marked nocturnal sleep disturbance not due to any other specific sleep disorder. Seven of the patients had previously failed to respond to moclobemide, while seven had previously been treated with other conventional antidepressant therapy. The mean dose of nefazodone was 370 mg (range == 200–800 mg/day), with a strong preference for nocturnal dosing. One patient discontinued therapy after 4 weeks due to increased somnolence (200 mg/day). All other patients reached the 6-week assessment point. The mean duration of treatment for all patients was 20.8 (range == 4–40) weeks.
Of the 10 patients, eight (80%) reported at least some improvement in the key symptom of fatigue, with four (40%) reporting moderate or marked improvement in this defining feature. The other key symptoms assessed showed a similar pattern with sleep disturbance being improved moderately or markedly in seven (70%), while mood was similarly improved in eight (80%). Five of the patients (50%) achieved at least a moderate improvement in overall functional outcome and were able to return to work or their previous level of role function. Two patients showed no improvement on any of the assessment parameters (with one ceasing treatment at 4 weeks).
Discussion
Nefazodone appears to provide benefits for some of the key features of CFS and to result in sustained functional improvement in at least a subgroup of patients. Improvements in quality of sleep (with decreased awakenings reported most frequently) and mood instability were characteristic of those with the best response. The improved sleep was associated with a reduction in daytime fatigue and assisted with the behavioural program designed to normalise the sleep-wake cycle distortions (i.e. reduction of both prolonged nocturnal sleeping and sleeping during the day). Although mood was substantially improved in this study, the improvement in fatigue and/or sleep did not appear to be secondary to an antidepressant effect. Seven of the patients had failed to respond previously to conventional antidepressant therapy and seven, specifically, to our preferred agent for the combination of fatigue and depression (i.e. moclobemide) [8, [10], [11]].
In this open study, patients were also instructed in a range of behavioural principles that are of benefit to patients with CFS [3, [4], [5], [6]]. This may have led to a greater apparent functional response than would be predicted from trials of other antidepressant therapies [8, [9], [10], [11]]. As in all open studies, other non-specific treatment effects are likely to be large. Nefazodone, however, appears to be worthy of more formal evaluation in patients with CFS. Ideally, this would occur within a trial design that evaluates the additional effect of behavioural measures designed to normalise the sleep-wake cycle of these patients.
Footnotes
Acknowledgements
The editorial assistance of Tracey Davenport is greatly appreciated.