The Pharmacotherapy of Minor Depression JONATHAN W. STEWART, M.D.* FREDERIC M. QUITKIN, M.D.** DONALD F. KLEIN, M.D.*** While not as extensively studied as major depression, several pharmacologic studies of patients with variously diagnosed minor depression confirm response rates similar to those found for patients with major depression. We conclude that standard trials of antidepressant medications are indicated for patients with minor depression.
Minor depression applies to a mixed group of mood disorders that do not meet criteria for major depression. In DSM-III-R this includes dysthymia, depression not otherwise specified, cyclothymia, and adjustment disorder with depressed mood. One also might include late-luteal-phase disorder, since this can include a few days to a week or two each month of depressed mood. DSM-III used the term dysthymic disorder instead of dysthymia, but with slightly different criteria. In addition, for DSM-III-R's depression not otherwise specified DSM-III had atypical depression, a "waste basket" term not to be confused with the Columbia group's use of atypical depression to connote a depressive disorder specifically responsive to monoamine oxidase inhibitors, and DSM-III did not recognize late-luteal-phase disorder. The pre-DSM-III system, Research Diagnostic Criteria, included cyclothymia, intermittent depressive disorder and minor depressive disorder. All of these disorders may be characterized by either too few symptoms to meet criteria for major depression (e.g., dysthymia, cyclothymia, depression not otherwise specified, RDC minor depressive disorder), or lack of the persistency required for major depression (e.g., RDC intermittent depression and "Research Psychiatrist, New York State Psychiatric Institute; Associate Professor of Clinical Psychiatry, Columbia University College of Physicians and Surgeons. Mailing address: New York State Psychiatric Institute, 722 West 168th Street, New York, New York 10032. **Research Psychiatrist, New York State Psychiatric Institute; Professor of Clinical Psychiatry, Columbia University College of Physicians and Surgeons. ***Research Psychiatrist, New York State Psychiatric Institute; Professor of Psychiatry, Columbia University College of Physicians and Surgeons. AMERICAN JOURNAL OF PSYCHOTHERAPY, Vol. XLVI, No. 1, January 1992
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AMERICAN JOURNAL OF PSYCHOTHERAPY
late-luteal-phase disorder [PMS]). Thus, the clinician is to consider these disorders only when major depression is not present. DSM-I and II used terms such as neurotic depression and depressive personality to describe some patients whom the later systems would label as having nonmajor depression. Some patients who received these DSM-I and II labels would now meet criteria for major depression. Therefore, neurotic depression and depressive personality are not necessarily synonymous with nonmajor depression. The conceptual issue sidestepped by DSM-III and DSM-III-R's atheoretical approach is the relationship of major to nonmajor depression. Are these categories to be considered totally separate disorders, or are at least some of them subsyndromal, premorbid or partially remitted forms of major depression? This question is currently unanswerable. If some disorders subsumed under minor depression are subsyndromal or premorbid manifestations of major depression, then the same treatments used for the latter also might be effective. Alternatively, if minor depressions identify patients having different disorders than major depression, then it seems less likely that the same treatments would be effective. These alternatives generate testable hypotheses that can be supported or refuted by the literature on antidepressant treatment. In this chapter we summarize investigations of antidepressant medication for minor depression to determine whether the literature supports antidepressant medications for patients with nonmajor depression. If antidepressants are effective for the minor depressions, this would be consistent with at least some minor depressions being variants of major depression. Failure of standard antidepressants to benefit patients with minor depression would favor their having another disorder. Antidepressant medications have proven efficacy for patients with major depression. The literature is less clear for the minor depressions, mainly because most efficacy studies have required a diagnosis of major depression for entry into their protocols. Nonetheless, Table I (pp. 26,27) summarizes the literature we found which addresses the treatment of minor depression with antidepressant medications. This literature cannot be considered definitive because there are too few well-designed studies for any one diagnostic system or for a given category within a system. Also, since the studies used multiple diagnostic systems and addressed different diagnoses within any system, it cannot be assumed that patients diagnosed as having nonmajor depression by one system would meet criteria for even a similar sounding label in another system. Patients meeting DSM-III criteria for dysthymic disorder, for example, would not necessarily meet DSM-III-R criteria for 1
24
The Pharmacotherapy of Minor Depression
dysthymia, since DSM-III-R included substantive modifications in the symptoms required, the time frame for periods of well-being, and whether onset could include an episode of major depression. Nevertheless, the data clearly point to efficacy of standard antidepressant medications in this probably heterogeneous group of disorders. PLACEBO-CONTROLLED STUDIES
There are only a handful of double-blind, placebo-controlled studies of patients identified as depressed, but who did not have a major depression. Kocsis et al. document the efficacy of imipramine relative to placebo for patients with dysthymia, but note that all but one patient also met criteria for major depression. Therefore, this report addresses the major depressive episode of so-called "double depression" rather than "simple" dysthymia. In 74 patients with neurotic depression, vander Velde et al. report both maprotiline (70% responded) and imipramine (62% responded) to be significantly more effective than placebo (20% responded). Bohm et al. reports buspirone (92% responded) superior to placebo (13% responded) in 20 patients with neurotic depression. As noted, it is unclear that patients with neurotic depression would not meet criteria for major depression, so these studies may not address nonmajor depression only. Stewart et al. ' reported on 64 depressed patients randomly assigned to six weeks treatment with desipramine or placebo, 21 of whom did not have major depression. The active drug (36% responded) was somewhat more effective than placebo (20% responded) in the patients without major depression. Since this difference was not statistically significant, the inference was that tricyclic antidepressants are ineffective for patients with nonmajor depression. Davidson et al. reported isocarboxazid ineffective in 35 patients with nonmajor depression. Stewart et al. subsequently reported on a larger group of patients including 72 without major depression. In this later study, they found imipramine (68% responded), and phenelzine (62% responded) both significantly more effective than placebo (36% responded) for patients with minor depression. The two active medications were not different from each other. This study had three times as many patients as the earlier Stewart et al. study suggesting that the failure of the earlier study may have been due to insufficient power (i.e., too few patients to be likely to show a difference). The studies of Stewart et al. ' also reported outcome for patients who specifically had dysthymic disorder. The 1985 publication reported desipramine to be ineffective for dysthymic disorder, while the 1989 report found both imipramine and phenelzine to be superior to placebo. As noted 2
3
4
5
6 7
8
9
7 9
25
Table I LITERATURE SUMMARY OF ANTIDEPRESSANT TREATMENT O F NONMAJOR DEPRESSION drug 1
Authors
percent response
drug 2
percent response
% placebo response
comment
neurotic depression vander Velde (1981) Bohm et al. (1990) Banerji et al. (1989)
70 (16/23) 92 (11/12) 68 (32/47)
imipramine
62 (16/26)
amitriptyline
76 (38/50)
fluoxetine
87 (13/15)
nomifensine
69 (9/13)
non-TCA
TCA 74 (81/110)
maprotiline
4
buspirone
5
alprazolam
20
Taneri & Kohler (1989)
21
TOTAL
nonmajor
Davidson et al. (1988) Stewart et al. (1985) de Sousa & Tropa (1989)
isocarboxazid
Robinson (1991)
8
71 (54/76)
37 (7/19) desipramine
7
36 (4/11) 64%*
74%*
AMI or IMI
phenelzine
74 (17/23)
amitriptyline
71 (10/14)
phenelzine
62 (8/13) 58 (32/55)
imipramine
68 (21/31) 63 (35/56)
fengabine
20 (5/25) 13 (1/8)
18 (6/33)
38 (6/16) 20 (2/10)
17
22
Stewart et al. (1989) TOTAL
9
non-TCA
DjlfC Jrivij Brzezinski et al. (1990) Harrison et al. (1990) Harrison et al. (1989) Stone et al. (1991) TOTAL
12
11
d-fenfluramine
71 (12/17)
18 (3/17)
alprazolam
70 (21/30)
30 (9/30) nortriptyline
25
fluoxetine
13
TCA
36 (10/28) 33 (18/54)
90 (9/10) 74 (42/57)
73 (8/11)
73 (8/11)
20 (2/10) 25 (14/57)
dysthymia Stewart et al. (1985) Stabl et al. (1989)
7
moclobemide
10
Guelfi et al. (1989)
18
Stewart et al. (1989)
Akiskal etal. (1981) Kemali (1989) 23
26
9
desipramine
22 (2/9)
41 (9/23)
tianeptine
78*
amitriptyline
83*
phenelzine
58 (7/12)
imipramine
68 (21/31)
unstated
40 (20/50)
24
amineptine
77 (46/60)
22 (2/9) 17 (4/24)
33 (9/27)
both drugs superior to placebo buspirone superior to placebo both drugs equally effective, but no placebo for comparison both drugs equally effective, but no placebo for comparison T C A and non-TCA both seem effective, but M D D may be present no suggestion of efficacy no suggestion of efficacy both drugs equally effective, but no placebo for comparison both drugs equally effective, but no placebo for comparison only imipramine statistically superior to placebo T C A and non-TCA are superior to placebo cross-over trial—d-fenfluramine is superior to placebo cross-over trial—alprazolam is superior to placebo open trial in patients refractory to alprazolam or placebo cross-over trial—fluoxetine is superior to placebo several types of drugs seem effective, although trials are small no suggestion of efficacy, but sample size is small there is a trend for moclobemide to be superior to placebo both drugs were equally effective, but no placebo for comparison imipramine is superior to placebo; phenelzine sample size is too small to judge efficacy probably various T C A were used in uncontrolled treatment no placebo group for comparison
Table I
(continued) drug 1
Authors Vellejo et al. (1987) DeLeo (1985)
percent response
phenelzine
1
drug 2
percent response
% placebo response
Imipramine
26
non-TCA
TOTAL
65 (62/95)
TCA
48 (43/90)
25 (15/60)
phenelzine superior to imipramine, but no placebo for comparison S-adenosyl-l-methionine effective in an open trial of 25 patients both T C A and non-TCA appear superior to placebo
double depression Harrison et al. (1986)
Kocsis et al. (1988)
15
(4/5)
2
Stewart et al. (1989) TOTAL
phenelzine
9
0 ( 0/ 7 )
phenelzine
non-TCA
(12/15) 80 (16/20)
Imipramine
59 ( 13/22)
13 (3/24)
Imipramine
60 (12/20) 60 (25/42)
42 (5/12) 19 (8/43)
TCA
adjustment disorder with depressed mood
S-adenosyl-l-methionine effective in an open trial of 17 patients stimulants may help AIDS dysphoria
DeLeo (1985) 26
Holmes et al. methyl(1989) phenidate DSM-III-R depression NOS Stewart et al. (1985) Kemali amineptine (1989) 27
(4/5) desipramine
7
23
100 (2/2)
100 (1/1)
100 (1/1)
TOTAL
non-TCA
75 (9/12)
TOTAI^-doubleblind placebocontrolled studies TOTAL—other double-blind studies
non-TCA
63 TCA (93/147)
56 (47/84)
non-TCA
73 (62/85)
TCA
74 (57/77)
TOTAL (open trials)
non-TCA
76 (54/71)
TCA
46 (28/61 )
GRAND TOTAL (all trials)
non-TCA
9
50 (1/2)
74 (8/11)
phenelzine
Stewart et al. (1989) DeLeo (1985)
discontinuation trial showing phenelzine superior to placebo, but most had MDD imipramine superior to placebo but all but one patient had M D D phenelzine superior to placebo both drugs superior to placebo but most patients had M D D
26
TCA
69 TCA (213/308)
100 (2/2)
59 ( 132/222)
67 (2/3)
25 (42/168)
25 (42/168)
sample too small to judge efficacy most patients improved, but no placebo comparison sample too small to judge efficacy S-adenosyl-l-methionine effective in an open trial of 33 patients few numbers and possible high placebo response preclude conclusions about efficacy T C A and non-TCA seem equally effective and clearly superior to placebo T C A and non-TCA seem equally effective; conclusions are tentative due to no placebo comparison non-TCA would appear more effective than T C A but non-random assignment precludes conclusions T C A and non-TCA appear equally effective and both are superior to placebo
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AMERICAN JOURNAL OF PSYCHOTHERAPY
above, the larger numbers in the latter study lend greater credence to the positive results. Stabl et al. found moclobemide, a reversible MAOI, significantly more effective for patients with dysthymic disorder (9/23 = 41% responded) than was placebo (4/24 = 17% responded). Four studies report results from double-blind, cross-over comparisons with placebo in late-luteal-phase disorder. Brzezinski et al. found d-fenfluramine effective for 71 percent of 17 patients with late-luteal-phase disorder compared to 18 percent improving on placebo. Harrison et al. similarly found alprazolam helpful for the premenstrual irritability and dysphoria in 70 percent of 30 women with late-luteal-phase disorder, compared to 30 percent response to placebo. Stone et al. found fluoxetine effective in nine of 10 women with late-luteal-phase disorder, as compared to two who improved with placebo. Rickels et al. have reported buspirone significantly more effective than placebo for late-luteal-phase disorder, but did not indicate proportion responding. Double-blind studies have included too few patients diagnosed as having DSM-III atypical depression (DSM-III-R depression not otherwise specified) to speculate on drug responsivity in patients who seem depressed but do not meet specific diagnostic criteria. Three studies identified patients with double depression (i.e., major depression superimposed on dysthymia). Stewart et al. found both imipramine and phenelzine superior to placebo in patients with double depression. Harrison et al. found phenelzine more effective than placebo in preventing relapse in 12 patients, mostly with double depression, who had improved with phenelzine, then were continued on medication double-blind or switched to placebo for six months. As noted, Kocsis et al. found imipramine more effective than placebo in the acute treatment of patients with double depression. These authors have also suggested that imipramine is effective for long-term maintenance in patients with chronic depression. We are unaware of additional double-blind, placebo-controlled studies giving separate outcomes for nonmajor depression, or of any double-blind, placebo-controlled studies of antidepressants in adjustment disorder with depressed mood. 10
11
12
13
14
9
15
2
16
OTHER DOUBLE-BLIND STUDIES
Several double-blind trials have compared a novel antidepressant to a standard, such as imipramine, but have not included a placebo. Therefore, the finding of no difference between drugs could be due to their both being effective, or to neither being specifically effective agents for the patients studied. These studies include de Sousa and Tropa who reported fengabine 17
28
The Pharmacotherapy of Minor Depression
(74%) and amitriptyline or imipramine (64%) to both be effective for minor depression, Guelfi et al. who found both tianeptine (78%) and amitriptyline (83%) effective for dysthymia, and Vellejo et al. who found phenelzine more effective than imipramine for dysthymic disorder. For neurotic depression, Banerji et al. found alprazolam and amitriptyline equally effective, as did Taneri and Kohler for fluoxetine and nomifensine. Robinson found phenelzine and amitriptyline equally effective for patients with nonmajor depression. 18
19
20
21
22
OPEN CLINICAL TRIALS
Most open trials also suggest efficacy of antidepressants in depressed patients who do not have major depression. Lack of a control group and failure to assert whether the patients also had major depression limit any inference that the antidepressants given in these studies are effective for patients with nonmajor depression. These studies include Kemali suggesting efficacy for amineptine in dysthymia (77% responded) and depression not otherwise specified (74% responded), and Akiskal et al. who felt tricyclic antidepressants (TCA) were helpful for 40 percent of patients whom clinicians now probably would diagnose as having dysthymia. Harrison et al. report nortriptyline was effective in an open trial of 11 women with late-luteal-phase disorder (73% responded). We found two trials of medications in patients having adjustment disorder with depressed mood. DeLeo reported S-adenosyl-l-methionine to be ineffective, while Holmes et al. found psychostimulants helpful for depressed AIDS patients. 23
24
25
26
27
CONCLUSION
The placebo-controlled trials definitively support the efficacy for a variety of antidepressants in the treatment of variously defined patients with nonmajor depression. Tricyclic antidepressants, MAOFs, and several novel antidepressants all appear at least modestly more effective than placebo regardless of specific diagnosis addressed. Not every patient will benefit from a given medication, but clearly the odds are better with medication than without. These data do not imply that adjunctive psychotherapy may not also be useful, but research has not addressed this in nonmajor depression. It might be suggested that apparent efficacy was due to a few studies that included mostly patients with major depression (e.g., Kocsis et al. ). Perhaps inclusion of these studies in the total accounts for the apparent drug-placebo difference shown. We therefore added together the seven studies (Table I) 2
29
AMERICAN JOURNAL OF PSYCHOTHERAPY
that clearly excluded patients with major depression, or reported separately those patients who did not have major depression. These are Davidson et al., Stewart et al., Stewart et al., Brzezinski et al., Harrison et al., Stabl et al. and Stone et al. The combined results from these studies still show response rates of 59 percent (66/112) to nontricyclic antidepressants, 60 percent to tricyclics (25/42), and 27 percent (36/135) to placebo. Adding the individual chi squares of each study together and using the number of studies as degrees of freedom yields significant statistical testing for both tricyclic and nontricyclic antidepressants (X = 6.74, df = 2, p = .03, and X = 34.52, df = 6, p = .00001, respectively). Antidepressant medications seem clearly superior to placebo in treating nonmajor depression whether or not major depression is or has been also present. Howland recently reached the same conclusion. Therefore, the hypothesis that the minor depressions are subsyndromal variants of major depression seems better supported by the treatment response literature than does the hypothesis that they represent different disorders. Considerable additional data would be required before the issue could be considered settled, and etiologic distinctions may yet surface between disorders included here under minor depression. Nevertheless, a reasonable working hypothesis currently is to consider depressions that do not meet criteria for major depression as probably having the same underlying pathology, and to treat the patient accordingly, that is, to use standard antidepressant medications. 8
7
10
9
11
12
13
2
2
28
A SUGGESTED TREATMENT APPROACH FOR MINOR DEPRESSION
The evidence seems convincing that usual antidepressant medications are effective for patients with nonmajor depression, particularly dysthymia, and probably late-luteal-phase disorder. Particularly if supportive or more specific psychotherapy" has not relieved symptoms in three months, we feel strongly that sequential trials of standard antidepressants are indicated. The literature to date support the use of tricyclic antidepressants or monoamine oxidase inhibitors for dysthymia, and perhaps other agents for late-lutealphase disorder. The utility of fluoxetine for nonmajor depression is not addressed. However, since the evidence supports treatment of minor depression as if it were major depression, andfluoxetineis at least as effective as *In their "NIMH treatment of depression collaborative research program: General effectiveness of treatments" (Archives of General Psychiatry, 46:971-82, 1989), Elkin et al. could not show efficacy of psychotherapy relative to placebo/medical management in less severely depressed patients.
30
The Pharmacotherapy of Minor Depression
other antidepressants, our first choice isfluoxetine.Iffluoxetine'shigh cost is prohibitive for an individual patient, we begin with imipramine. FLUOXETINE
Dosing. We begin fluoxetine at 20 mg a day unless spontaneous panic attacks are a prominent part of the picture. In the latter case, we begin at 2.5 mg daily and gradually increase the dose to 20 mg/day over about three weeks, depending on patient tolerance. We then leave patients on 20 mg a day for six weeks. If symptoms are not then completely remitted, we increase the dose by 20 mg every two weeks to 80 mg a day or until complete remission occurs or side effects intervene. If symptoms have not remitted after a month on 80 mg/d or maximally tolerated dose, we add an adjunct (see below) or change to another antidepressant. Side effects. For most patients the side effects offluoxetineare mild and transient. Indigestion, lightheadedness, sleep disturbance and headaches are common, but are rarely severe and usually remit within a few days to a few weeks. Sexual dysfunction, especially anorgasmia, is also frequent, occasionally remits but more typically continues. Most patients takingfluoxetinehave no side effects after the first two months. A more troublesome side effect is agitation, which particularly affects patients with panic disorder. This overstimulation usually remits over time and does not require discontinuation of the medication. Rather, lowering the dose for a time allows the body to accommodate. Then the dose can be gradually increased again, if indicated. Temporary use of benzodiazepines often helps control overstimulation until accommodation occurs. The dangerous problem requiring discontinuation of fluoxetine is a serum sicknesslike allergic reaction consisting of maculopapular rash, arthralgias, fevers and occasionally pneumonitis. Some constellation of these symptoms occurs in about 3 percent of patients takingfluoxetine.The drug should be discontinued upon recognition of these symptoms. Symptoms recede over a few days to a week or two after drug discontinuation and do not generally require treatment unless there is a delay in stopping the medication. Suicide potential. There has recently been a spate of publicity in the lay press suggesting the potential for increased ideation of violence to self or others. This is largely based on a single article describing the reemergence or new onset of suicidal ideation in six depressed patients at various times after starting treatment withfluoxetine.Publicity of a homicide/suicide of a man taking fluoxetine followed shortly. Clearly, emergence of symptoms following any event could be coincidental, and emergence of violent thoughts 29
31
AMERICAN JOURNAL OF PSYCHOTHERAPY
in these cases does not prove thatfluoxetinewas the causal agent. To our knowledge, no study exists comparingfluoxetineto no treatment or to other antidepressants that supports the idea thatfluoxetinecauses violent thoughts or actions, but two negative studies have appeared. Fava and Rosenbaum reviewed the charts of 1017 patients treated at the Massachusetts General Hospital Clinical Psychopharmacology Clinic during the first two years after the marketing offluoxetine.There was no difference in rate of new suicidal ideation or suicidal behavior in patients treated with fluoxetine compared with patients treated with other antidepressants during the same time. This was a chart review of patients not randomly assigned treatment, so possibly fewer potentially suicidal patients received fluoxetine. Nevertheless, the results do not appear to support the idea that frequent onset of suicidal ideation or behavior is to be expected with fluoxetine. A second study analyzed the composite data from 17 double-blind trials comparing fluoxetine to imipramine, placebo, or both. These studies included 1765 patients treated with fluoxetine, 731 with imipramine, and 569 with placebo. Suicidal acts occurred infrequently, but no more often on fluoxetine than with the other two treatments. Emergence of significant suicidal ideation occurred significantly less often onfluoxetinethan on the other two treatments. These results suggest the conclusion that fluoxetine does not cause violent thinking. If it does, this must be a rare phenomenon. Compared with its general safety and the clear morbidity and mortality of depressive illness, this seems a risk worth taking in the context of monitored psychiatric care. 30
31
IMIPRAMINE
Dosing. If fluoxetine is ineffective, our next trial would be with imipramine. Unfortunately, the slow removal of fluoxetine from the body (approximately one month) combined with its effect on increasing the blood level of tricyclic antidepressants, complicate the institution of a tricyclic immediately followingfluoxetine.Our approach is to discontinue fluoxetine, and immediately begin imipramine 25 mg hs. We then instruct the patient to increase the dose by 25 mg hs every two days if tolerated to 150 mg/d. If the patient tolerates the drug and is not completely remitted after two weeks on 150 mg/d, we then increase the dose by 50 mg hs twice a week to 300 mg/d. After one week on 300 mg/d, we get a serum level of imipramine and an electrocardiogram. If the combined I M I + DMI level is not above 350 ng/ml and the electrocardiogram does not show significant conduction delays, we then increase the dose to 350 mg hs for one week, then 400 mg/d 32
The Pharmacotherapy of Minor Depression
for two weeks. If insufficient improvement occurs, we taper imipramine over one to two weeks and switch to another antidepressant. Side effects. Typical side effects of imipramine and other tricyclic antidepressants are more nuisances than dangerous. They are not trivial, however, since sometimes they convince patients to discontinue the medication or not to use a maximally effective dose. These include dry mouth, lightheadedness on standing, day-time grogginess, weight gain, urinary hesitancy, constipation and sexual dysfunction. Occasional patients will experience a mild skin rash, which unlike the severe rash sometimes associated with fluoxetine, almost never requires discontinuation, and usually resolves without treatment. Since tricyclic antidepressants have a quinidine-like effect, they should be used with caution in patients with cardiac conduction delays. They also lower the seizure threshold and can exacerbate narrow-angle glaucoma, so should be used in such patients only in consultation with a competent neurologist or ophthalmologist, respectively. The orthostatic hypotension, which many patients experience at least mildly, often subsides over several weeks, but is particularly worrisome in elderly patients where there is increased risk of falls and fractures. Nortriptyline or smaller starting doses and increments are wise in the elderly. MONOAMINE OXIDASE INHIBITORS
Dosing. Our next choice would be a monoamine oxidase inhibitor (MAOI), for example, tranylcypromine. Upon discontinuation of imipramine, or five weeks after stopping fluoxetine, we begin tranylcypromine 10 mg daily, increasing the dose twice weekly by 10 mg if tolerated to 40 mg/d. If we see no benefit after two weeks on 40 mg/d and the patient is tolerating the drug, we then increase the dose to 50 mg/d for one week then 60 mg/d. Side effects. The "cheese effect'' is not a side effect as much as a drug interaction. It has been known for almost 30 years that eating tyraminecontaining foods while using MAOIs can result in life-threatening hypertensive crisis. It is therefore necessary to avoid tyramine-containing foods in all patients treated with a MAOI. These foods include aged cheeses, red wine, imported beer, yeast and aged meats, but published lists should be consulted and given to any patient begun on a MAOI. We prescribe nifedipine 20 mg sublingually to be taken immediately by the patient if they experience a sudden pounding occipital headache. They should then immediately visit the nearest emergency room and contact their physician. True side effects to MAOIs include orthostatic hypotension, weight gain, sleep disturbance, sexual dysfunction and myoclonus. Lupus-like reactions 32
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AMERICAN JOURNAL OF PSYCHOTHERAPY
have been reported with the hydrazine-containing MAOIs. While not directly life-threatening, these side effects are sometimes severe enough that patients prefer their depression. AUGMENTERS AND ALTERNATIVES
Various augmentation strategies have been suggested for each class of antidepressants. However, the most convincing reports have utilized inpatients with major depression. We are unaware of convincing reports that they are useful for outpatients with nonmajor depression, and have seen only occasional patients who seem to benefit. In refractory patients, addition of lithium or thyroid hormone may be tried. Also, several reports support the usefulness of combining desipramine with fluoxetine. Although the literature supporting the use of psychostimulants predates DSM-III, they appear effective and well-tolerated in occasional patients who have not improved with more conventional antidepressants. Responsive patients do not usually develop the tolerance or other symptoms of dependence concern for which have led to their underutilization. While patients with a history suggesting attention deficit disorder in childhood are probably prime candidates for a trial of psychostimulants, these drugs probably also deserve a trial in other refractory patients. Typical doses are 5-40 mg/d for dextroamphetamine, and 5-60 mg/d for methylphenidate. 33
SUMMARY
Although the literature appears to demonstrate the efficacy of standard antidepressant medications for the short-term treatment of patients with minor depression, they are not widely prescribed. In comparison, psychotherapy is generally recommended, but without convincing data to support this conviction. We, therefore, advocate successive trials with antidepressants in any depressed patient, particularly if they have failed to benefit from psychotherapy or other supportive measures for three months. REFERENCES 1. Klein, D. F., Gittelman, R., Quitkin, F. & Rifkin, A. (1980). Diagnosis and drug treatment of psychiatric disorders: Adults and children, Second Edition. Baltimore: Williams and Wilkins, pp. 268-408. 2. Kocsis, J. H., Frances, A. J., Voss, C , et al. (1988). Imipramine treatment for chronic depression. Archives of General Psychiatry, 45:253-251. 3. Keller, M., & Shapiro, R. W. (1982). "Double depression": Superimposition of acute depressive episodes on chronic depressive disorders. American journal of Psychiatry, 139:438-442. 4. vander Velde, C. (1981). Maprotiline versus imipramine and placebo in neurotic depression, journal of Clinical Psychiatry, 42:138-141. 5. Bohm, C , Robinson, D. S., Gammans, R. E., et al. (1990). Buspirone therapy in anxious elderly patients: A controlled clinical trial, journal of Clinical Psychopharmacology, 10:47S-51S. 6. Stewart, J. W., Quitkin, F. M., Liebowitz, M. R., et al. (1983). Efficacy of desipramine in depressed
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7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
21. 22. 23. 24. 25. 26. 27. 28.
outpatients: Response according to research diagnostic criteria diagnoses and severity of illness. Archives of General Psychiatry, 40:202-207. Stewart, J. W., McGrath, P. J., Liebowitz, M. R., et al. (1985). Treatment outcome validation of DSM-III depressive subtypes: Clinical usefulness in outpatients with mild to moderate depression. Archives of General Psychiatry, 42:1148-1153. Davidson, J. T., Giller, E. L., Zisook, S., & Overall J. E. (1988). An efficacy study of isocarboxazid and placebo in depression, and its relationship to depressive nosology. Archives of General Psychiatry, 45:120-127. Stewart, J. W., McGrath, P. J., Quitkin, F. M., et al. (1989). Relevance of DSM-III depressive subtype and chronicity of antidepressant efficacy in atypical depression: Differential response to phenelzine, imipramine, and placebo. Archives of General Psychiatry, 46:1080-1087. Stabl, M., Biziere, K., Schmid-Burg, K. W., & Amrein, R. (1989). Review of comparative clinical trials: Moclobemide vs tricyclic antidepressants and vs placebo in depressive states. Journal of Neural Transmission, 28:77-89. Brzezinski, A. A., Wurtman, J. J., Wurtman, R. J., et al. (1990). d-fenfluramine suppresses the increased calorie and carbohydrate intakes and improves the mood of women with premenstrual depression. Obstetrics and Gynecology, 76:296-301. Harrison, W. M., Endicott, J., & Nee, J. (1990). Treatment of premenstrual dysphoria with alprazolam: A controlled study. Archives of General Psychiatry, 47:270-275. Stone, A. B., Pearlstein, T. B., & Brown, W. A. (1991). Fluoxetine in the treatment of late-lutealphase dysphoric disorder. Journal of Clinical Psychiatry>, 52:290-293. Rickels, K., Freeman, E . , & Sonheimer, S. (1989). Buspirone in treatment of premenstrual syndrome. Lancet, i:777. Harrison, W., Rabkin, J., Stewart, J. W., et al. (1986). Phenelzine for chronic depression: A study of continuation treatment. Journal of Clinical Psychiatry, 47:346-349. Kocsis, J. H., Sutton, B. M., & Frances, A. J. (1991). Long-term follow-up of chronic depression treated with imipramine. Journal of Clinical Psychiatry, 52:56-59. de Sousa, M. P., & Tropa, J. (1989). Evaluation of the efficacy of amineptine in a population of 1229 depressed patients: Results of a multicenter study carried out by 135 general practitioners. Clinical Neuropharmacology (Suppl2), 12:S77-S86. Guelfi, J. D., Pichot, P., & Dreyfus, J. F. (1989). Efficacy of tianeptine in anxious-depressed patients: Results of a controlled multicenter trial versus amitriptyline. Neuropsychobiology, 22:42-48. Vallejo, J., Gasto, C , Catalan, R., & Salamero, M. (1987). Double-blind study of imipramine versus phenelzine in melancholias and dysthymic disorders. British Journal of Psychiatry, 151:639-651. Banerji, J. R., Brantingham, P., McEwan, G. D., et al. (1989). A comparison of alprazolam with amitriptyline in the treatment of patients with neurotic or reactive depression: A report of a randomized, double blind study by a General Practitioner Working Party. Irish Journal of Medical Science 1989;158:110-113. Taneri, Z., & Kohler, R. (1989). Fluoxetine versus nomifensine in outpatients with neurotic or reactive depressive disorder. International ClinicalPsychopharmacology (Suppl 4), 1:57-61. Ravaris, C , Robinson, D., Ives, J., et al. (1980). Phenelzine and amitriptyline in the treatment of depression. Archives of General Psychiatry, 37:1075-1080; update of data by Robinson, D., in personal communication, Sept. 1991. Kemali, D. (1989). A multicenter Italian study of amineptine (survector 100). Clinical Neuropharmacology, (Suppl. 2) 12:S41-S50. Akiskal, H. S., King, D., Rosenthal, T. L., et al. (1981). Chronic depressions: Part 1. Clinical and familial characteristics in 137 probands. Journal of Affective Disorders, 3:297-315. Harrison, W. M., Endicott, J., & Nee, J. (1989). Treatment of premenstrual depression with nortriptyline: A pilot study. Journal of Clinical Psychiatry, 50:136-139. DeLeo, D. (1985). S-adenosyl-l-methionine (SAMe) in clinical practice: Preliminary report on 75 minor depressives. Current Therapeutic Research, 37:658-661. Holmes, V. F., Fernandez, F., & Levy, J. K. (1989). Psychostimulant response in AIDS-related complex patients. Journal of Clinical Psychiatry, 50:5-7. Howland, R. H. (1991). Pharmacotherapy of dysthymia: A review. Journal of Clinical Psychopharmacology, 11:83-92.
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AMERICAN JOURNAL OF PSYCHOTHERAPY 29. Teicher, M. H., Glod, C , & Cole, J. O. (1990). Emergence of intense suicidal preoccupation during Fluoxetine treatment. American Journal of Psychiatry, 147:207-210. 30. Fava, M., & Rosenbaum, J. F. (1991). Suicidally andfluoxetine:Is there a relationship? Journal of Clinical Psychiatry, 52:108-111. 31. Beasley, C. M., Jr., Dornseif, B. E., Bosomworth, J. C , et al. (1991). Fluoxetine and suicide: a meta-analysis of controlled trials of treatment for depression. British Journal of Psychiatry, 303:685-692. 32. Blackwell, B. (1963). Hypertensive crisis due to monamine-oxidase inhibitors. Lancet, ii:763—764. 33. Chiarello, R. J., & Cole, J. O. (1987). The use of psychostimulants in general psychiatry. Archives of General Psychiatry, 44:286-295.
36
Minor depression applies to a mixed group of mood disorders that do not meet criteria for major depression. In DSM-III-R this includes dysthymia, depression not otherwise specified, cyclothymia, and adjustment disorder with depressed mood. One also might include late-luteal-phase disorder, since this can include a few days to a week or two each month of depressed mood. DSM-III used the term dysthymic disorder instead of dysthymia, but with slightly different criteria. In addition, for DSM-III-R's depression not otherwise specified DSM-III had atypical depression, a "waste basket" term not to be confused with the Columbia group's use of atypical depression to connote a depressive disorder specifically responsive to monoamine oxidase inhibitors, and DSM-III did not recognize late-luteal-phase disorder. The pre-DSM-III system, Research Diagnostic Criteria, included cyclothymia, intermittent depressive disorder and minor depressive disorder. All of these disorders may be characterized by either too few symptoms to meet criteria for major depression (e.g., dysthymia, cyclothymia, depression not otherwise specified, RDC minor depressive disorder), or lack of the persistency required for major depression (e.g., RDC intermittent depression and "Research Psychiatrist, New York State Psychiatric Institute; Associate Professor of Clinical Psychiatry, Columbia University College of Physicians and Surgeons. Mailing address: New York State Psychiatric Institute, 722 West 168th Street, New York, New York 10032. **Research Psychiatrist, New York State Psychiatric Institute; Professor of Clinical Psychiatry, Columbia University College of Physicians and Surgeons. ***Research Psychiatrist, New York State Psychiatric Institute; Professor of Psychiatry, Columbia University College of Physicians and Surgeons. AMERICAN JOURNAL OF PSYCHOTHERAPY, Vol. XLVI, No. 1, January 1992
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AMERICAN JOURNAL OF PSYCHOTHERAPY
late-luteal-phase disorder [PMS]). Thus, the clinician is to consider these disorders only when major depression is not present. DSM-I and II used terms such as neurotic depression and depressive personality to describe some patients whom the later systems would label as having nonmajor depression. Some patients who received these DSM-I and II labels would now meet criteria for major depression. Therefore, neurotic depression and depressive personality are not necessarily synonymous with nonmajor depression. The conceptual issue sidestepped by DSM-III and DSM-III-R's atheoretical approach is the relationship of major to nonmajor depression. Are these categories to be considered totally separate disorders, or are at least some of them subsyndromal, premorbid or partially remitted forms of major depression? This question is currently unanswerable. If some disorders subsumed under minor depression are subsyndromal or premorbid manifestations of major depression, then the same treatments used for the latter also might be effective. Alternatively, if minor depressions identify patients having different disorders than major depression, then it seems less likely that the same treatments would be effective. These alternatives generate testable hypotheses that can be supported or refuted by the literature on antidepressant treatment. In this chapter we summarize investigations of antidepressant medication for minor depression to determine whether the literature supports antidepressant medications for patients with nonmajor depression. If antidepressants are effective for the minor depressions, this would be consistent with at least some minor depressions being variants of major depression. Failure of standard antidepressants to benefit patients with minor depression would favor their having another disorder. Antidepressant medications have proven efficacy for patients with major depression. The literature is less clear for the minor depressions, mainly because most efficacy studies have required a diagnosis of major depression for entry into their protocols. Nonetheless, Table I (pp. 26,27) summarizes the literature we found which addresses the treatment of minor depression with antidepressant medications. This literature cannot be considered definitive because there are too few well-designed studies for any one diagnostic system or for a given category within a system. Also, since the studies used multiple diagnostic systems and addressed different diagnoses within any system, it cannot be assumed that patients diagnosed as having nonmajor depression by one system would meet criteria for even a similar sounding label in another system. Patients meeting DSM-III criteria for dysthymic disorder, for example, would not necessarily meet DSM-III-R criteria for 1
24
The Pharmacotherapy of Minor Depression
dysthymia, since DSM-III-R included substantive modifications in the symptoms required, the time frame for periods of well-being, and whether onset could include an episode of major depression. Nevertheless, the data clearly point to efficacy of standard antidepressant medications in this probably heterogeneous group of disorders. PLACEBO-CONTROLLED STUDIES
There are only a handful of double-blind, placebo-controlled studies of patients identified as depressed, but who did not have a major depression. Kocsis et al. document the efficacy of imipramine relative to placebo for patients with dysthymia, but note that all but one patient also met criteria for major depression. Therefore, this report addresses the major depressive episode of so-called "double depression" rather than "simple" dysthymia. In 74 patients with neurotic depression, vander Velde et al. report both maprotiline (70% responded) and imipramine (62% responded) to be significantly more effective than placebo (20% responded). Bohm et al. reports buspirone (92% responded) superior to placebo (13% responded) in 20 patients with neurotic depression. As noted, it is unclear that patients with neurotic depression would not meet criteria for major depression, so these studies may not address nonmajor depression only. Stewart et al. ' reported on 64 depressed patients randomly assigned to six weeks treatment with desipramine or placebo, 21 of whom did not have major depression. The active drug (36% responded) was somewhat more effective than placebo (20% responded) in the patients without major depression. Since this difference was not statistically significant, the inference was that tricyclic antidepressants are ineffective for patients with nonmajor depression. Davidson et al. reported isocarboxazid ineffective in 35 patients with nonmajor depression. Stewart et al. subsequently reported on a larger group of patients including 72 without major depression. In this later study, they found imipramine (68% responded), and phenelzine (62% responded) both significantly more effective than placebo (36% responded) for patients with minor depression. The two active medications were not different from each other. This study had three times as many patients as the earlier Stewart et al. study suggesting that the failure of the earlier study may have been due to insufficient power (i.e., too few patients to be likely to show a difference). The studies of Stewart et al. ' also reported outcome for patients who specifically had dysthymic disorder. The 1985 publication reported desipramine to be ineffective for dysthymic disorder, while the 1989 report found both imipramine and phenelzine to be superior to placebo. As noted 2
3
4
5
6 7
8
9
7 9
25
Table I LITERATURE SUMMARY OF ANTIDEPRESSANT TREATMENT O F NONMAJOR DEPRESSION drug 1
Authors
percent response
drug 2
percent response
% placebo response
comment
neurotic depression vander Velde (1981) Bohm et al. (1990) Banerji et al. (1989)
70 (16/23) 92 (11/12) 68 (32/47)
imipramine
62 (16/26)
amitriptyline
76 (38/50)
fluoxetine
87 (13/15)
nomifensine
69 (9/13)
non-TCA
TCA 74 (81/110)
maprotiline
4
buspirone
5
alprazolam
20
Taneri & Kohler (1989)
21
TOTAL
nonmajor
Davidson et al. (1988) Stewart et al. (1985) de Sousa & Tropa (1989)
isocarboxazid
Robinson (1991)
8
71 (54/76)
37 (7/19) desipramine
7
36 (4/11) 64%*
74%*
AMI or IMI
phenelzine
74 (17/23)
amitriptyline
71 (10/14)
phenelzine
62 (8/13) 58 (32/55)
imipramine
68 (21/31) 63 (35/56)
fengabine
20 (5/25) 13 (1/8)
18 (6/33)
38 (6/16) 20 (2/10)
17
22
Stewart et al. (1989) TOTAL
9
non-TCA
DjlfC Jrivij Brzezinski et al. (1990) Harrison et al. (1990) Harrison et al. (1989) Stone et al. (1991) TOTAL
12
11
d-fenfluramine
71 (12/17)
18 (3/17)
alprazolam
70 (21/30)
30 (9/30) nortriptyline
25
fluoxetine
13
TCA
36 (10/28) 33 (18/54)
90 (9/10) 74 (42/57)
73 (8/11)
73 (8/11)
20 (2/10) 25 (14/57)
dysthymia Stewart et al. (1985) Stabl et al. (1989)
7
moclobemide
10
Guelfi et al. (1989)
18
Stewart et al. (1989)
Akiskal etal. (1981) Kemali (1989) 23
26
9
desipramine
22 (2/9)
41 (9/23)
tianeptine
78*
amitriptyline
83*
phenelzine
58 (7/12)
imipramine
68 (21/31)
unstated
40 (20/50)
24
amineptine
77 (46/60)
22 (2/9) 17 (4/24)
33 (9/27)
both drugs superior to placebo buspirone superior to placebo both drugs equally effective, but no placebo for comparison both drugs equally effective, but no placebo for comparison T C A and non-TCA both seem effective, but M D D may be present no suggestion of efficacy no suggestion of efficacy both drugs equally effective, but no placebo for comparison both drugs equally effective, but no placebo for comparison only imipramine statistically superior to placebo T C A and non-TCA are superior to placebo cross-over trial—d-fenfluramine is superior to placebo cross-over trial—alprazolam is superior to placebo open trial in patients refractory to alprazolam or placebo cross-over trial—fluoxetine is superior to placebo several types of drugs seem effective, although trials are small no suggestion of efficacy, but sample size is small there is a trend for moclobemide to be superior to placebo both drugs were equally effective, but no placebo for comparison imipramine is superior to placebo; phenelzine sample size is too small to judge efficacy probably various T C A were used in uncontrolled treatment no placebo group for comparison
Table I
(continued) drug 1
Authors Vellejo et al. (1987) DeLeo (1985)
percent response
phenelzine
1
drug 2
percent response
% placebo response
Imipramine
26
non-TCA
TOTAL
65 (62/95)
TCA
48 (43/90)
25 (15/60)
phenelzine superior to imipramine, but no placebo for comparison S-adenosyl-l-methionine effective in an open trial of 25 patients both T C A and non-TCA appear superior to placebo
double depression Harrison et al. (1986)
Kocsis et al. (1988)
15
(4/5)
2
Stewart et al. (1989) TOTAL
phenelzine
9
0 ( 0/ 7 )
phenelzine
non-TCA
(12/15) 80 (16/20)
Imipramine
59 ( 13/22)
13 (3/24)
Imipramine
60 (12/20) 60 (25/42)
42 (5/12) 19 (8/43)
TCA
adjustment disorder with depressed mood
S-adenosyl-l-methionine effective in an open trial of 17 patients stimulants may help AIDS dysphoria
DeLeo (1985) 26
Holmes et al. methyl(1989) phenidate DSM-III-R depression NOS Stewart et al. (1985) Kemali amineptine (1989) 27
(4/5) desipramine
7
23
100 (2/2)
100 (1/1)
100 (1/1)
TOTAL
non-TCA
75 (9/12)
TOTAI^-doubleblind placebocontrolled studies TOTAL—other double-blind studies
non-TCA
63 TCA (93/147)
56 (47/84)
non-TCA
73 (62/85)
TCA
74 (57/77)
TOTAL (open trials)
non-TCA
76 (54/71)
TCA
46 (28/61 )
GRAND TOTAL (all trials)
non-TCA
9
50 (1/2)
74 (8/11)
phenelzine
Stewart et al. (1989) DeLeo (1985)
discontinuation trial showing phenelzine superior to placebo, but most had MDD imipramine superior to placebo but all but one patient had M D D phenelzine superior to placebo both drugs superior to placebo but most patients had M D D
26
TCA
69 TCA (213/308)
100 (2/2)
59 ( 132/222)
67 (2/3)
25 (42/168)
25 (42/168)
sample too small to judge efficacy most patients improved, but no placebo comparison sample too small to judge efficacy S-adenosyl-l-methionine effective in an open trial of 33 patients few numbers and possible high placebo response preclude conclusions about efficacy T C A and non-TCA seem equally effective and clearly superior to placebo T C A and non-TCA seem equally effective; conclusions are tentative due to no placebo comparison non-TCA would appear more effective than T C A but non-random assignment precludes conclusions T C A and non-TCA appear equally effective and both are superior to placebo
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AMERICAN JOURNAL OF PSYCHOTHERAPY
above, the larger numbers in the latter study lend greater credence to the positive results. Stabl et al. found moclobemide, a reversible MAOI, significantly more effective for patients with dysthymic disorder (9/23 = 41% responded) than was placebo (4/24 = 17% responded). Four studies report results from double-blind, cross-over comparisons with placebo in late-luteal-phase disorder. Brzezinski et al. found d-fenfluramine effective for 71 percent of 17 patients with late-luteal-phase disorder compared to 18 percent improving on placebo. Harrison et al. similarly found alprazolam helpful for the premenstrual irritability and dysphoria in 70 percent of 30 women with late-luteal-phase disorder, compared to 30 percent response to placebo. Stone et al. found fluoxetine effective in nine of 10 women with late-luteal-phase disorder, as compared to two who improved with placebo. Rickels et al. have reported buspirone significantly more effective than placebo for late-luteal-phase disorder, but did not indicate proportion responding. Double-blind studies have included too few patients diagnosed as having DSM-III atypical depression (DSM-III-R depression not otherwise specified) to speculate on drug responsivity in patients who seem depressed but do not meet specific diagnostic criteria. Three studies identified patients with double depression (i.e., major depression superimposed on dysthymia). Stewart et al. found both imipramine and phenelzine superior to placebo in patients with double depression. Harrison et al. found phenelzine more effective than placebo in preventing relapse in 12 patients, mostly with double depression, who had improved with phenelzine, then were continued on medication double-blind or switched to placebo for six months. As noted, Kocsis et al. found imipramine more effective than placebo in the acute treatment of patients with double depression. These authors have also suggested that imipramine is effective for long-term maintenance in patients with chronic depression. We are unaware of additional double-blind, placebo-controlled studies giving separate outcomes for nonmajor depression, or of any double-blind, placebo-controlled studies of antidepressants in adjustment disorder with depressed mood. 10
11
12
13
14
9
15
2
16
OTHER DOUBLE-BLIND STUDIES
Several double-blind trials have compared a novel antidepressant to a standard, such as imipramine, but have not included a placebo. Therefore, the finding of no difference between drugs could be due to their both being effective, or to neither being specifically effective agents for the patients studied. These studies include de Sousa and Tropa who reported fengabine 17
28
The Pharmacotherapy of Minor Depression
(74%) and amitriptyline or imipramine (64%) to both be effective for minor depression, Guelfi et al. who found both tianeptine (78%) and amitriptyline (83%) effective for dysthymia, and Vellejo et al. who found phenelzine more effective than imipramine for dysthymic disorder. For neurotic depression, Banerji et al. found alprazolam and amitriptyline equally effective, as did Taneri and Kohler for fluoxetine and nomifensine. Robinson found phenelzine and amitriptyline equally effective for patients with nonmajor depression. 18
19
20
21
22
OPEN CLINICAL TRIALS
Most open trials also suggest efficacy of antidepressants in depressed patients who do not have major depression. Lack of a control group and failure to assert whether the patients also had major depression limit any inference that the antidepressants given in these studies are effective for patients with nonmajor depression. These studies include Kemali suggesting efficacy for amineptine in dysthymia (77% responded) and depression not otherwise specified (74% responded), and Akiskal et al. who felt tricyclic antidepressants (TCA) were helpful for 40 percent of patients whom clinicians now probably would diagnose as having dysthymia. Harrison et al. report nortriptyline was effective in an open trial of 11 women with late-luteal-phase disorder (73% responded). We found two trials of medications in patients having adjustment disorder with depressed mood. DeLeo reported S-adenosyl-l-methionine to be ineffective, while Holmes et al. found psychostimulants helpful for depressed AIDS patients. 23
24
25
26
27
CONCLUSION
The placebo-controlled trials definitively support the efficacy for a variety of antidepressants in the treatment of variously defined patients with nonmajor depression. Tricyclic antidepressants, MAOFs, and several novel antidepressants all appear at least modestly more effective than placebo regardless of specific diagnosis addressed. Not every patient will benefit from a given medication, but clearly the odds are better with medication than without. These data do not imply that adjunctive psychotherapy may not also be useful, but research has not addressed this in nonmajor depression. It might be suggested that apparent efficacy was due to a few studies that included mostly patients with major depression (e.g., Kocsis et al. ). Perhaps inclusion of these studies in the total accounts for the apparent drug-placebo difference shown. We therefore added together the seven studies (Table I) 2
29
AMERICAN JOURNAL OF PSYCHOTHERAPY
that clearly excluded patients with major depression, or reported separately those patients who did not have major depression. These are Davidson et al., Stewart et al., Stewart et al., Brzezinski et al., Harrison et al., Stabl et al. and Stone et al. The combined results from these studies still show response rates of 59 percent (66/112) to nontricyclic antidepressants, 60 percent to tricyclics (25/42), and 27 percent (36/135) to placebo. Adding the individual chi squares of each study together and using the number of studies as degrees of freedom yields significant statistical testing for both tricyclic and nontricyclic antidepressants (X = 6.74, df = 2, p = .03, and X = 34.52, df = 6, p = .00001, respectively). Antidepressant medications seem clearly superior to placebo in treating nonmajor depression whether or not major depression is or has been also present. Howland recently reached the same conclusion. Therefore, the hypothesis that the minor depressions are subsyndromal variants of major depression seems better supported by the treatment response literature than does the hypothesis that they represent different disorders. Considerable additional data would be required before the issue could be considered settled, and etiologic distinctions may yet surface between disorders included here under minor depression. Nevertheless, a reasonable working hypothesis currently is to consider depressions that do not meet criteria for major depression as probably having the same underlying pathology, and to treat the patient accordingly, that is, to use standard antidepressant medications. 8
7
10
9
11
12
13
2
2
28
A SUGGESTED TREATMENT APPROACH FOR MINOR DEPRESSION
The evidence seems convincing that usual antidepressant medications are effective for patients with nonmajor depression, particularly dysthymia, and probably late-luteal-phase disorder. Particularly if supportive or more specific psychotherapy" has not relieved symptoms in three months, we feel strongly that sequential trials of standard antidepressants are indicated. The literature to date support the use of tricyclic antidepressants or monoamine oxidase inhibitors for dysthymia, and perhaps other agents for late-lutealphase disorder. The utility of fluoxetine for nonmajor depression is not addressed. However, since the evidence supports treatment of minor depression as if it were major depression, andfluoxetineis at least as effective as *In their "NIMH treatment of depression collaborative research program: General effectiveness of treatments" (Archives of General Psychiatry, 46:971-82, 1989), Elkin et al. could not show efficacy of psychotherapy relative to placebo/medical management in less severely depressed patients.
30
The Pharmacotherapy of Minor Depression
other antidepressants, our first choice isfluoxetine.Iffluoxetine'shigh cost is prohibitive for an individual patient, we begin with imipramine. FLUOXETINE
Dosing. We begin fluoxetine at 20 mg a day unless spontaneous panic attacks are a prominent part of the picture. In the latter case, we begin at 2.5 mg daily and gradually increase the dose to 20 mg/day over about three weeks, depending on patient tolerance. We then leave patients on 20 mg a day for six weeks. If symptoms are not then completely remitted, we increase the dose by 20 mg every two weeks to 80 mg a day or until complete remission occurs or side effects intervene. If symptoms have not remitted after a month on 80 mg/d or maximally tolerated dose, we add an adjunct (see below) or change to another antidepressant. Side effects. For most patients the side effects offluoxetineare mild and transient. Indigestion, lightheadedness, sleep disturbance and headaches are common, but are rarely severe and usually remit within a few days to a few weeks. Sexual dysfunction, especially anorgasmia, is also frequent, occasionally remits but more typically continues. Most patients takingfluoxetinehave no side effects after the first two months. A more troublesome side effect is agitation, which particularly affects patients with panic disorder. This overstimulation usually remits over time and does not require discontinuation of the medication. Rather, lowering the dose for a time allows the body to accommodate. Then the dose can be gradually increased again, if indicated. Temporary use of benzodiazepines often helps control overstimulation until accommodation occurs. The dangerous problem requiring discontinuation of fluoxetine is a serum sicknesslike allergic reaction consisting of maculopapular rash, arthralgias, fevers and occasionally pneumonitis. Some constellation of these symptoms occurs in about 3 percent of patients takingfluoxetine.The drug should be discontinued upon recognition of these symptoms. Symptoms recede over a few days to a week or two after drug discontinuation and do not generally require treatment unless there is a delay in stopping the medication. Suicide potential. There has recently been a spate of publicity in the lay press suggesting the potential for increased ideation of violence to self or others. This is largely based on a single article describing the reemergence or new onset of suicidal ideation in six depressed patients at various times after starting treatment withfluoxetine.Publicity of a homicide/suicide of a man taking fluoxetine followed shortly. Clearly, emergence of symptoms following any event could be coincidental, and emergence of violent thoughts 29
31
AMERICAN JOURNAL OF PSYCHOTHERAPY
in these cases does not prove thatfluoxetinewas the causal agent. To our knowledge, no study exists comparingfluoxetineto no treatment or to other antidepressants that supports the idea thatfluoxetinecauses violent thoughts or actions, but two negative studies have appeared. Fava and Rosenbaum reviewed the charts of 1017 patients treated at the Massachusetts General Hospital Clinical Psychopharmacology Clinic during the first two years after the marketing offluoxetine.There was no difference in rate of new suicidal ideation or suicidal behavior in patients treated with fluoxetine compared with patients treated with other antidepressants during the same time. This was a chart review of patients not randomly assigned treatment, so possibly fewer potentially suicidal patients received fluoxetine. Nevertheless, the results do not appear to support the idea that frequent onset of suicidal ideation or behavior is to be expected with fluoxetine. A second study analyzed the composite data from 17 double-blind trials comparing fluoxetine to imipramine, placebo, or both. These studies included 1765 patients treated with fluoxetine, 731 with imipramine, and 569 with placebo. Suicidal acts occurred infrequently, but no more often on fluoxetine than with the other two treatments. Emergence of significant suicidal ideation occurred significantly less often onfluoxetinethan on the other two treatments. These results suggest the conclusion that fluoxetine does not cause violent thinking. If it does, this must be a rare phenomenon. Compared with its general safety and the clear morbidity and mortality of depressive illness, this seems a risk worth taking in the context of monitored psychiatric care. 30
31
IMIPRAMINE
Dosing. If fluoxetine is ineffective, our next trial would be with imipramine. Unfortunately, the slow removal of fluoxetine from the body (approximately one month) combined with its effect on increasing the blood level of tricyclic antidepressants, complicate the institution of a tricyclic immediately followingfluoxetine.Our approach is to discontinue fluoxetine, and immediately begin imipramine 25 mg hs. We then instruct the patient to increase the dose by 25 mg hs every two days if tolerated to 150 mg/d. If the patient tolerates the drug and is not completely remitted after two weeks on 150 mg/d, we then increase the dose by 50 mg hs twice a week to 300 mg/d. After one week on 300 mg/d, we get a serum level of imipramine and an electrocardiogram. If the combined I M I + DMI level is not above 350 ng/ml and the electrocardiogram does not show significant conduction delays, we then increase the dose to 350 mg hs for one week, then 400 mg/d 32
The Pharmacotherapy of Minor Depression
for two weeks. If insufficient improvement occurs, we taper imipramine over one to two weeks and switch to another antidepressant. Side effects. Typical side effects of imipramine and other tricyclic antidepressants are more nuisances than dangerous. They are not trivial, however, since sometimes they convince patients to discontinue the medication or not to use a maximally effective dose. These include dry mouth, lightheadedness on standing, day-time grogginess, weight gain, urinary hesitancy, constipation and sexual dysfunction. Occasional patients will experience a mild skin rash, which unlike the severe rash sometimes associated with fluoxetine, almost never requires discontinuation, and usually resolves without treatment. Since tricyclic antidepressants have a quinidine-like effect, they should be used with caution in patients with cardiac conduction delays. They also lower the seizure threshold and can exacerbate narrow-angle glaucoma, so should be used in such patients only in consultation with a competent neurologist or ophthalmologist, respectively. The orthostatic hypotension, which many patients experience at least mildly, often subsides over several weeks, but is particularly worrisome in elderly patients where there is increased risk of falls and fractures. Nortriptyline or smaller starting doses and increments are wise in the elderly. MONOAMINE OXIDASE INHIBITORS
Dosing. Our next choice would be a monoamine oxidase inhibitor (MAOI), for example, tranylcypromine. Upon discontinuation of imipramine, or five weeks after stopping fluoxetine, we begin tranylcypromine 10 mg daily, increasing the dose twice weekly by 10 mg if tolerated to 40 mg/d. If we see no benefit after two weeks on 40 mg/d and the patient is tolerating the drug, we then increase the dose to 50 mg/d for one week then 60 mg/d. Side effects. The "cheese effect'' is not a side effect as much as a drug interaction. It has been known for almost 30 years that eating tyraminecontaining foods while using MAOIs can result in life-threatening hypertensive crisis. It is therefore necessary to avoid tyramine-containing foods in all patients treated with a MAOI. These foods include aged cheeses, red wine, imported beer, yeast and aged meats, but published lists should be consulted and given to any patient begun on a MAOI. We prescribe nifedipine 20 mg sublingually to be taken immediately by the patient if they experience a sudden pounding occipital headache. They should then immediately visit the nearest emergency room and contact their physician. True side effects to MAOIs include orthostatic hypotension, weight gain, sleep disturbance, sexual dysfunction and myoclonus. Lupus-like reactions 32
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have been reported with the hydrazine-containing MAOIs. While not directly life-threatening, these side effects are sometimes severe enough that patients prefer their depression. AUGMENTERS AND ALTERNATIVES
Various augmentation strategies have been suggested for each class of antidepressants. However, the most convincing reports have utilized inpatients with major depression. We are unaware of convincing reports that they are useful for outpatients with nonmajor depression, and have seen only occasional patients who seem to benefit. In refractory patients, addition of lithium or thyroid hormone may be tried. Also, several reports support the usefulness of combining desipramine with fluoxetine. Although the literature supporting the use of psychostimulants predates DSM-III, they appear effective and well-tolerated in occasional patients who have not improved with more conventional antidepressants. Responsive patients do not usually develop the tolerance or other symptoms of dependence concern for which have led to their underutilization. While patients with a history suggesting attention deficit disorder in childhood are probably prime candidates for a trial of psychostimulants, these drugs probably also deserve a trial in other refractory patients. Typical doses are 5-40 mg/d for dextroamphetamine, and 5-60 mg/d for methylphenidate. 33
SUMMARY
Although the literature appears to demonstrate the efficacy of standard antidepressant medications for the short-term treatment of patients with minor depression, they are not widely prescribed. In comparison, psychotherapy is generally recommended, but without convincing data to support this conviction. We, therefore, advocate successive trials with antidepressants in any depressed patient, particularly if they have failed to benefit from psychotherapy or other supportive measures for three months. REFERENCES 1. Klein, D. F., Gittelman, R., Quitkin, F. & Rifkin, A. (1980). Diagnosis and drug treatment of psychiatric disorders: Adults and children, Second Edition. Baltimore: Williams and Wilkins, pp. 268-408. 2. Kocsis, J. H., Frances, A. J., Voss, C , et al. (1988). Imipramine treatment for chronic depression. Archives of General Psychiatry, 45:253-251. 3. Keller, M., & Shapiro, R. W. (1982). "Double depression": Superimposition of acute depressive episodes on chronic depressive disorders. American journal of Psychiatry, 139:438-442. 4. vander Velde, C. (1981). Maprotiline versus imipramine and placebo in neurotic depression, journal of Clinical Psychiatry, 42:138-141. 5. Bohm, C , Robinson, D. S., Gammans, R. E., et al. (1990). Buspirone therapy in anxious elderly patients: A controlled clinical trial, journal of Clinical Psychopharmacology, 10:47S-51S. 6. Stewart, J. W., Quitkin, F. M., Liebowitz, M. R., et al. (1983). Efficacy of desipramine in depressed
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7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
21. 22. 23. 24. 25. 26. 27. 28.
outpatients: Response according to research diagnostic criteria diagnoses and severity of illness. Archives of General Psychiatry, 40:202-207. Stewart, J. W., McGrath, P. J., Liebowitz, M. R., et al. (1985). Treatment outcome validation of DSM-III depressive subtypes: Clinical usefulness in outpatients with mild to moderate depression. Archives of General Psychiatry, 42:1148-1153. Davidson, J. T., Giller, E. L., Zisook, S., & Overall J. E. (1988). An efficacy study of isocarboxazid and placebo in depression, and its relationship to depressive nosology. Archives of General Psychiatry, 45:120-127. Stewart, J. W., McGrath, P. J., Quitkin, F. M., et al. (1989). Relevance of DSM-III depressive subtype and chronicity of antidepressant efficacy in atypical depression: Differential response to phenelzine, imipramine, and placebo. Archives of General Psychiatry, 46:1080-1087. Stabl, M., Biziere, K., Schmid-Burg, K. W., & Amrein, R. (1989). Review of comparative clinical trials: Moclobemide vs tricyclic antidepressants and vs placebo in depressive states. Journal of Neural Transmission, 28:77-89. Brzezinski, A. A., Wurtman, J. J., Wurtman, R. J., et al. (1990). d-fenfluramine suppresses the increased calorie and carbohydrate intakes and improves the mood of women with premenstrual depression. Obstetrics and Gynecology, 76:296-301. Harrison, W. M., Endicott, J., & Nee, J. (1990). Treatment of premenstrual dysphoria with alprazolam: A controlled study. Archives of General Psychiatry, 47:270-275. Stone, A. B., Pearlstein, T. B., & Brown, W. A. (1991). Fluoxetine in the treatment of late-lutealphase dysphoric disorder. Journal of Clinical Psychiatry>, 52:290-293. Rickels, K., Freeman, E . , & Sonheimer, S. (1989). Buspirone in treatment of premenstrual syndrome. Lancet, i:777. Harrison, W., Rabkin, J., Stewart, J. W., et al. (1986). Phenelzine for chronic depression: A study of continuation treatment. Journal of Clinical Psychiatry, 47:346-349. Kocsis, J. H., Sutton, B. M., & Frances, A. J. (1991). Long-term follow-up of chronic depression treated with imipramine. Journal of Clinical Psychiatry, 52:56-59. de Sousa, M. P., & Tropa, J. (1989). Evaluation of the efficacy of amineptine in a population of 1229 depressed patients: Results of a multicenter study carried out by 135 general practitioners. Clinical Neuropharmacology (Suppl2), 12:S77-S86. Guelfi, J. D., Pichot, P., & Dreyfus, J. F. (1989). Efficacy of tianeptine in anxious-depressed patients: Results of a controlled multicenter trial versus amitriptyline. Neuropsychobiology, 22:42-48. Vallejo, J., Gasto, C , Catalan, R., & Salamero, M. (1987). Double-blind study of imipramine versus phenelzine in melancholias and dysthymic disorders. British Journal of Psychiatry, 151:639-651. Banerji, J. R., Brantingham, P., McEwan, G. D., et al. (1989). A comparison of alprazolam with amitriptyline in the treatment of patients with neurotic or reactive depression: A report of a randomized, double blind study by a General Practitioner Working Party. Irish Journal of Medical Science 1989;158:110-113. Taneri, Z., & Kohler, R. (1989). Fluoxetine versus nomifensine in outpatients with neurotic or reactive depressive disorder. International ClinicalPsychopharmacology (Suppl 4), 1:57-61. Ravaris, C , Robinson, D., Ives, J., et al. (1980). Phenelzine and amitriptyline in the treatment of depression. Archives of General Psychiatry, 37:1075-1080; update of data by Robinson, D., in personal communication, Sept. 1991. Kemali, D. (1989). A multicenter Italian study of amineptine (survector 100). Clinical Neuropharmacology, (Suppl. 2) 12:S41-S50. Akiskal, H. S., King, D., Rosenthal, T. L., et al. (1981). Chronic depressions: Part 1. Clinical and familial characteristics in 137 probands. Journal of Affective Disorders, 3:297-315. Harrison, W. M., Endicott, J., & Nee, J. (1989). Treatment of premenstrual depression with nortriptyline: A pilot study. Journal of Clinical Psychiatry, 50:136-139. DeLeo, D. (1985). S-adenosyl-l-methionine (SAMe) in clinical practice: Preliminary report on 75 minor depressives. Current Therapeutic Research, 37:658-661. Holmes, V. F., Fernandez, F., & Levy, J. K. (1989). Psychostimulant response in AIDS-related complex patients. Journal of Clinical Psychiatry, 50:5-7. Howland, R. H. (1991). Pharmacotherapy of dysthymia: A review. Journal of Clinical Psychopharmacology, 11:83-92.
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AMERICAN JOURNAL OF PSYCHOTHERAPY 29. Teicher, M. H., Glod, C , & Cole, J. O. (1990). Emergence of intense suicidal preoccupation during Fluoxetine treatment. American Journal of Psychiatry, 147:207-210. 30. Fava, M., & Rosenbaum, J. F. (1991). Suicidally andfluoxetine:Is there a relationship? Journal of Clinical Psychiatry, 52:108-111. 31. Beasley, C. M., Jr., Dornseif, B. E., Bosomworth, J. C , et al. (1991). Fluoxetine and suicide: a meta-analysis of controlled trials of treatment for depression. British Journal of Psychiatry, 303:685-692. 32. Blackwell, B. (1963). Hypertensive crisis due to monamine-oxidase inhibitors. Lancet, ii:763—764. 33. Chiarello, R. J., & Cole, J. O. (1987). The use of psychostimulants in general psychiatry. Archives of General Psychiatry, 44:286-295.
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