THE MANAGEMENT OF TREATMENT-RESISTANT DEPRESSION IN DISORDERS ON THE INTERFACE OF PSYCHIATRY AND MEDICINE

TREATMENT-RESISTANT DEPRESSION

0193-953X/96 $0.00

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THE MANAGEMENT OF TREATMENT-RESISTANT DEPRESSION IN DISORDERS ON THE INTERFACE OF PSYCHIATRY AND MEDICINE Fibromyalgia, Chronic Fatigue Syndrome, Migraine, Irritable Bowel Syndrome, Atypical Facial Pain, and Premenstrual Dysphoric Disorder Amanda J. Gruber, MD, James I. Hudson, MD, and Harrison G. Pope, Jr, MD

A number of disorders lie on the interface between psychiatry and medicine that are not easily classified solely as mental or physical illnesses. These disorders include various types of headache, syndromes of regional and widespread musculoskeletal pain, upper and lower gastrointestinal pain and dysfunction, pain and other symptoms occurring during the premenstrual period, and chronic fatigue associated with flu-like symptoms. Although the causes of these conditions are unknown and their nosology is debated, many of these disorders may be associated with mood disorders, and they appear to respond to antidepressant medications. In this article, we discuss psychotropic drug treatment of six of these conditions: fibromyalgia, chronic fatigue syndrome, migraine, irritable bowel syndrome, atypical facial pain, and premenstrual dysphoric disorder. We chose these disorders because (1) they represent reasonably well-defined conditions; (2) there is evidence suggesting an association between these disor-

From the Biological Psychiatry Laboratory, McLean Hospital, Belmont; and the Department of Psychiatry, Harvard Medical School, Boston, Massachusetts

THE PSYCHIATRIC CLINICS OF NORTH AMERICA VOLUME 19 * NUMBER 2 JUNE 1996

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GRUBER et a1

ders and depression; and (3) they have been shown to respond, at least to some degree, to psychotropic agents. We are discussing these disorders in the context of "treatment-resistant depression" because the depression seen in these conditions is often underrecognized, undertreated, and more refractory to treatment than uncomplicated depression. Psychotropic drug treatment of these disorders, however, may not only relieve associated depression but also may benefit the entire syndrome. This observation suggests that the depression seen in these disorders is not simply an isolated symptom, or merely a reaction to having a severe medical illness. Rather, these disorders may share some biologic abnormality with major depression: there may be a common "step" in the chain of etiologic "steps" that links both depression and these various disorders. Several lines of evidence support this hypothesis?'j,37,55 First, the various disorders discussed in this article have been shown to improve with antidepressant drugs from several families, and these several drug families are chemically unrelated. Note that if the various disorders shared a common response to only one chemical family of antidepressant agents, it would not follow that these disorders were necessarily related. For example, the antidepressant clomipramine is effective not only for the treatment of depression but also acts as an antibiotic in the treatment of leishmaniasis (kala-azar), a parasitic disease. But this observation does not permit us to conclude that major depression and kala-azar share a common etiologic "step." On the other hand, as in the case of the disorders reviewed in this article, if two disorders each respond to several antidepressant medications from several different chemical classes, then the likelihood becomes remote that all of these different drugs benefit the disorders by independent mechanisms. A more likely hypothesis is that the disorders share a specific biologic abnormality in common with major depression, and that the various classes of antidepressant drugs benefit the disorders via their effect on this particular abnormality. Moreover, extensive data from phenomenologic studies, and to a lesser degree from family history studies, in these various disorders have suggested that patients with these disorders display a higher prevalence of major depressive disorder in their own lifetime histories, and in their first-degree relatives, than would be expected in the population at large.36,37, 54,55 These observations also favor the hypothesis that the various disorders are related in some way to major depressive disorder. These considerations, however, are primarily theoretic. Whatever the hypothesized mechanism by which antidepressant agents act in fibromyalgia, chronic fatigue syndrome, migraine, irritable bowel syndrome, atypical facial pain, or premenstrual dysphoric disorder, there is no doubt that various antidepressant drugs and other psychotropic medications have been found effective in the treatment of at least some patients with each of these syndromes. Thus, a review of psychotropic treatment of these disorders is clinically relevant regardless of any possible link between these disorders and depression. In selecting studies for presentation in this review, we have included all randomized, placebo-controlled, clinical trials found in a MEDLINE and manual literature search. We also have discussed the results of open clinical trials of medication in instances where no placebo-controlled trials have been performed for a given class of psychotropic agents. For example, we have reviewed an open study of the monoamine oxidase inhibitor (MAOI) phenelzine in migraine, as no placebo-controlled trial of an MA01 has been conducted in migraine. We have not included discussion of the numerous open trials of various tricyclic antidepressants (TCAs) in migraine, however, as several placebo-controlled studies of these agents have been published.

DISORDERS ON THE INTERFACE OF PSYCHIATRY AND MEDICINE

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Finally, we should point out that psychotropic agents are not the only effective treatment, nor even the most commonly used treatment, for many of these conditions. For example, migraine is treated primarily with ergot alkaloids, analgesic medications, or sumatriptan; irritable bowel syndrome often is treated with antispasmodic medications and bulking agents; and fibromyalgia often is treated with nonsteroidal anti-inflammatory drugs. In this article, however, we have restricted our attention to treatment with medications classified as psychotropic. Admittedly, determination of whether a medication is psychotropic is sometimes difficult. We have included under this term medications traditionally classified as antidepressant, anxiolytic, antipsychotic, and mood stabilizing. In addition, we also have included certain medications such as ondansetron (a 5-HT3antagonist), clonidine (a presynaptic a-adrenergic agonist), and P-adrenergic blockers, which are not conventionally classified as psychotropic agents, but which have become increasingly used for their psychotropic properties. FIBROMYALGIA Fibromyalgia is a syndrome characterized by diffuse musculoskeletal pain accompanied by increased tenderness at specific sites known as ”tender points.”n The musculoskeletal pain generally is associated with other symptoms, such as fatigue, sleep disturbance, depression, anxiety, headache, and gastrointestinal complaints. Studies of psychotropic medications in the treatment of fibromyalgia are summarized in Table 1. All but one of the studies reviewed are placebo-controlled trials. The one study39with a different design is a series of 23 N-of-1 randomized controlled trials. The results are shown in two parts: the response of tender points and the response of other features of the disorder, such as sleep quality, fatigue, morning stiffness, depression, and anxiety. Looking at the results, there is good evidence that TCAs are helpful for both pain measures and global measures in fibromyalgia, and tentative evidence that other drugs with antidepressant properties, such as fluoxetine, maprotiline, and S-adenosylmethionine, may be of value in this syndrome. Improvement in tender point measures, however, is not clearly correlated with improvement in global measures. Six of the studies5,6, 38, 59, n,76 also used some type of psychiatric rating scale among their various outcome measures. All of these assessed the correlation between improvement in psychiatric symptoms and fibromyalgia symptoms. Only one study” found a statistically significant correlation between these two measures; the other five5,6, 38, 59, 76 found little relationship between the two sets of symptoms. Four5,6, 38*76 of these five studies reported improvement on psychiatric rating scales during active treatment but not placebo treatment, even though they did not find a correlation between improvement in psychiatric symptoms and improvement in other symptoms of fibromyalgia. Most of the studies in fibromyalgia, especially those using TCAs, however, have used doses well below those normally considered therapeutic in the treatment of depression. Studies using more robust doses of antidepressant medications, and studies using antidepressant agents not previously assessed in fibromyalgia, might produce different results. Two of the studies included groups treated with nonsteroidal anti-inflammatory drugs in addition to the psychotropic agents. In one study;9 the combination of ibuprofen and alprazolam was superior to either drug alone, and both

@

wl

W

S-adenosyl-methionine S-adenosyl-methionine

Tavoni et al, 198772 Jacobsen et al, 199138

3 wk 6 wk

-

+

-

+

-

-

++ ++ ++ ++ ++ ++

-

Tender Points

+ ++

+ ++

+

++

++ ++ + ++ ++ + ++

Other Features

Resultst

*For parallel-group design, total length of trial; for crossover design, length of time on active drug. tResponse categories: +, statistically significant superiority of drug to placebo: +, at least one outcome measure showed superiority of drug to placebo: - , no difference between drug and placebo. $23 N-of-1 randomized clinical trials. Rand = randomized; DB = double-blind; PC = placebo-controlled; PG = parallel group: CD = crossover.

200 mg 800 mg

Other Psychotropic Agents 17 44

Rand: DB, PC, CO Rand: DB, PC, PG

Rand: DB, PC, PG Rand: DB, PC, CO

Alprazolam Temazepam

Russell et al, 199159 Hench et al, 198g30

6 wk 4 wk

Rand: DB, PC, CO

Benzodiazepines 0.5-3 mg 30 mg

Maprotiline

Bibolotti et al. 19865 63 10

Rand: DB, PC, PG

Atypical Antidepressant Agents 37 75 mg 3 wk

DB, PC, PG DB, PC, CO DB, PC, CO DB, PC, CO N-of-l$ DB, PC, PG DB, PC, CO DB, PC, PG

Selective Serotonin Reuptake Inhibitors 26 20 mg 6 wk

Rand: Rand: Rand: Rand: Rand: Rand: Rand: Rand:

Method

Fluoxetine

Agents 9 wk 2 wk 4 wk 4 wk 3-12 wk 6 mo 3 wk 8 wk

Length*

Wolfe et al, 199477

+

Daily Dose

Tricyclic-type Antidepressant 59 50 mg 58 25 mg 10 25 mg 36 50 mg 23 10-50 mg 126 50 mg 37 75 mg 52 75 mg

N

Amitriptyline Amitriptyline Amitriptyline Amitriptyline Amitriptyline Amitriptyline Clomipramine Dothiepin

Drug

Carette et al, 19867 Goldenberg et al, 1986*O Hench et al, 198g30 Scudds et al, 198g6’ Jaeschke et al, 199139 Carette et al, 19946 Bibolotti et al, 19865 Caruso et al, 19878

Study

Table 1. STUDIES OF ANTIDEPRESSANT AND OTHER PSYCHOTROPIC MEDICATIONS IN FIBROMYALGIA

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355

drugs alone were modestly (but not significantly) superior to placebo. In the other study,2Oamitriptyline, with or without naproxen, was superior to naproxen alone or to placebo. The combination produced a modest but not significant advantage over amitriptyline alone. Another study6 included a group treated with cyclobenzaprine, in addition to an amitriptyline group, and a placebo group. Cyclobenzaprine is a TCA that is not reported to have antidepressant effects but is indicated for muscle spasm. After 1 month, the efficacy of amitriptyline was indistinguishable from that of cyclobenzaprine, but both amitriptyline and cyclobenzaprine were significantly more efficacious than placebo. After 3 and 6 months, there were no statistically significant differences among any of the groups. In summary, 10 of 14 placebo-controlled studies of psychotropic medication use in fibromyalgia found the medication to be significantly superior to placebo on at least one measure. Clinically, however, fibromyalgia does not appear to respond to psychotropic medications as well as the two other pain syndromes presented, migraine and atypical facial pain. These latter disorders often remit completely with medications (see later sections), whereas medications seem to help some fibromyalgia symptoms but not others, and to improve the symptoms but not eliminate them. Nevertheless, compared with other types of treatments, antidepressant medications alone, or in combination with other agents-such as benzodiazepines, nonsteroidal anti-inflammatory drugs, and muscle relaxantsare probably the best treatment that presently can be offered to patients with fibromyalgia. CHRONIC FATIGUE SYNDROME

Chronic fatigue syndrome is characterized by fatigue associated with flulike symptoms, myalgia, arthralgia, sleep disturbance, depression, and gastrointestinal corn plaint^.^^ There is considerable overlap between the symptoms of chronic fatigue syndrome and those of fibromyalgia, and some investigators consider them as variants of the same d i ~ o r d e r . ~ ~ , ~ ~ Although psychotropic medications commonly are used to treat chronic fatigue syndrome in a manner similar to the way they are used in fibromyalgia, there has been very little investigation of psychotropic treatment of chronic fatigue syndrome. The only formal clinical trial in the literature is an open study of b ~ p r o p i o n .In ~ ~this study, nine patients with chronic fatigue syndrome exhibited significant improvement on the Hamilton Depression Rating Scale and Beck Depression Inventory after 8 weeks of receiving 300 mg/day of bupropion. Anecdotal reports have suggested that TCAs, selective serotonin reuptake inhibitors (SSRIs), and MAOIs also may be effective in chronic fatigue ~yndrome.'~, ~ 2~ , 531 , As in fibromyalgia, a partial response rather than a complete response is the usual result of antidepressant treatment. MIGRAINE

Chronic headaches of various types have been linked to major depressive disorder and have been treated with psychotropic medications. Among headache syndromes, migraine has been the most extensively studied with respect to its response to psychotropic agents and its relationship to depression. We have summarized the results of studies of antidepressant medications and other psychotropic agents in the treatment of migraine in Table 2. All of the

w w l m

Phenelzine

Mianserin Mianserin

Clonidine Valproate Valproate Valproate Valproate

Anthony et al, 196g3

Denaro et al, 1985” Monro et al, 19855i

Denaro et al, 1985” Hering et al, 199232 Gordon et al, 199324 Silberstein et al, 199363 Jensen et al, 19944i

++

Fluoxetine

Adly et al, 1992’

Daily Dose

Length*

30 mg 60 mg Other Psychotropic Agents 20 0.15 mg 29 800 mg 12 600 mg 107 1087 mg* 34 1000-1 500 mg

20 34

25 45 mg Atypical Antidepressant Agent

12 wk 8 wk 8 wk 12 wk 12 wk

12 wk 4 mo

5-24 mo

20 36.5 mg$ 27 wk 100 93.6 mg* 4 wk 273 50-75 mg 7 mo 30 50-150 mg 10 wk 36 100 mg§ 4 wk Selective Serotonin Reuptake Inhibitors 18 10-40 mg 8 wk Monoamine Oxidase Inhibitors

Tricyclic-type Antidepressant Agents

N

PC, CO PC, CO PC, PG PC, CO PC, CO

Rand: DB, Rand: DB, Rand: DB, Rand: DB, Rand: DB,

PC, PC, PC, PC, PC,

CO CO CO PG CO

Rand: DB, PC, CO Rand: DB, PC, PG

Open

Rand: DB, PC, PG

Rand: DB, Rand: DB, Rand: DB, Rand: DB, Rand: DB,

Method

+ ++ + ++ ++

+ +

+

++

-

++ ++ + ++

Resultst

‘For parallel-group design, total length of trial; for crossover design, length of time on active drug. tResponse categories: , statistically significant superiority of drug to placebo; +, at least one outcome measure showed superiority of drug to placebo; - , no difference between drug and placebo in placebo-controlled trial, or low response rate in open trial. *Mean dose. §Maximum dose. Rand = randomized; DB = double-blind; PC = placebo-controlled; PG = parallel group; CO = crossover.

Amitriptyline Amitriptyline Amitriptyline Amitriptyline Clomipramine

Drug

Gomersall et al, 1973” Couch et al, 1979’O Mathew, 198146 Ziegler et al, 198779 Langohr et al, 198543

Study

Table 2. STUDIES OF ANTIDEPRESSANT AND OTHER PSYCHOTROPIC MEDICATIONS IN MIGRAINE

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357

studies used psychotropic medications for the prophylaxis of recurrent migraine rather than for acute treatment of headaches. Improvement generally was assessed by measures of migraine frequency, duration, and severity or intensity. On balance, antidepressant agents of several types have proved efficacious for migraine. Only of the studies reviewed was negative, but this study used an unusually short treatment period of only 4 weeks. The other studies, with one exception,’O used treatment periods at least twice as long. It may be that more than 4 weeks are required for a medication to begin to have a prophylactic effect on migraine. Among psychotropic medications other than antidepressant agents, valproate deserves special mention because of consistent efficacy demonstrated in four placebo-controlled studiesz4,32, 41, 63 Five studies also used measurements of psychiatric symptoms, such as the Hamilton Depression Rating Scale,’O, 11, 79 the Zung Self-Rating Depression Scale,’, lo, 79 the Beck Depression Inventory,51 and the Spielberger State-Trait Anxiety Inventory.79Three of these found no change in scores,],51, 79 one found a change independent of the antimigraine effect of amitriptyline,’O and one found no change in the overall Hamilton score but a reduction in the anxiety cluster score.” Several of the studies reviewed also included beta-blockers. One43found that metoprolol was statistically significantly more effective than clomipramine, but that neither medication was significantly different from placebo. Another s h ~ d yfound ~ ~ that amitriptyline and propranolol were equally effective, and that both were statistically significantly more effective than placebo. A third study46 is difficult to interpret because the patients were divided into eight groups, each receiving different combinations of propranolol, amitriptyline, and biofeedback. The evidence collected to date is strong enough to warrant trials of antidepressant medications and valproate in patients suffering from migraine. Despite the small number of studies of medications other than amitriptyline and valproate, it is probable that other antidepressants are effective for migraine. Indeed, fluoxetine appears to be used commonly in clinical practice to treat this disorder. Of the disorders discussed, psychotropic medications have the most marked response in migraine, often eliminating episodes of migraine in responders. IRRITABLE BOWEL SYNDROME

Many studies have assessed the response of various ”functional” gastrointestinal symptoms to psychotropic medications. We limited our review, however, to studies that had included only patients whose diagnosis was described as ”irritable bowel (or colon) syndrome” and who had hsd a negative work-up for organic pathology. These studies are summarized in Table 3. The principal outcome measures in most studies consisted of some type of global clinical impression. Symptoms mentioned by all investigators were abdominal pain, diarrhea, and constipation. Other symptoms monitored by different investigators were nausea, vomiting, flatulence, abdominal distention, insomnia, fatigue, other pain syndromes such as headache or back pain, psychiatric symptoms such as depression and anxiety, and interference with activities of daily living.26.29.48. 52. 53, 66. 68 Interpretation of overall response is complicated by differing designs and by methodologic limitations of many of the studies. Nevertheless, all studies reported at least some degree of positive results with varying degrees of cer-

W

w UI

N

Dailv Dose

Arnitriptyline Desipramine Desipramine Trirniprarnine Trirniprarnine Trirniprarnine

Tricyclic-type Antidepressant Agents 14 50 rng 31 150 rng 28 150 rng 61 50 rng 50 30 rng 428 30-50 rng Atypical Antidepressant Agents Arnoxapine 27 NR Trazodone 12 NR Benzodiazepines Lorazeparn 96 2 rng Other Psychotropic Agents Fluphenazinehortriptyline 38 1.5 rng/30 rng Ondansetron 50 12 rng Ondansetron 11 48 rng Thioridazine 21 NR Trifluoperazine 19 NR

Drua

4 wk 4 wk

NR

12 wk 4 wk 4 wk 2 4 wk

12 wk

2

2

4 wk 4-8 wk 6 wk 4 wk 5 wk 6 wk

Lenath'

PC, CO PC, PG PC, CO PC, PG PC, PG PC, PG

Rand: DB, PC, PG Rand: DB, PC, CO Rand: DB, PC, CO Open Open

Rand: DB, PC, CO

Open Open

Rand: DB, Rand: DB, Rand: DB, Rand: DB, Rand: DB, Rand: DB,

Method

++

++ ++ + + +

+

+ +

+ ++ ++ + ++ ++

Resultst

*For parallel-group design, total length of trial; for crossover design, length of time on active drug. , statistically significant superiority of drug to placebo; +, at least one outcome measure showed superiority of drug to placebo. tResponse categories: Rand = randomized; DB = double-blind; PC = placebo-controlled; PG = parallel group; CO = crossover; SB = single-blind (most likely); NR = not reported.

Lancaster-Smith et al, 198242 Maxton et al, 199148 Steadrnan et al, 199266 Clouse et al, 19949 Hislop, 197133

Ritchie et al, 197g5'

Clouse et al, 19949 Clouse et al, 19949

Steinhart et al, 19816* Heefner et al, 197829 Greenbaurn et al, 198726 Myren et al, 198252 Tripathi et al, 198374 Myren et al, 198453

Studv

Table 3. STUDIES OF ANTIDEPRESSANT AND OTHER PSYCHOTROPIC MEDICATIONS IN IRRITABLE BOWEL SYNDROME

DISORDERS O N THE INTERFACE OF PSYCHIATRY AND MEDICINE

359

tainty. Of the six placebo-controlled studies with TCAs, fourZ6, 29, 53, 74 found a statistically significant response compared with placebo, and the other found a statistically significant response compared with baseline but not with placebo. Both of the latter, however, found a very high placebo response rate. One study5Zreported a good response to trimipramine but did not compare the rate directly with placebo, which itself was associated with a 50% reduction in symptoms. There is some evidence from open studies that amoxapine and trazodone may be effective in treating irritable bowel s y n d r ~ m eOther .~ classes of antidepressant agents, such as MAOIs and SSRIs, have not been studied. With regard to other psychotropic medications, ondansetron proved significantly superior to placebo in one study:* but only marginally superior to placebo in One placebo-controlled trial of 10razepam~~ and open trials of alprazolam9,73 have suggested that benzodiazepines may benefit irritable bowel syndrome. Finally, antipsychotic medications have been reported to be helpful in some patients with irritable bowel syndrome?, 33*42 A number of the studies included some type of psychiatric assessment instr-ment.9, Z6,29,42, 68,73,74 The majority9,42.68,74 performed psychiatric ratings only at baseline, making it impossible to determine whether the medication was affecting psychiatric symptoms. Of these, one study9 reported that baseline psychiatric morbidity did not predict treatment response in irritable bowel symptoms; reported that high psychiatric morbidity predicted better response; and onea reported that low psychiatric morbidity predicted better response. Of the two studies that repeated psychiatric rating scales as an outcome measure, one did not find a relationship between improvement in psychiatric symptoms and irritable bowel symptom~,2~ and the other” reported a correlation between the severity of psychiatric symptoms and irritable bowel symptoms both at baseline and after treatment. On balance, it appears that TCAs and probably other types of antidepressant agents benefit irritable bowel syndrome, and should be considered seriously in the management of patients with this condition. Benzodiazepines also may prove useful. Despite some evidence for efficacy, antipsychotic agents probably should be reserved for treatment-refractory patients, given the high incidence of untoward effects of these agents, and the risk of developing tardive dyskinesia. ATYPICAL FACIAL PAIN

Atypical facial pain appears to be a disorder of multiple causes and presentations. To attempt to look at the effect of psychotropic medications in reasonably homogeneous samples, we included studies only if they appeared to contain a majority of subjects suffering from temporomandibular joint pain, as this type of facial pain has been best documented to respond to antidepressant agents. Nevertheless, even in the studies presented (Table 4), the subjects are not entirely homogeneous. In all studies, work-ups were done to exclude organic causes for the subjects’ pain. In one study,44the location of the patient’s pain was not specified and was speculated to have multiple causes. It should be noted in this connection that psychotropic medications have been tried in other types of facial pain as well as other pain syndromes with some success.12,14,45 The outcome measures consisted of some manner of rating pain, such as clinical impression,4°,44 a Visual Analog 62 or a 4-point scale.I3 Some studies also used an instrument to measure depression, such as the Hamilton Depression Rating Scale,”, or the Montgomery-Asberg Depression Rating

0

m

W

Amitriptyline Dothiepin

Phenelzine

Clonazepam Diazepam

Diazepam

Sharav et al, 1 98762 Feinmann et al, 198413

Lascelles, 1 96644

Harkins et al, 199127 Jagger, 1 97340

Roldan et al, 1 99056

Daily Dose

Length*

28 93

Tricyclic-type Antidepressant Agents 30-150 mg 4 wk 130 mg 9 wk Monoamine Oxidase Inhibitors 20 45 mg 4 wk Benzodiazepines 20 0.375mg* 1 mo 29 6-15 mg 1 wk 2 wk 41 2 mg

N

Rand: DB, PC, PG Rand: DB, PC, CO Rand: DB, PC, PG

Rand: DB, PC, CO

Rand: DB, PC, CO Rand: DB, PC, PG

Method

'For parallel-group design, total length of trial; for crossover design, length of time on active drug. tResponse categories: + + , statistically significant superiority of drug to placebo; -, no difference between drug and placebo. *Mean dose. Rand = randomized; DB = double-blind; PC = placebo-controlled; PG = parallel group; CO = crossover; SB = single-blind (most likely).

Drug

Study

Table 4. STUDIES OF ANTIDEPRESSANT AND OTHER PSYCHOTROPIC MEDICATIONS IN ATYPICAL FACIAL PAIN

-

+- +

++

++ ++

Resultst

DISORDERS ON THE INTERFACE OF PSYCHIATRY AND MEDICINE

361

Scale.I3Two studies13, found that pain relief was independent of antidepressant effects,whereas the third” found that pain relief was related to improvement in depressive symptoms. The results of these studies indicate good efficacy for tricyclic-type antidepressants and MAOIs in atypical facial pain. Benzodiazepines appear somewhat less effective, with one study of clonazepam reporting significant improvement relative to placebo, but with two studies of diazepam reporting no difference compared with placebo. Although only three studies of antidepressant medications have been performed, all three were strongly positive, with responders tending to display a complete remission of their pain. Thus, antidepressant agents should be studied more extensively in the treatment of atypical facial pain, and patients with this disorder clearly deserve trials of antidepressant medications. PREMENSTRUAL DYSPHORIC DISORDER Premenstrual dysphoric disorder is characterized by psychological symptoms (including depression, anxiety, affective lability, and decreased interest in activities) and physical symptoms (including breast tenderness or swelling, headache, myalgia, arthralgia, and a sensation of ”bloating”) occurring during the last week of the luteal phase (i.e., premenstrually). This syndrome is included as a proposed category in DSM-IV, and represents only a slight modification of the proposed entity in DSM-111-R termed ”late luteal phase dysphoric disorder.” Similar constructs appear in the literature under the term ”premenstrual syndrome.” We have reviewed together studies using all of these appellations, as they define essentially the same condition. Twelve4,15, 16, 49, 56! 60, 67* 69-71, 78 of the nineteen studies reviewed ensured that their subjects met DSM-111-R criteria for late luteal phase dysphoric disorder by having potential subjects keep a daily diary of premenstrual symptoms for at least two menstrual cycles. Some of these studies, however, did not rigorously exclude subjects with a concomitant psychiatric illness, the symptoms of which required were exacerbated during the late luteal phase. A thirteenth potential subjects to keep a daily diary for only a month, and required that only one symptom worsen during the luteal phase. The remaining five studiesI8,19. 47, 64, 75 enrolled subjects without formal diagnostic criteria, generally stating that the subjects complained of various symptoms prior to their menses. Studies of psychotropic agents in premenstrual dysphoric disorder are summarized in Table 5. The effects of the medication on psychiatric and physical symptoms are shown in separate columns. Examining studies using various classes of antidepressant agents, there appears to be a consensus that antidepressant medications from several chemical families are effective for the psychological symptoms of premenstrual dysphoric disorder. Many of the available studies, however, did not rate changes in physical symptoms, or if they did, found a less pronounced treatment response as compared with the response of psychological symptoms. In practice, other treatments such as hormones, diuretics, and nonsteroidal anti-inflammatory agents are frequently used with good efficacy for the physical symptoms of premenstrual dysphoric disorder.2 Overall, the most impressive evidence comes from studies using fluoxetine.49, 67, 69, 78 These studies, all published within the last 5 years, used rigorous criteria for subject selection and for measurement of drug efficacy; they provide persuasive evidence that fluoxetine is effective in this disorder. It is not possible, however, to conclude that fluoxetine is necessarily superior to other antidepres-

Clomipramine Clomipramine lmipramine

Fluoxetine Fluoxetine

Fluoxetine Fluoxetine Fluvoxamine

Phenelzine

Stone et al, 199169 Menkes et al, 199250 & 199349 Wood et al, 199278 Steiner et al, 1 99P7 Veeninga et al, 199075

Glick et al, 1991l9

Drug

Sunblad et al, 199271 Sunblad et al, 199370 Glick et al, 199119

Study

Daily Dose

Length*

17

8 180 20

40 29 10

'

3 cycles 6 cycles 2 cycles

Monoamine Oxidase Inhibitors 60-90 mg 12 wk

150 mg

20 mg 20-60 mg

Tricyclic-type Antidepressant Agents 3 cycles 25-75 mg 25-75 mg 3 cycles 200-300 mg 12 wk Selective Serotonin Reuptake Inhibitors 20 20mg 2 cycles 3 cycles 16 20 mg

N

Rand: DB, PC, PG

Rand: DB, PC, CO Rand: DB, PC, PG Rand: DB, PC, PG

Rand: DB, PC, PG Rand: DB, PC, CO

Rand: DB, PC, PG Rand: DB, PC, PG Rand: DB, PC, PG

Method

+

++ + ++ ++

++ ++ +

Psychological

Resultst

Table 5. STUDIES OF ANTIDEPRESSANT AND OTHER PSYCHOTROPIC MEDICATIONS IN PREMENSTRUAL DYSPHORIC DISORDER

NR

-

NR

++

-L

++

NR

+ +

Physical

W m W

Alprazolam Alprazolam Alprazolam Alprazolam Alprazolam

Buspirone clonidine Lithium Lithium

Smith et al, 198765 Harrison et al, 199028 Schmidt, 199360 Berger et al, 1 9944 Freeman et al, 199516

Rickels et al, 198g5'j Giannini et al, 198P Mattson & Schoultz, 197447 Singer et al, 1 97464

34 24 18 19

14 30 20 31 138

47

Atypical Antidepressant Agents 319 mg* 8 wk Benzodiazepines 0.75 mg 2 cycles 2.25 mgS 3 cycles 0.25-0.75mg 2 cycles 0.5-3 mg 3 cycles 1.5 mg 3 cycles Other Psychotropic Agents 25 mg* 3 cycles 17 CI.g/kg 2 cycles 0.7-1.5mEq/Lg 2 cycles 0.8-1.3mEq/L§ 1-8 cycles Rand: Rand: Rand: Rand:

Rand: Rand: Rand: Rand: Rand:

Open

DB, DB, DB, DB,

DB, DB, DB, DB, DB, PC, PG PC, CO PC, CO PC, CO

PC, CO PC, CO PC, CO PC, CO PC, PG

++ ++ +

++ ++ ++ ++ ++

+

+

-

NR

++

-

NR

-

-

++

NR

'For parallel-group design, total length of trial; for crossover design, length of time on active drug. tResults presented separately for psychological and physical symptoms of disorder. Response categories: + + , statistically significant superiority of drug to placebo; + , at least one outcome measure showed superiority of drug to placebo; - , no difference between drug and placebo in placebo-controlled trial, or low response rate in open trial. $Mean dose. §Dose titrated to given range of serum lithium level. Rand = randomized; DB = double-blind; PC = placebo-controlled; PG = parallel group; CO = crossover; NR = not reported.

Nefazodone

Freeman et al. 199415

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sant medications. There is simply insufficient evidence with these other agents, possibly because trials of antidepressant drugs in premenstrual dysphoric disorder generally have appeared much more recently than those in the disorders reviewed previously-and hence the older antidepressant agents are less well represented. Of the five studies4,16, 28, 65 examining alprazolam in premenstrual dysphoric disorder, all found at least some significant differences between alprazolam and placebo. The results, however, are not as strongly positive as might be suggested by Table 5 . One study60found only one significant difference between drug and placebo, on the Beck Depression Inventory, among numerous outcome measures. The authors concluded that alprazolam was not an effective agent for the treatment of premenstrual dysphoric disorder. Another study4 examined two groups of subjects, one of which (N = 17) was rated as "well-adjusted," and the other (N = 14) was rated as having mild dysphoric or anxiety symptoms during the follicular phase. Although alprazolam proved significantly superior to placebo in the "well-adjusted group," no significant difference was observed in the group with dysphoric or anxiety symptoms. Of the studies of premenstrual dysphoric disorder using other psychotropic medications, one of buspirone used rigorous measures for assessing diagnosis and outcome. Buspirone proved superior to placebo for both psychological and physical symptoms as assessed by the subjects on a 17-item daily rating scale. The other three studies, using clonidineI8 and lithium, respectively,'", 64 are older investigations that did not use rigorous diagnostic criteria comparable to those of more recent studies. Thus, although some benefit was reported for both of these agents, the results must be interpreted with caution. In summary, many of the available studies of premenstrual dysphoric disorder benefit from modern designs using rigorous diagnostic criteria and detailed outcome measures. Thus, especially in the case of fluoxetine, it can be concluded with confidence that antidepressant treatment is effective in this disorder, either alone or in combination with other treatment modalities. Studies with other antidepressant families, using similarly rigorous designs, however, are still needed. SUMMARY

We have reviewed studies examining the efficacy of various psychotropic medications, primarily antidepressant agents, in the treatment of a group of disorders that appear to exhibit some phenomenologic and genetic relationship to major depression. These disorders all appear to benefit (albeit to varying degrees) from antidepressant medications of several different chemical families. This observation has important theoretical and clinical implications. From a theoretical perspective, these results invite the hypothesis that these various disorders may share some particular etiologic "step" in common with major depression-and that the various antidepressant classes benefit these various disorders and major depression via a common action at this hypothetical "step." Although there is an appealing parsimony to this hypothesis, several reservations must be considered. First, it must be recognized that the quality of the available studies varies widely. As noted in the text, these studies used numerous different designs, varying diagnostic criteria for the disorders under study, and diverse methods of rating outcome. Interpretation is further complicated by the fact that many

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studies included other concomitant medications or therapeutic interventions in addition to the psychotropic drugs administered. Also, the dose of antidepressant medications administered in many of these studies, especially those using TCAs, was often much less than that normally administered in the treatment of major depressive disorder itself. Finally, many of the studies did not systematically evaluate improvement in both the physical and psychological symptoms of a given disorder. For all of these reasons, any theoretic discussion of the results must be tentative. Nevertheless, the overall tally of results strongly favors the hypothesis that antidepressant agents, regardless of their chemical class, are generally useful in the treatment of these disorders. At a minimum, therefore, we can conclude that antidepressant treatment in these disorders deserves aggressive further investigation in studies with modern, rigorous designs. Second, even allowing that multiple antidepressant agents are effective in these various disorders, it still may be premature to conclude that these disorders are related to major depressive disorder. In particular, many of the studies found little correlation between improvement in psychological symptoms and physical symptoms of a given disorder. This observation would seem to argue against a relationship with major depressive disorder. The alternative hypothesis, however, namely, that these disorders do not share a common etiologic "step," seems even less attractive. It would be a remarkable coincidence if, say, fluoxetine possessed an antidepressant property, an independent antimigraine property, and a third, independent, antipremenstrual dysphoric disorder property. And it would be even more peculiar if various other antidepressant medications chemically unrelated to fluoxetine also, by chance alone, benefited all of these same disorders via still other independent mechanisms. Although we cannot, of course, rule out the possibility of multiple mechanisms and multiple causes, the experience of scientific research often has been that the simpler explanation of a phenomenon has proved to be correct. Therefore, the possibility of a link among these various antidepressant-responsive disorders deserves investigation. From a clinical perspective, too, these results are important. They suggest that trials of antidepressant medications should be strongly considered in patients with these disorders. Furthermore, other types of psychotropic medication appear to have a role in the treatment of individual disorders, as discussed in the corresponding sections. In summary, the management of patients with fibromyalgia, chronic fatigue syndrome, migraine, irritable bowel syndrome, atypical facial pain, and premenstrual dysphoric disorder is often difficult, and many patients remain refractory to treatment. Psychotropic drug treatment, particularly with antidepressant medications, however, appears to be often at least partially effective in the treatment of these conditions, along with their associated depressive symptoms. Further research will be required to assess whether these observations indicate a link between these disorders and major depressive disorder. References 1. Adly C, Straumanis J, Chesson A: Fluoxetine prophylaxis of migraine. Headache 32:101-104, 1992 2. Altshuler LL, Hendrick V, Parry B Pharmacological management of premenstrual disorder. Harvard Rev Psychiatry 2:233-245, 1995 3. Anthony M, Lance J W Monoamine oxidase inhibition in the treatment of migraine. Arch Neurol 21:263-268, 1969

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