Category: Clinical Trial

Randomized, double blind, controlled placebo-phase in trial of low dose phenelzine in the chronic fatigue syndrome

Abstract:

Because of the striking similarity of the clinical manifestations produced by use of the drug reserpine and seen in patients with the chronic fatigue syndrome (CFS), we theorized that CFS was a disorder of reduced central sympathetic drive. Because of the pharmacology of control of this central sympathetic system, we further postulated that CFS symptoms would respond quickly to low dose treatment with a monamine oxidase inhibitor. To test these hypotheses, we designed a randomized, double blind placebo controlled study using phenelzine.

No patient in the trial had a diagnosis of lifetime or current psychiatric disorder and none had depressed mood in the range of clinically depressed patients on a paper and pencil test of depression. Patients in the placebo group received placebo for 6 weeks while those in the drug treatment group were treated in three 2-week segments-placebo, 15 mg phenelzine every other day, and then 15 mg daily. This treatment regimen produced a significant pattern of improvement compared to worsening in 20 self report vehicles of CFS symptoms, illness severity, mood or functional status.

Thus the data support our hypothesis of reduced sympathetic drive, although an alternative hypothesis of pain alleviation is also possible. The study design also allowed us to evaluate patients for a placebo effect: no evidence for this was found, suggesting that CFS is not an illness due to patients’ being overly suggestible.

 

Source: Natelson BH, Cheu J, Pareja J, Ellis SP, Policastro T, Findley TW. Randomized, double blind, controlled placebo-phase in trial of low dose phenelzine in the chronic fatigue syndrome. Psychopharmacology (Berl). 1996 Apr;124(3):226-30. http://www.ncbi.nlm.nih.gov/pubmed/8740043

 

Randomised, double-blind, placebo-controlled study of fluoxetine in chronic fatigue syndrome

Abstract:

BACKGROUND: No somatic treatment has been found to be effective for chronic fatigue syndrome (CFS). Antidepressant therapy is commonly used. Fluoxetine is recommended in preference to tricyclic agents because it has fewer sedative and autonomic nervous system effects. However, there have been no randomised, placebo-controlled, double-blind studies showing the effectiveness of antidepressant therapy in CFS. We have carried out such a study to assess the effect of fluoxetine in depressed and non-depressed CFS patients.

METHODS: In this randomised, double-blind study, we recruited 44 patients to the depressed CFS group, and 52 to the non-depressed CFS group. In each group participants were randomly assigned to receive either fluoxetine (20 mg once daily) or placebo for 8 weeks. The effect of fluoxetine was assessed by questionnaires, self-observation lists, standard neuropsychological tests, and a motion-sensing device (Actometer), which were applied on the day treatment started and on the last day.

FINDINGS: The two groups were well matched in terms of age, sex distribution, employment and marital status, and duration of CFS. There were no significant differences between the placebo and fluoxetine-treated groups in the change during the 8-week treatment period for any dimension of CFS. There was no change in subjective assessments of fatigue, severity of depression, functional impairment, sleep disturbances, neuropsychological function, cognitions, or physical activity in the depressed or the non-depressed subgroup.

INTERPRETATION: Fluoxetine in a 20 mg daily dose does not have a beneficial effect on any characteristic of CFS. The lack of effect of fluoxetine on depressive symptoms in CFS suggests that processes underlying the presentation of depressive symptoms in CFS may differ from those in patients with major depressive disorder.

 

Source: Vercoulen JH, Swanink CM, Zitman FG, Vreden SG, Hoofs MP, Fennis JF, Galama JM, van der Meer JW, Bleijenberg G. Randomised, double-blind, placebo-controlled study of fluoxetine in chronic fatigue syndrome. Lancet. 1996 Mar 30;347(9005):858-61. http://www.ncbi.nlm.nih.gov/pubmed/8622391

 

Cognitive behaviour therapy for the chronic fatigue syndrome: a randomized controlled trial

Abstract:

OBJECTIVE: To evaluate the acceptability and efficacy of adding cognitive behaviour therapy to the medical care of patients presenting with thechronic fatigue syndrome.

DESIGN: Randomised controlled trial with final assessment at 12 months.

SETTING: An infectious diseases outpatient clinic.

SUBJECTS: 60 consecutively referred patients meeting consensus criteria for the chronic fatigue syndrome.

INTERVENTIONS: Medical care comprised assessment, advice, and follow up in general practice. Patients who received cognitive behaviour therapy were offered 16 individual weekly sessions in addition to their medical care.

MAIN OUTCOME MEASURES: The proportions of patients (a) who achieved normal daily functioning (Karnofsky score 80 or more) and (b) who achieved a clinically significant improvement in functioning (change in Karnofsky score 10 points or more) by 12 months after randomisation.

RESULTS: Only two eligible patients refused to participate. All randomised patients completed treatment. An intention to treat analysis showed that 73% (22/30) of recipients of cognitive behaviour therapy achieved a satisfactory outcome as compared with 27% (8/30) of patients who were given only medical care (difference 47 percentage points; 95% confidence interval 24 to 69). Similar differences were observed in subsidiary outcome measures. The improvement in disability among patients given cognitive behaviour therapy continued after completion of therapy. Illness beliefs and coping behaviour previously associated with a poor outcome changed more with cognitive behaviour therapy than with medical care alone.

CONCLUSION: Adding cognitive behaviour therapy to the medical care of patients with the chronic fatigue syndrome is acceptable to patients and leads to a sustained reduction in functional impairment.

Comment in:

Cognitive behaviour therapy for the chronic fatigue syndrome. Good general care may offer as much benefit as cognitive behaviour therapy. [BMJ. 1996]

Cognitive behaviour therapy for the chronic fatigue syndrome. Patients were not representative of all patients with the syndrome. [BMJ. 1996]

Cognitive behaviour therapy for the chronic fatigue syndrome. Cognitive behavior therapy should be compared with placebo treatments. [BMJ. 1996]

ACP J Club. 1996 May-Jun;124(3):71.

Cognitive behaviour therapy for the chronic fatigue syndrome. Use an interdisciplinary approach. [BMJ. 1996]

Cognitive behaviour therapy for the chronic fatigue syndrome. Patients’ beliefs about their illness were probably not a major factor. [BMJ. 1996]

Cognitive behaviour therapy for the chronic fatigue syndrome. Evening primrose oil and magnesium have been shown to be effective. [BMJ. 1996]

Cognitive behaviour therapy for the chronic fatigue syndrome. Essential elements of the treatment must be identified. [BMJ. 1996]

 

Source: Sharpe M, Hawton K, Simkin S, Surawy C, Hackmann A, Klimes I, Peto T, Warrell D, Seagroatt V. Cognitive behaviour therapy for the chronic fatigue syndrome: a randomized controlled trial. BMJ. 1996 Jan 6;312(7022):22-6. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2349693/

Note: You can read the full article here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2349693/pdf/bmj00523-0026.pdf

 

 

Lessons from a pilot study of transfer factor in chronic fatigue syndrome

Abstract:

Transfer Factor (TF) was used in a placebo controlled pilot study of 20 patients with chronic fatigue syndrome (CFS). Efficacy of the treatment was evaluated by clinical monitoring and testing for antibodies to Epstein-Barr virus (EBV) and human herpes virus-6 (HHV-6). Of the 20 patients in the placebo-controlled trial, improvement was observed in 12 patients, generally within 3-6 weeks of beginning treatment. Herpes virus serology seldom correlated with clinical response. This study provided experience with oral TF, useful in designing a larger placebo-controlled clinical trial.

 

Source: De Vinci C, Levine PH, Pizza G, Fudenberg HH, Orens P, Pearson G, Viza D. Lessons from a pilot study of transfer factor in chronic fatigue syndrome. Biotherapy. 1996;9(1-3):87-90. http://www.ncbi.nlm.nih.gov/pubmed/8993764

 

alpha-Interferon treatment of patients with chronic fatigue syndrome

Abstract:

Thirty patients who fulfilled clinical criteria defined by the CDC for Chronic Fatigue Syndrome were treated with alfa 2a interferon or placebo in a double-blind crossover study. Outcome was evaluated by Natural Killer (NK) cell function, lymphocyte proliferation to mitogens and soluble antigens, CD4/CD8 counts and a 10 item Quality of Life (QOL) survey.

Although mean NK function rose from 87.8 +/- 19.6 to 129.3 +/- 20.7 lytic untis (LU; p < .05) with 12 weeks of interferon therapy, there was no significant change in the other immunologic parameters or QOL scores. When the 26 patients who completed the study were stratified according to their baseline NK function and lymphocyte proliferation, 4 groups were identified: 3 patients had normal NK cell function and lymphocyte proliferation when compared to normal, healthy controls, 9 had isolated deficiency in lymphocyte proliferation, 7 had diminished NK function only, and 7 had abnormalities for both parameters.

QOL scores were not significantly different for the four groups at baseline. After 12 weeks of interferon therapy, QOL score significantly improved in each of the seven patients with isolated NK cell dysfunction (mean score, 16.3 +/- 7.9) compared to baseline (39.7 +/- 12.1; p < .05). In these patients the mean NK function increased from 35.1 +/- 11.7 to 91.5 +/- 22.7 LU (p < .01). Significant improvement was not recorded for QOL in the other three groups. Thus, therapy with alpha interferon has a significant effect on the QOL of that subgroup of patients with CFS manifesting an isolated decrease in NK function.

 

Source: See DM, Tilles JG. alpha-Interferon treatment of patients with chronic fatigue syndrome. Immunol Invest. 1996 Jan-Mar;25(1-2):153-64. http://www.ncbi.nlm.nih.gov/pubmed/8675231

 

Double-blind placebo-controlled study of the efficacy of oral terfenadine in the treatment of chronic fatigue syndrome

Abstract:

BACKGROUND: There is no established treatment for chronic fatigue syndrome (CFS), an illness characterized by disabling fatigue exacerbated by physical activity. A variety of immunologic abnormalities have been reported, including a high incidence of atopy and hypoergy or anergy.

OBJECTIVE: Because of anecdotal reports and uncontrolled trials showing antihistamine efficacy in CFS, we evaluated the clinical efficacy of the antihistamine terfenadine (60 mg twice daily) in a placebo-controlled study.

METHODS: Thirty patients with CFS were enrolled in a 2-month, double-blind, placebo-controlled trial of terfenadine. Participants underwent a battery of both immediate- and delayed-type hypersensitivity skin tests and completed a self-assessment questionnaire used to measure severity of symptoms, physical and social functioning, health perceptions, and mental health before each of six biweekly visits.

RESULTS: Twenty-eight patients completed the trial. History of atopy and positive immediate skin test results were prevalent, 73% and 53%, respectively. No evidence for hypoergy or anergy after delayed-type hypersensitivity skin testing was found. No therapeutic benefit from terfenadine could be detected in terms of symptom amelioration, improved physical or social functioning, health perceptions, or mental health. A high incidence of atopy in patients with CFS was confirmed.

CONCLUSION: Although this trial involved a small number of patients, the results suggest that terfenadine is unlikely to be of clinical benefit in treating CFS symptoms.

 

Source: Steinberg P, McNutt BE, Marshall P, Schenck C, Lurie N, Pheley A, Peterson PK. Double-blind placebo-controlled study of the efficacy of oral terfenadine in the treatment of chronic fatigue syndrome. J Allergy Clin Immunol. 1996 Jan;97(1 Pt 1):119-26. http://www.ncbi.nlm.nih.gov/pubmed/8568124

 

Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome

Abstract:

Levels of 2′,5′-oligoadenylate (2-5A) synthetase, bioactive 2-5A, and RNase L were measured in extracts of peripheral blood mononuclear cells (PBMCs) from 15 individuals with chronic fatigue syndrome (CFS) before and during therapy with the biological response modifier poly(I).poly(C12U) and were compared with levels in healthy controls.

Patients differed significantly from controls in having a lower mean basal level of latent 2-5A synthetase (P < .0001), a higher pretreatment level of bioactive 2-5A (P = .002), and a higher level of pretherapy RNase L activity (P < .0001). PBMC extracts from 10 persons with CFS had a mean basal level of activated 2-5A synthetase higher than the corresponding control value (P = .009). All seven pretherapy PBMC extracts tested were positive for the replication of human herpesvirus 6 (HHV-6).

Therapy with poly(I).poly(C12U) resulted in a significant decrease in HHV-6 activity (P < .01) and in downregulation of the 2-5A synthetase/RNase L pathway in temporal association with clinical and neuropsychological improvement. The upregulated 2-5A pathway in CFS before therapy is consistent with an activated immune state and a role for persistent viral infection in the pathogenesis of CFS. The response to therapy suggests direct or indirect antiviral activity of poly(I).poly(C12U) in this situation.

 

Source: Suhadolnik RJ, Reichenbach NL, Hitzges P, Sobol RW, Peterson DL, Henry B, Ablashi DV, Müller WE, Schröder HC, Carter WA, et al. Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome. Clin Infect Dis. 1994 Jan;18 Suppl 1:S96-104. http://www.ncbi.nlm.nih.gov/pubmed/8148461

 

A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a physically debilitating illness associated with immunologic abnormalities, viral reactivation, and impairment of cognition.

In a randomized, multicenter, placebo-controlled, double-blind study of 92 patients meeting the CFS case definition of the Centers for Disease Control and Prevention, the response of several laboratory and clinical variables to an antiviral and immunomodulatory drug, poly(I).poly(C12U), was determined.

Measures of clinical response included Karnofsky performance score, a cognition scale derived from a self-administered instrument assessing symptomatology (SCL-90-R), an activities of daily living scale, and exercise treadmill performance.

After 24 weeks, patients receiving poly(I).poly(C12U) had higher scores for both global performance and perceived cognition than did patients receiving placebo. In particular, patients given poly(I).poly(C12U) had increased Karnofsky performance scores (P < .03), exhibited a greater ability to do work during exercise treadmill testing (P = .01), displayed an enhanced capacity to perform the activities of daily living (P < .04), had a reduced cognitive deficit (P = .05), and required less use of other medications (P < .05).

 

Source: Strayer DR, Carter WA, Brodsky I, Cheney P, Peterson D, Salvato P, Thompson C, Loveless M, Shapiro DE, Elsasser W, et al. A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome. Clin Infect Dis. 1994 Jan;18 Suppl 1:S88-95. http://www.ncbi.nlm.nih.gov/pubmed/8148460

 

Immunologic and psychologic therapy for patients with chronic fatigue syndrome: a double-blind, placebo-controlled trial

Abstract:

PURPOSE: To evaluate the potential benefit of immunologic therapy with dialyzable leukocyte extract and psychologic treatment in the form of cognitive-behavioral therapy (CBT) in patients with chronic fatigue syndrome (CFS).

PATIENTS AND METHODS: Immunologic and psychologic treatments were administered to 90 adult patients who fulfilled diagnostic criteria for CFS in a double-blind, randomized, and placebo-controlled study. A four-cell trial design allowed the assessment of benefit from immunologic and psychologic treatment individually or in combination. Outcome was evaluated by measurement of global well-being (visual analogue scales), physical capacity (standardized diaries of daily activities), functional status (Karnofsky performance scale), and psychologic morbidity (Profile of Mood States questionnaire), and cell-mediated immunity was evaluated by peripheral blood T-cell subset analysis and delayed-type hypersensitivity skin testing.

RESULTS: Neither dialyzable leukocyte extract nor CBT (alone or in combination) provided greater benefit than the nonspecific treatment regimens.

CONCLUSIONS: In this study, patients with CFS did not demonstrate a specific response to immunologic and/or psychologic therapy. The improvement recorded in the group as a whole may reflect both nonspecific treatment effects and a propensity to remission in the natural history of this disorder.

Comment in:

Treatment for chronic fatigue syndrome. [Am J Med. 1994]

Cognitive behavior therapy for chronic fatigue syndrome. [Am J Med. 1995]

Cognitive behavior therapy for chronic fatigue syndrome. [Am J Med. 1995]

 

Source: Lloyd AR, Hickie I, Brockman A, Hickie C, Wilson A, Dwyer J, Wakefield D. Immunologic and psychologic therapy for patients with chronic fatigue syndrome: a double-blind, placebo-controlled trial. Am J Med. 1993 Feb;94(2):197-203. http://www.ncbi.nlm.nih.gov/pubmed/8430715

 

Bupropion treatment of fluoxetine-resistant chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) includes many symptoms of major depression. For this reason, many antidepressants have been used to treat the symptoms of this disorder. Among the more recently released antidepressants are fluoxetine and bupropion.

In this open study, nine CFS patients who either could not tolerate or did not respond to fluoxetine showed significant response when administered 300 mg/day of bupropion for an 8-week period in both rating of HDRS (t = 4.80, p < 0.01) and BDI (t = 2.48, p < 0.05). Furthermore, bupropion improvement in Hamilton Depression Rating Scale correlated significantly with change in plasma homovanillic acid (HVA) (r = 0.96, p < 0.01).

Plasma total methylhydroxyphenolglycol (MHPG) also increased significantly during bupropion treatment (t = 2.37, p = 0.05). Measures of T1 microsomal antibodies also decreased over treatment time; increases in natural killer cell numbers correlated inversely with change in plasma levels of free MHPG (r = -0.88, p < 0.05). Bupropion responders were more likely to have trough blood levels above 30 ng/ml (chi 2 = 3.6, p = 0.05).

 

Source: Goodnick PJ, Sandoval R, Brickman A, Klimas NG. Bupropion treatment of fluoxetine-resistant chronic fatigue syndrome. Biol Psychiatry. 1992 Nov 1;32(9):834-8. http://www.ncbi.nlm.nih.gov/pubmed/1450297