fluoxetine – American ME and CFS Society

Central 5-HTergic hyperactivity induces myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)-like pathophysiology

Abstract:

Objectives: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a significant medical challenge, with no indisputable pathophysiological mechanism identified to date.

Methods: Based on clinical clues, we hypothesized that 5-hydroxytryptamine (5-HT) hyperactivation is implicated in the pathogenic causes of ME/CFS and the associated symptoms. We experimentally evaluated this hypothesis in a series of mouse models.

Results: High-dose selective serotonin reuptake inhibitor (SSRI) treatment induced intra- and extracellular serotonin spillover in the dorsal raphe nuclei of mice. This condition resulted in severe fatigue (rota-rod, fatigue rotating wheel and home-cage activity tests) and ME/CFS-associated symptoms (nest building, plantar and open field test), along with dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis response to exercise challenge. These ME/CFS-like features induced by excess serotonin were additionally verified using both a 5-HT synthesis inhibitor and viral vector for Htr1a (5-HT_1A receptor) gene knockdown.

Conclusions: Our findings support the involvement of 5-HTergic hyperactivity in the pathophysiology of ME/CFS. This ME/CFS-mimicking animal model would be useful for understanding ME/CFS biology and its therapeutic approaches.

Source: Lee JS, Kang JY, Park SY, Hwang SJ, Bae SJ, Son CG. Central 5-HTergic hyperactivity induces myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)-like pathophysiology. J Transl Med. 2024 Jan 8;22(1):34. doi: 10.1186/s12967-023-04808-x. PMID: 38191373. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04808-x (Full text)

Amisulpride vs. fluoxetine treatment of chronic fatigue syndrome: a pilot study

Abstract:

Different pharmacologic agents have been evaluated in the treatment of Chronic Fatigue Syndrome (CFS), albeit with moderate efficacy. Among the compounds thought to present with potential to be efficacious in CFS patients stands out low-dose amisulpride, a substituted benzamide that has been shown to be an useful treatment for conditions which exhibit some overlap with CFS such as dysthymia and somatoform disorders.

We thus recruited forty non-depressed CFS patients that were randomized to receive either amisulpride 25mg bid, or fluoxetine 20mg uid; all subjects were un-blinded to the treatment regimen. At the time of enrollment in the study and after twelve weeks of treatment, enrolled subjects completed the Krupp Fatigue Severity Scale, the Hospital Anxiety and Depression Scale and a visual analog scale focused on pain and bodily discomfort. Moreover, all subjects were evaluated by a clinician, blinded to the treatment regimen, using the Clinical Global Impression Severity Scale.

Our data revealed a significant improvement both in self-report, and observer-based measures for the amisulpride-treated, but not for the fluoxetine-treated patients. Amisulpride-treated subjects also presented with a significant reduction of somatic complaints, while the amisulpride effect on anxiety and mood levels was not significant. Both drugs were equally well tolerated.

Summing up, we showed a positive symptomatic effect of amisulpride, compared to SSRI treatment, in a group of non-depressed CSF patients on self-report and on observer-based measures of fatigue and somatic complaints. If confirmed by larger, blinded studies, amisulpride thus could represent an effective approach to this difficult-to-treat condition.

Source: Pardini M, Guida S, Primavera A, Krueger F, Cocito L, Gialloreti LE. Amisulpride vs. fluoxetine treatment of chronic fatigue syndrome: a pilot study. Eur Neuropsychopharmacol. 2011 Mar;21(3):282-6. doi: 10.1016/j.euroneuro.2010.10.008. Epub 2010 Nov 26. https://www.ncbi.nlm.nih.gov/pubmed/21112746

Randomised, double-blind, placebo-controlled treatment trial of fluoxetine and graded exercise for chronic fatigue syndrome

Erratum in: Br J Psychiatry 1998 Jul;173:89.

Abstract:

BACKGROUND: The Joint Working Group of the Royal Colleges of Physicians, Psychiatrists and General Practitioners (1996) recommended graded exercise and antidepressants for patients with chronic fatigue syndrome. We assessed efficacy and acceptability of these treatments.

METHOD: Six-month prospective randomised placebo and therapist contact time controlled trial with allocation to one of four treatment cells: exercise and 20 mg fluoxetine, exercise and placebo drug, appointments only and 20 mg fluoxetine, appointments and placebo drug. Drug treatment was double blind and patients were blind to assignment to exercise or appointments.

RESULTS: Ninety-six (71%) of 136 patients completed the trial. Patients were more likely to drop out of exercise than non-exercise treatment (P = 0.05). In an intention to treat analysis, exercise resulted in fewer patients with case level fatigue than appointments only at 26 weeks (12 (18%) v. 4 (6%) respectively P = 0.025) and improvement in functional work capacity at 12 (P = 0.005) and 26 weeks (P = 0.03). Fluoxetine had a significant effect on depression at week 12 only (P = 0.04). Exercise significantly improved health perception (P = 0.012) and fatigue (P = 0.028) at 28 weeks.

CONCLUSIONS: Graded exercise produced improvements in functional work capacity and fatigue, while fluoxetine improved depression only.

Comment in:

Commentary on: randomised, double-blind, placebo-controlled trial of fluoxetine and graded exercise for chronic fatigue syndrome. [Br J Psychiatry. 1998]

Analysis of drop-out data in treatment trials. [Br J Psychiatry. 1998]

Fluoxetine and graded exercise in chronic fatigue syndrome. [Br J Psychiatry. 1998]

Source: Wearden AJ, Morriss RK, Mullis R, Strickland PL, Pearson DJ, Appleby L, Campbell IT, Morris JA. Randomised, double-blind, placebo-controlled treatment trial of fluoxetine and graded exercise for chronic fatigue syndrome. Br J Psychiatry. 1998 Jun;172:485-90. http://www.ncbi.nlm.nih.gov/pubmed/9828987

Fibromyalgia, chronic fatigue syndrome, and myofascial pain

Abstract:

Epidemiologic studies continue to provide evidence that fibromyalgia is part of a spectrum of chronic widespread pain. The prevalence of chronic widespread pain is several times higher than fibromyalgia as defined by the 1990 American College of Rheumatology guidelines. There is now compelling evidence of a familial clustering of fibromyalgia cases in female sufferers; whether this clustering results from nature or nature remains to be elucidated. A wide spectrum of fibromyalgia-associated symptomatology and syndromes continues to be described.

During the past year the association with interstitial cystitis has been explored, and neurally mediated hypotension has been documented in both fibromyalgia and chronic fatigue syndrome. Abnormalities of the growth hormone-insulin-like growth factor-1 axis have been also documented in both fibromyalgia and chronic fatigue syndrome. The commonly reported but anecdotal association of fibromyalgia with whiplash-type neck trauma was validated in a report from Israel. However, unlike North America, 100% of Israeli patients with posttraumatic fibromyalgia returned to work.

Basic research in fibromyalgia continues to pinpoint abnormal sensory processing as being integral to understanding fibromyalgia pain. Drugs such as ketamine, which block N-methyl-D-aspartate receptors (which are often upregulated in central pain states) were shown to benefit fibromyalgia pain in an experimental setting. The combination of fluoxetine and amitriptyline was reported to be more beneficial than either drug alone in patients with fibromyalgia.

A high prevalence of autoantibodies to cytoskeletal and nuclear envelope proteins was found in chronic fatigue syndrome, and an increased prevalence of antipolymer antibodies was found in symptomatic silicone breast implant recipients who often have fibromyalgia.

Source: Bennett R. Fibromyalgia, chronic fatigue syndrome, and myofascial pain. Curr Opin Rheumatol. 1998 Mar;10(2):95-103. http://www.ncbi.nlm.nih.gov/pubmed/9567202

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

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