It needs to be emphasized that these drugs are helpful not because patients are primarily depressed (although depression may occur as a result of the illness), but because they often have low levels of the neurotransmitters serotonin and dopamine.⁴

I find that almost all of my patients benefit from treatment with antidepressants. The chart at this link is not intended to be comprehensive, but rather to represent classes of drugs that may be helpful. Following is a brief discussion of research on the benefits of antidepressants and the process that I use when deciding which drug to try with a patient.

Review of Research
A small number of trials have been conducted to assess the possible value of antidepressants for CFS, and for the most part have provided evidence of their usefulness in treating specific symptoms.

A minority of patients in a six-week treatment study of Nardil (phenelzine), a monoamine oxidase inhibitor (MAOI), reported significant improvement, although some had to drop out of the trial due to side effects.¹ Trials of Manerix (moclobemide), another MAOI, with CFS patients have showed significant reductions in fatigue.^3,4 Unfortunately, moclobemide is not available in the United States.

Pamelor (nortriptyline), a tricyclic antidepressant (TCA), was tested in a single-case, double-blind study for CFS. A 60 mg-per day dose significantly reduced CFS symptom scores.⁵ In controlled trials, TCAs have also proven beneficial in the treatment of fibro-myalgia (FM), an illness that shares many clinical features with CFS.⁶

Despite encouraging results from earlier case studies, a trial of Prozac (fluoxetine) conducted in the Netherlands with 44 CFS patients with concomitant depression and 52 with CFS but no evidence of depression failed to show significant beneficial effects. The researchers suggested that the fact that even the depressed group failed to improve indicates chemical changes in the brain in CFS that are very dissimilar to depression.⁷

In an uncontrolled trial, 79 patients with CFS who showed no signs of depression reported seeing major improvement (particularly regarding levels of fatigue, muscle pain and sleep disturbance) after treatment with Zoloft (sertraline).⁸

Antidepressants may also benefit the immune system in CFS. Dr. Nancy Klimas at the University of Miami has studied the effect of selective serotonin reuptake inhibitors (SSRIs) on the immune system. She has reported that CFS patients given Prozac for three months showed moderate to marked improvement in the number of natural killer cells present.⁹

Choosing the Right Drug
The first question I ask when deciding which antidepressant to prescribe for a CFS patient is whether the individual is having difficulty sleeping. Three drugs listedin the chart at this link, Desyrel (trazadone), Remeron (mirtazapine) and Serzone (nefazadone) are more sedating and may be useful in assisting sleep. Desyrel in particular increases stage 3 and 4 (or "deep") sleep.

Wellbutrin (bupropion), Prozac and Zoloft are more activating drugs in terms of increasing CFS patients' perceived energy levels, but they may actually interfere with deep sleep. Some stimulating drugs may also increase the risk of seizure activity by causing hyperexcitability in the central nervous system.

Pain control is another factor that I consider. TCAs increase levels of norepinephrine in the central nervous system, which will increase the patient's pain threshold. This is why Elavil (amitriptyline) is often used to treat FM and CFS. However, while Elavil has a soporific effect, it reduces deep sleep and in the long run may not be the best choice for patients having trouble sleeping. Effexor (venlafaxine) is a serotonin and norepinephrine reuptake inhibitor that mayalso increase the pain threshold.

Wellbutrin is the first antidepressant on the market to increase levels of the neurotransmitter dopamine, which is typically "balanced" with serotonin in the brain. If a patient has tried serotonin agonists and does not tolerate them well, then Wellbutrin may be a good choice. Wellbutrin may be taken alone or with other antidepressants.

Remeron is another unique drug in that it affects alpha 2 receptors and histamine receptors in the brain. At lower doses (7.5 to 30 mg), the histaminic effect can induce sleep. Starting at 30 mg, the alpha 2 effect appears, which can give patients increased energy levels. Clinicians should be aware that 30 mg is the highest recommended dose according to the manufacturer, although psychiatrists occasionally prescribe45 or 60 mg doses.

The histaminic effect of Remeron can stimulate appetite, so patients on low-dose therapy with this drug usually gain weight rapidly. Clinicians may want to use Remeron only with individuals who are low weight or losing weight.

If the patient has neurally mediated hypotension or orthostatic intolerance, which can cause fluctuations in blood pressure and heart rate, clinicians may want to choose an antidepressant that can improve those symptoms as well. Prozac, Zoloft and Paxil (paroxetine) have been shown in controlled, blinded studies to improve autonomic function.

Antidepressant drugs have been associated with numerous side effects. Wellbutrin, Desyrel, Remeron and Serzone show the least incidence of sexual dysfunction as a side effect, while Prozac, Zoloft and Paxil are most likely to suppress libido. The drugs with the highest anitcholinergic effect, Paxil, Elavil and Desyrel, can lead to dry eyes and mouth and blurred vision.

Some antidepressants can also affect the cytochrome P450 system, which detoxifies the liver. If that system is blocked by the drug, other medications cannot be metabolized and build up in the body, leading to a higher risk of adverse effects.

Additional Clinical Suggestions
Selecting the most efficacious agent depends upon taking a good patient history and tailoring drug therapy to the patient's specific symptoms. Clinicians should be aware that CFS patients often have sensitivities and idiosyncratic reactions to medication. They also may show a therapeutic response at much lower doses than individuals suffering from major depression.

I start low and go slow, using one-half to one-third of the usual dose at first (see chart for specific dose suggestions). Some patients require even lower doses. Using medications that are available in the liquid form, such as Sinequan (doxepin), may be helpful, since the dose is infinitely adjustable.

References

1. Natelson BH et al. Randomized, double blind, controlled placebo-phase in trial of low dose phenelzine in the chronic fatigue syndrome. Psychopharmacol. 1996; 124: 226-30.
2. Goodnick PJ. Treatment of CFS with verlafaxine. Am J Psychiatry. 1996; 153: 294.
3. White PD and Cleary KJ. An open study of the efficacy and adverse effects of moclobemide in patients with the chronic fatigue syndrome. Int Clin Psychopharmacol. 1997; 12: 47-52.
4. Hickie IB et al. A randomized, double-blind, placebo-controlled trial of moclobemide in patients with chronic fatigue syndrome. J Clin Psych. 2000; 61: 643-8.
5. Goodnick PJ and Sandoval R. Psychotropic treatment of chronic fatigue syndrome and related disorders. J Clin Psych. 1993; 54: 13-20.
6. Blondel-Hill E and Shafran SD. Treatment of chronic fatigue syndrome. A review and practical guide. Drugs. 1993; 46: 639-51.
7. Vercoulen J et al. Randomized, double-blind, placebo-controlled study of fluoxetine in chronic fatigue syndrome. Lancet. 1996; 347: 858-61 and 1770-2.
8. Behan P et al. A pilot study of sertraline for the treatment of chronic fatigue syndrome. Clin Infect Dis. 1994; 18 (suppl 1): S111.
9. Information presented by Nancy Klimas at The CFIDS Association of America's 1990 research conference in Charlotte, NC.

Dr. Lapp practices internal medicine at the Hunter-Hopkins Center in Charlotte, NC. He is also a Clinical Associate Professor of Family and Community Medicine at Duke University.