Antidepressant Therapy for Unexplained Symptoms and Symptom Syndromes

Fifteen of the 21 randomized trials evaluating tricyclic therapy in headache prophylaxis demonstrated improvement in headache symptoms. Thirteen of 16 placebo-controlled trials^{37,38,41,44,51,52,54,55,57,59-62} demonstrated some improvement in one of the following outcomes: decreased headache frequency, duration or severity of headache,^{37,38,41,44,54,59,60-62} global improvement,^51,55,57 or decreased analgesic use.⁵⁴ In the 2 studies comparing tricyclics with nonantidepressant controls, one study³⁹ showed a tricyclic antidepressant to be superior to propranolol, biofeedback, or abortive therapy given as required. The other⁴⁰ showed no benefit of amitriptyline compared with dihydroergotamine. A major limitation of this group of tricyclic studies, however, is that in 10 out of the 21 more than 20% of the randomized patients withdrew from the study.^{37,39-44,52,58,59}

Of the 8 placebo-controlled trials of SSRIs for headache, 5 reported efficacy.^{45,48,49,62,63} The single study that demonstrated efficacy and controlled for depression showed an independent effect of fluoxetine on a headache index score.⁴⁸ However, in this study as with the other SSRI studies on migraine, there was a significant withdrawal rate, 14 out of 32 randomized participants.

Fibromyalgia. For fibromyalgia, there were 18 trials (16 were placebo-controlled) of which 11 studied TCAs,^66-76 3 studied SSRIs,^78-80 2 studied a methylator (S-adenosylmethionine [SAMe]),^81,82 one studied an antiserotonin agent,⁸³ and one examined a TCA, an SSRI, and a combination of both, against placebo.⁷⁷

Of the 12 TCA trials (9 using amitriptyline),^66-73,77 all but one⁶⁷ showed benefit for one or more of the following outcomes: pain,^66,68,70-77 morning stiffness,^66,70 global improvement,^{66,68,69,76,77} sleep,^{66,68,70,76,77} fatigue,^{68,70,75,76,77} tender point score (a score based on the number and severity of tender points),^70,73-75 and functional symptoms.^71,76,77 One study compared 2 TCAs, clomipramine and maprotiline, in a placebo-controlled crossover design and showed benefit for both but also showed a patient preference for maprotiline.⁷⁴

There were 4 studies of SSRIs,^77-80 of which one was against a nonantidepressant control.⁷⁹ Two of the studies (both fluoxetine)^77,79 demonstrated benefit for pain, functional status,⁷⁷ global well-being,⁷⁷ sleep,⁷⁷ morning stiffness,⁷⁹ and tender points.⁷⁹ The one study that compared fluoxetine with amitriptyline or the combination of the 2 drugs, showed that both agents were effective and that the combination was most effective.⁷⁷

SAMe is a naturally occurring molecule that is involved in methylation reactions within catecholinergic and serotoninergic neurons and has been demonstrated to be efficacious for the treatment of depression.¹¹² Both studies of SAMe in fibromyalgia demonstrated improvement in pain,^81,82 and one also demonstrated improvement in trigger points⁸² while the other also demonstrated improvement in morning stiffness and fatigue.⁸¹

The single study of the antiserotonin agent ritanserin demonstrated improvement in headache and feeling refreshed in the morning but no improvement in body pain, fatigue, sleep, morning stiffness, anxiety, and tender points.⁸³

Functional Gastrointestinal Disorders. For functional GI disorders there were 13 trials (12 placebo-controlled) of which 10 studied a TCA (8 in irritable bowel syndrome and 2 in functional dyspepsia);^84-93 one trial studied the antiserotonin antidepressant mianserin (in both functional dyspepsia and irritable bowel syndrome);⁹⁵ one trial studied both mianserin and a TCA for functional dyspepsia;⁹⁴ and one trial studied trazodone in idiopathic esophageal contraction abnormalities.⁹⁶

Of the 11 placebo-controlled studies of irritable bowel syndrome or functional dyspepsia, 10 studied TCAs (trimipramine,^87-89 desipramine,^85,86 amitriptyline,^84,90,91 doxepin,⁹² and clomipramine⁹⁴) and 2 studied mianserin.^94,95 All showed benefit for at least one of the following outcomes: functional status,^86,95 stool frequency,⁸⁵ symptom scores,^84,87,88 pain^85,90,94,95 and rectosigmoid contractions.⁸⁵ Thus, every study except one⁹³ of an antidepressant for irritable bowel syndrome or functional dyspepsia showed some improvement associated with the antidepressant. The single study of patients with symptomatic but unexplained esophageal contraction abnormalities showed a benefit of trazodone over placebo in improving global well-being.⁹⁶

Idiopathic Pain. For the category of idiopathic pain, we empirically grouped studies that evaluated symptoms or symptom syndromes that did not have accepted diagnostic criteria, were described as idiopathic or psychogenic, or described unexplained symptoms arising from a general anatomical area as opposed to an organ system. This included low back pain, facial pain, pelvic pain, chest pain, temporomandibular joint pain, and idiopathic pain.

Eleven studies were included in this group.^1,94,97-105 Seven examined TCAs, most of which were for nonspecific musculoskeletal symptoms;^1,97-102 1 studied the antiserotonin antagonist mianserin for musculoskeletal symptoms;¹⁰³ one studied both a TCA and an antiserotonin agent for multiple idiopathic syndromes;⁹⁴ and 2 studied SSRIs (zimelidine for musculoskeletal symptoms and sertraline for pelvic pain).^104,105

Of the 8 TCA trials, all were placebo controlled, and 6 showed improvement in pain,^1,97,98,100 analgesic use,⁹⁸ global well-being,⁹⁹ or functional status.¹⁰¹ One of the studies compared a TCA with an antiserotonin agent (mianserin) and showed no benefit for either.⁹⁴