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Comparative efficacy and safety of MAOIs versus TCAs in treating depression in the elderly
BIOL PSYCHIATRY 1986;21:1155-1166
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Comparative Efficacy and Safety of MAOIs versus TCAs in Treating Depression in the Elderly Anastasios Georgotas, Robert E. McCue, William Hapworth, Eitan Friedman, 0. Mary Kim, Joan Welkowitz, Irene Chang, and Thomas B. Cooper
This comprehensive study investigated both the role of antidepressant drugs in the treatment of affective disorders of later life and their safety with careful clinical and pharmacological monitoring. A 7-week double-blind comparison was made of the eficacy and safety of nortriptyline (a tricyclic), phenelzine (a monoamine oxidase inhibitor), and placebo. The results indicated a response rate of approximately 60% for both nortriptyline and phenelzine versus a 1390 response rate for placebo. Anticholinergic side effects were more frequently reported in the nortriptyline group. Orthostatic symptoms were reported with similar frequency in both drug groups. Overall, both drugs were well tolerated.
Introduction Affective disorders in the elderly constitute the most commonly encountered psychiatric illness (Blazer and Williams 1980; Gurland 1980; Walker and Cogington 1982). Despite this, depression in the elderly has not been studied extensively, and there is confusion and uncertainty about both its prevalence and treatment. This is due partially to diagnostic difficulties resulting from the heterogeneity of these disorders, and to some extent, to the unidimensional focus on the dementias (Georgotas 1983), which has partly overshadowed interest in geriatric depression. In addition, the frequently exaggerated claims about the supremacy of second generation antidepressants have interfered with the study of the efficacy and safety of first generation antidepressants in the elderly. As a result, there is a paucity of well-designed studies with antidepressant drugs in the elderly (Jarvik and Gershon 1985). The depressed elderly have generally been managed under principles largely determined by anecdotal experience and by the limited information from the work of a few investigators. Furthermore, depressed elderly patients have generally been treated like younger individuals, despite certain physical, physiological, and biochemical changes
FromtheDepartmentsofPsychiatry(A.G.,R.E.McC., W.H.,E.F.,O.M.K.),Psychology(J.W.),andPharmacology(E.F.), and the Depression Studies Program (A.G., IX.), New York University School of Medicine; the Department of Clinical Psychopharmacology in Psychiatry (T.B.C.), College of Physicians and Surgeons, Columbia University; the Analytical Psychopharmacology Laboratory (T.B.C.), Nathan Kline Institute, and the New York State Psychiatric Institute (T.B.C.), New York, NY. Supported in pat by NIMH Grant MH351% (A.G.). Address reprint requests to Dr. A. Georgotas, N.Y.U. Medical Center, Department of Psychiatry, 550 First Avenue, New York, NY 10016. Received February 12, 1986; revised April 11,1986.
0 1986 Society of Biological Psychiatry
0006-3223/86/$03.50
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BIOL PSYCHIATRY 19R6:Zi:I 1% -1 ihh
that occur with aging (Nies et al. J977: Walker and Cogington f982: Georgotas et al. 1983a). Of the tricyclic antidepressants (TCAs), nortriptyline seems to be a promising drug for the treatment of the depressed elderly due to its moderately low anticholinergic protile and the accumulated evidence that suggests that it might have fewer cardiovascular side effects particularly orthostatic hypotension (Roose et al. 198l f. Data from several studies (Asberg et al. 1971; Kragh-S~rcnsen et al. 1973; ZiegIer et al. 1976: Montgomery et al. 1378; Sdrensen et al. I9781 seem to indicate that the ‘*therapeutic window” for no~~ptyIinc (NT) does apply to the elderly and falls between 50 and 180 ngimi. As to NTs efficacy, S~renscn et al. ( 19%) treated 19 older patients with good results t 16 responders}. It is also worthy of note that many of the NT responders in the six studies previously cited were above 60 years of age. ~reIimina~ results from our own open study ~Ge~~r~otasct al. 1983af showed a response rate approximating 700/n, and most of the responders had achieved NT plasma levels within the above-described therapeutic range. Monoamine oxidase inhibitors (MAOIs) have been used much less frequently in elderly depressed patients, and there is still a divergence of opinions regarding their use, despite recent findings suggesting a safety profile comparable to TCAs and a broader spectrum of antidcpr~ssant efficacy ~Robinson et al. 1978) than TCAs. These findings, as well as their low level of anticholinergic activity, have prompted some recent studies with promising results in the use of MAOIs in geriatric ~pulations (Ashford and Ford. 1979). In our piiot study (Georgotas et al. I983bf. 20 elderly patients with the Research Diagnostic Criteria IRDC) diagnosis of major depressive illness were treated with phenel2ine (PE) for 2-7 weeks. with few side effects and good results (65% response rate). This is despite the chronicity of some of the cases invoived and their resistance to previous antidepressant treatments. The present study sought to investigate if antidepressant drugs are indicated for treatment of geriatric depression and if careful clinical and pharmacological monitoring would provide an acceptable margin of safety. An additional goal was to assess the comparative efficacy and safety of no~r~ptyline and phenelzine over placebo in depressed geriatric patients.
The study was conducted at the Depression Studies Program of New York University, a research academic facility for the study and treatment of affective disorders. Men and women, 55 years of age and older, complaining of depressive symptoms, were evaluated for entry into this outpatient study. During the initial screening, the treatment plan and study requirements were fully explained and written informed consent secured. Patients inctuded in the study were independently diagnosed by two psychiatrists as suffering from a major depressive disorder as defined by the Research Diagnostic Criteria (Spitzer et al. 1978). A score of 16 or greater on the Hamilton Rating Scale for Depression was also required for inclusion. The depressive subtype (endogenous/nonendogenous) according to RDC was also ascertained. Patients were excluded if they showed evidence of moderate to severe dementia, drug or alcohol dependence as defined by DSM-III, mental re~rdat~on, serious n~urologicai disorders, other preexisting major psychiatric disorders, serious medicaf illness, urinary retention, narrow-angle glaucoma, or supersensitivity to TCAs or MAOIs. The severity
MAOIs vs. TCAs in Elderly Depression
BIOL PSYCHIATRY 1986;21:1155-1166
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of the d~~r~ss~onor its resistance to previous tr~atrn~~t was not a deterrent to inclusion, provided that patients were not actively suicidal and that they had a responsible friend or family member who was in frequent contact with our research team. The treatment of severely depressed patients was both feasible and safe because of optimal monitoring, which included a skilled staff exclusively involved in the study, frequent visits and telephone contact, drug levels, and medical follow-up when indicated. Following this initial phase, patients were given a complete physical examination, electr~ardiogram (ECG), and clinical laboratory evaluations to r&e out active medical problems. Patients with chronic illnesses that were under control were included provided that they met the other criteria and bad obtained clearance from their personal physician. All patients accepted for the study were placed on dietary restrictions for MAOIs.
Assessments Diagnostic evaluation was performed by experienced psychiatrists. An unstructured interview evaluating the patient’s overall psychiatric condition was followed by a more structured interview based on the RDC. Cognitive functioning was rated on the Global Dete~oration Scale (GDS) {Reisberg et ai. f982), which is based on both objective cognitive testing (Guild Memory Test) and on clinical evaluation. Patients included in the study had GDS ratings of 1, 2, or 3 (normal, very mild, mild, res~ctively). Patients with moderate or worse (GDS of 4 or more) cognitive impai~ent were excluded. Severity of depression and efficacy were assessed by the 21-item Hamilton Depression Scale and the Zung Self-Rating Scale and the Clinical Global Impression Scale. Drug safety was monitored th~ughout the trial by utilizing a standard Treatment Emergent Symptom Scale (TESS) and check list.
Study Design and Objective Patients who met the entry criteria were administered placebo during a single-blind washout period of at least 7 days. Any patient not meeting the entry criteria at the end of the washout period was not admitted to the doubIe-blind portion of the study, which lasted 7 weeks. Patients who were admitted were ~ndomly assigned to one of three treatment conditions: no~~ptyline (NT), phenelzine (PE), or placebo (PL). All three substances were in identical capsules that contained either 25 mg of NT, 15 mg of PE, or an inert substance. The initial dose of one capsule for 3 days was increased to two capsules on days 4-7. At the end of the first ~eatment week, the daily dose was increased to three capsules. Blood samples obtained at the end of week 2 were assayed for either NT plasma level or MAO platelet inhibition. Patients on NT who attained a plasma level between 50 and 180 ng/ml remained on three capsules. In patients whose levels were below this therapeutic window, the dosage was raised to four capsules, and if, on the basis of the sample taken at the end of ~eatment week 3, therapeutic levels had still not been achieved, the dose was raised to five capsules. A similar regimen was followed for patients on PE those who did not attain a 70% or greater percentage of MAO inhibition by week 2 were prescribed a dose of four capsules and the dose was raised to five capsules if the specified percent MAO inhibition had not been achieved by week 3. The dose of placebo was aiso adjusted. In the event of side effects that interfered with functioning to a significant degree, dosage was decreased, i~es~ct~ve of percent platelet MAO inhibition or NT level. During each of the seven weekly visits, the patient’s general clinical condition was
noted and the Hamilton scale, Zung scale, CGI, and TESS were completed by a physician blind to the patient’s treatment. Vital signs in both the supine and upright positions were taken. ECGs were completed at the end of the third week and at the final week. Blood samples were obtained each visit from all patients and analyzed for NT plasma level or percent MAO inhibition. Routine laboratory analysis was repeated at the end of the study ,. and a patient termination record was completed. Criteria for Including andlor Excluding Certain Patients from Final Data Analysis Patients completing less than 28 days of treatment for any reason were excluded from the final data analysis. except when signi~cant drug-related adverse reactions required wi~dmwal of medication, or when there was a signi~cant dete~orat~o~ of clinical condition in any patient treated for at least 14 days. All patients completing at least 28 days of active drug treatment were included in the iinal data analysis, unless they failed to achieve NT levels within therapeutic range (50- 180 nglml) or platelet MAO inhibition less than 70% for at least 2 weeks, or if they developed intercurrent illness or were removed from the study due to other reasons not related to psychiatric pathology or study drugs, such as evidence of noncompliance or alcohol or other drug abuse.
The Hamilton and Zung scores over the 7-week treatment period were tested using a repeated measures multiple regression analysis. The baseline score was used as a covariate. The variables of treatment, time, and treatment by time interaction were entered into the analysis. Additional analyses of Hamilton and Zung scores were performed using weekby-week Analyses of Covariance (ANCOVA) with the baseline score as the covariate. Chi-square analyses were used to compare treatment groups for each of the three CGl scales. The frequency of a side effect, the number of patients who reported it, and its mean duration over the treatment period were evaluated using an Analysis of Variance (ANOVA).
Results
Two hundred and ninety-five men and women received an initial evaluation, However, only 137 were found to meet the inclusion criteria of the study. Of these, 11 were never entered into the single-blind placebo washout period. The remaining 126 entered the single blind placebo washout phase, and of these, 36 withdrew or were discontinued prior to entry into the doubly-blind treatment phase for the following reasons: 10 could not obtain medical clearance, 5 dropped out because of subjective side effects on placebo, 3 were placebo responders, 10 could not follow the program requirements, 5 dropped out because of clinical deterioration, aod 3 could not abide by the guidelines for the washout period. Of the 90 patients entered in the double-blind treatment phase, I5 were excluded from the final data analysis for not meeting the criteria for inclusion for that analysis (inadequate levels. premature te~~nations, noncompliances.
BIOL PSYCHIATRY
MAOIs vs. TCAs in Elderly Depression
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1986;21:1155-1166
Table 1. Clinical Ch~acte~sti~s of Patient Sample Placebo (n = 28) Age (years, mean 2
SD)
Sex (m~e~fem~es) Race (white/black) Current medical status (significant health problems/ fair health/good health) RDC subtypes (endogen~s/ nonendogenous) GDS (mean + SD)
Nortriptyline (n = 25)
Phenelzine (n = 22)
Comparison
f 7.6 (range: 55-75) 13115
64.6 -c 6.4 (range: 55-76) 7118
65.5 k 4.4 (range: 56-72) 9113
p = 0.88
2111
24/l
2111
p = 0.98
o/17/11
2/11/6
311118
p = 0.25
19i9
2015
1715
p = 0.56
1.9 + 0.8
2.2 2 0.8
2.0 2 0.8
p = 0.58
64.1
p = 0.38
Table I shows the major demographic and clinical characteristics of the 75 patients used for the efficacy analysis. There were no significant differences, by either x2 or ANOVA, in these factors among the three treatment groups. The patients were predominantly white women, presently or previously married, who had had past depressive episodes. The average length of the present episode was around 4 months. Most patients fit RDC for endogenous depression. A clear precipitant to the present episode was variably present. The patients studied ranged from being moderately to severely ill on the CGI Severity of Illness Scale. None of the patients were delusion~ly depressed. The mean GDS score was 2 for these patients, indicating that for most, only a very mild degree of cognitive impairment was present. None of the patients had pseudodementia. Of the 75 patients who met inclusion criteria for the efficacy analysis, 56 finished 7 weeks of active treatment after 1 week of placebo washout. Of the 19 patients who terminated prematurely, 11 (57.9%) had been in the placebo treatment group and terminated because of clinical dete~oration. Five patients (one placebo, two no~ptyline, two pheneizine) had responded at the time of termination. Two patients in the nortriptyline group and two patients in the phenelzine group dropped out due to side effects. Dosage and Blood Levels The no~~ptyIine group took an average of 79.0 mgfday, whereas the phenelzine patients took an average of 53.9 mglday. The phenelzine-treated patients took significantly more capsules (p < 0.04) during weeks 2-4. After week 4, there were no significant differences in dosage among the three groups. Patients treated with nortriptyline generally reached the optimal range (50-180 t&ml) at week 1, but the phenelzine-treated patients did not reach the minimally acceptable level (>70% inhibition) until week 3. Eficacy Hamilton Depression Scale. A repeated measures analysis comparing changes over time in the total score of the Hamilton Depression Scale, while partialling out the baseline score, showed a signific~t ~eatment effect (p < 0.001). Subsequent pairwise comparisons of treatment groups using a similar repeated measures model showed significant
differences
between no~ripty~ine
and placebo {IT < 0.001) and between phene~zine and patients having s~gni~~ant~y greater reductions in their Hamilton scores than placebo-treated patients. There was no significant difference (p :> 0.10) between nortriptyiine and phenelzine in reducing patients’ totai Hamilton scores. The weekly changes in Hamilton scores were further investigated with ANCOVAS covarying for the baseline score. As shown in Table 2. an overall comparison of the treatment effect shows significant differences (p = 0.037) beginning at week 2. Pairwise ANCOVAs show this to be due to significantly lower Hamilton scores {mean 17.41) in the no~ript~~~~n~ group than in the placebo group (mean 21.65). At week 2, no s~gnj~cant differences were found in Hamilton scores between either the phenetzine (mean 20.561 and placebo patients (f’ = 0.63) or the no~r~ptyl~ne and phene~z~ne patients (p = 0.37). Phenel~jn~-treated patients had signi~cant~y lower Hamilton scores than did pfacehrttreated patients f f4.92 versus 19.79; 13 = O.K!i beginning at week 4. After this point. both the nortriptyline and phenelzine groups were significantly different from the placebo group. At no time were there significant differences in Hamilton scores in comparing no~riptyiin~ and phenelzine patients. Another way of looking at the treatment effect was to classify patients as responders or nonresponders, with a responder having a total Hamilton score of less than or equal to IO. Table 3 shows weekly y’ comparisons of the distribution of responders and nonresponders. Significant differences were found at week\ 3 and 7. The majority (>50%) of no~~pty~ine-treated patients did not respond untit week 5. whereas the majority of phene~~ine-treated patients were not responders until week 7 Of 54 patients who had Hamilton ratings at week 7. 13.3% (2) of the placebo patients. 6f .9% ( 13) of the no~r~ptyline patients. and 61.1% t I I t of the phenetzine patients were responders. fn Iookinp at ail 75 patients who were treald, 10.7% (31 of the placebo group, 60.0% (15) of the nortriptyfine group. and 59. t 54 (1.3) uf the phenelzine had responded during the 7 weeks. In summary, nortriptyline and phenelzine appeared to be signiticantly better in treating depression, as measured by decreases in the Hamilton Depression Scale, than did placebo. There was no significant difference in the treatment effect of nortriptyhne versus phenelzine over the entire 7-week period. Around 60% of patients treated with either drug were responders. Antidepressant-treated patients showed signs of improvement beginning at week 2 for the no~rjpt~lin~ group and at week 4 for the phenclzine group. Most of ptacebo fp CC.O.Wl f, with the antjd~pressant-treated
Table 2. Weekly ~~~~pa~s~~nof Adjuste& Mean T&d -Adjusted Mean Hamilton Placebo Baseline Week 1 Week 2 Week 3 Week 4 Week S Week 6 Week 7
23 .O7
21.65 21.65 19.02 19.79 20.01 19.16 20.32
Nortriptyline
Hamilton Scores Corstparison
by ANCOVA
Overall
PI_. vs. NT
PL vs. PE
NT vs. PE I__,
Scores Phenelzine
23.58 19.7.3 17.11 15.40 13.32
22.14 2I”OO 2O.xl 15.27 I*~.%
[’ -= 0.65 p -= 0.308 p ‘:- 0.037 p = 0.037 {> L= 0.014
p = O.Ol?h p = O.Ol@ p = O.004”
,> r-. 0.54 (r .L. 0.054 17 -2 O.O2h
p = 0.12 p = 0.66 p = 0.53
I l.?J
11.1.
p -= 0.001 p =. Cl.#lh
p = wot~
p = 0.7%
IDS7 10.12
10.98 9.57
,7’ = 0.001 p c 0.001
p -I- O.OO2h p cc 0.0016
p = 0.88 p = 0.80
p z= O.OOlh p < O.OOi”
MAOIs vs. TCAs in
BIOL PSYCHIATRY 1~21:~~55-~1~
Elderly Depression
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Table 3. Percentage of Responders”Per Treatment Group x2 Comparison
Percentage responders (n) Placebo
Nortriptyline
Phenelzine
Overall
Week I Week 2
14.3% (4) 3.7% (1)
4.0% (1) 16.7% (4)
4.5% (1) 9.1% (2)
p = 0.301 p = 0.291
Week 3
21.7% (5)
40.0% (10)
38.1% (8)
p = 0.349
Week 4 Week 5 Week 6 Week 7
10.0% (2) 16.7% (3) 18.8% (3) 13.3% (2)
44.0% 52.2% 56.5% 61.9%
27.3% 47.4% 44.4% 61.1%
p = o.O42b p = 0.051
(1 I) (12) (13) (13)
(6) (9) (8) (II)
p = 0.061 p < o.Ow
PL vs. NT
PL vs. PE
p = p = 0.04* p = p = 0.04b p = p < O.Oib p < p = 0.03h
NT vs. PE
0.10
p = 0.37 p = 1.00
0.22
p = 0.65
0.30
O.OP p = 1.oa
Total Hamilton Score 6 10 “Significant at p i 0.05.
the nortriptyline-treated patients were not responders until week 5, whereas most of the phenelzine-treated patients were not responders until week 7. It appeared that the onset of improvement was earlier for the patients treated with nortriptyline as compared to those treated with phenelzine, although there was never a statistically significant difference between these two groups. This difference may be due to the 2-week lag in achieving optimal levels in the phenelzine group. Zupig SelfiRating SC&. A repeated measures analysis comparing changes over time in Zung scores, while partialling out the baseline score, showed a significant treatment effect (p < 0.05). Pairwise comparisons of treatment groups using a similar repeated measures model showed significant differences in comparing nortriptyline to placebo (p < 0.01) as well as comparing phenelzine to placebo (p < O.Ol), with the active substances causing greater drops in Zung scores over the 7-week period. No significant difference was found (p > 0.10) in comparing nortriptyline and phenelzine. The weekly changes in Zung scores were further investigated with ANCOVAs, partialling out the baseline score. Significant differences in Zung scores across the three treatment groups appeared at week 5 (p = 0.039). From week 5 on, both the no~ptyline and phenelzine patients had significantly lower Zung scores than did the placebo patients. The Zung scores of the no~~ptyline and phenelzine groups were not significantly different at any point in time. In summary, patients treated with either nortriptyline or phenelzine had significant decreases in their Zung scores as compared to patients treated with placebo. These decreases became statistically significant at week 5. No differences were found between the two antidepressants. Clinical Global Impressions (CGI) Scales. Chi-square analyses comparing the three treatment groups on the CGI Severity of Illness Scale showed nortriptyline-treated patients beginning at week 5 and phenelzine-treated patients at week 7 to be significantly more often classified as “normal” or “mildly ill” than placebo-treated patients. There were no signific~t differences in comp~ng the no~ptyline and phenelzine groups, In both ~tidepress~t treatment groups, the majority of patients were classified as “normal” or “mildly ill” beginning at week 5. On the CGI Global Improvement Scales, weekly x2 comparisons of all three treatment groups showed a significant improvement over placebo beginning at week 5 for the
no~riptylin~ group. There were no signihcant differences between the pheneIzine and nortriptyline groups. The majority of no~~ptyline-treated patients were classified as “improved” at week 5 and the majority of phenelzine-treated patients at week 6. Weekly x7 comparisons of the three treatment groups on the CGI Efficacy Scale showed a significant difference at week 5, although none of the subsequent pairwise xL comparisons were significant. At both weeks 6 and 7, antidepressant-treated patients were significantly more often classified as *‘improved” than were placebo-treated patients. In both antidepressant treatment groups. the majority of patients were classified as “improved” at week 5. There was no significant difference between the phenelzine and the nortriptyline groups. In summary, patients classified on the basis of the CC1 were significantly more often classified as “normal” to “mildly ill” or as “improved” if they had been treated with either phenelzine or no~riptyline as compared to placebo. These treatment differences generaIly became significant at week 5.
Side Effects Side effects were evaluated by utilizing a Treatment Emergent Symptom Scale (TESS). Patients were questioned weekly about the presence of symptomatology on the TESS. A side effect was considered to be present if a symptom had not been present at baseline or had been present to a lesser degree at baseline. Table 4 shows the frequencies and duration of the more commonly reported side effects during the 7-week treatment period. Six patients in the placebo group, one in the nortriptyline group, and two in the phenelzine group reported no side effects. The most frequently reported side effect was dry mouth; it occurred significantly more often in nortriptyline patients (79 times in 56% of patients) than in phenelzine patients (44 times in 59% of patients) and placebo patients (14 times in 36% of patients) and significantly more often in phenelzine patients than in placebo patients. The second most frequently reported side effect was constipation; it was reported significantly more often in the nortriptyline group (50 times in 52% of patients) than in the other two groups. The nortriptyline patients (19 times in 32% of patients) and the phenelzine patients (26 times in 45% of patients) reported significantly more drowsiness than placebo-treated patients (4 times in 11% of patients). In addition, phenelzine patients reported drowsiness significantly more frequently than nortriptyline patients. The phenelzine group had significantly more nasal congestion (9 times in 14% of patients), urinary symptoms (24 times in 32% of patients), and de~atological problems (10 times in I8% of patients) than both the nortriptyline and placebo groups. In addition, phenelzine-treated patients reported significantly more tremor (8 times in 14% of patients) than did placebo-treated patients (0 times), and more diarrhea (11 times in 27% of patients) than nortriptyline-treated patients (2 times in 4% of patients). Dizziness was reported fairly often in all three groups (PL,: 22 times in 36% of patients; NT: 36 times in 60% of patients; PE: 28 times in 50% of patients), with no significant differences among them. Orthostatic symptoms were present in roughly equal frequency in both nortriptyline (39 times in 60% of patients) and phenelzine (33 times in 45% of patients) groups and were significantly more frequent than in the placebo group (12 times in 21% of patients). Among patients who reported side effects, comparisons were also made of the duration of the side effect. Most side effects were reported for l-3 weeks, and there were no significant differences in the duration among the three treatment groups. Only dry mouth
4 0 14 7 1 6 22 12 3
“NT > PL, PE > PL at p < 0.05. bPE>PLatp<0.05. =NT>PL,PE>PL,NT>PEatpPLatp PL, NT > PE at p < 0.05. ‘PE > PL, PE > NT atp < 0.05. %PE1 NT at p < 0.05. 'NT > PL, PE > PL at p < 0.05. ‘PE > PL, PE > NT at p < 0.05.
Drowsiness Tremor Dry mouth Constipation Micturition Diarrhea Syncope/dizziness Orthostatic effects Dermatological
3 (11%) 0 (0%) 10 (36%) 3 (11%) 1 (3%) 4 (14%) 10 (36%) 6 (21%) 2 (7%)
No. of patients affected
Placebo
of Side Effects
No. of occurrences
Table 4. Comparison
1.3 0 1.4 2.3 1 1.5 2.2 2 1.5
Mean duration (weeks) 19 6 79 50 4 2 36 39 3
No. of occurrences 8 (32%) 3 (12%) 14 (56%) 13 (52%) 3 (12%) 2 (8%) 15 (60%) 15 (60%) 3 (12%)
No. of patients affected
Nortriptyline
2.4 2 5.6 3.8 1.3 1 2.4 2.6 1
Mean duration (weeks) 26 8 44 18 24 11 28 33 10
No. of occurrences 10 (45%) 3 (14%) 13 (59%) 6 (27%) 7 (32%) 6 (27%) 11 (50%) 10 (45%) 4 (18%)
No. of patients affected
Phenelzine
2.6 2.7 3.4 3 3.4 1.8 2.5 3.3 2.5
Mean duration (weeks)
No. of occurrences/ patient
NS 0.001” 0.026 NS 0.001’ p < O.OJd 0.001’ NS 0.001~ NS NS 0.018g NS NS p = o.c!W NS n = 0.027’ NS
p < p = p < p < p i p =
No. of occurrences
Comparison
was reported signihcantly longer (mean 5.6 weeks) by no~riptyl~ne patients than by either ~hene~zine (mean 3.4 weeks) or placebo (mean 1.4 weeks) patients. One phenelzine-treated patient had to have dosage reductions secondary to dry mouth. tremor. drowsiness, and blurred vision. No patients in the nortriptyline or placebo groups had to have dosage reductions because of side effects. Four patients prematurely terminated because of putative side effects. One no~ri~ty~ine-treated patient dropped out because of palpitations~ another stopped after the occurrence of visual haiIucinations. Two phene~zinc patients prematurely terminated due to possible side effects: one patient fell (no injuries). possibly due to orthostatic hypotension; the other patient reported multiple symptoms. such as pains in the extremities. nausea, blurred vision, and dizziness. In summary, the most frequently reported side effects were anticholinergic (dry mouth and c~~nstipation)and were present si~ni~cantiy more often in no~r~~tyline-treated patients. Dry mouth was atso reported for a si~ni~cantiy longer period of time in no~~~ty~ine patients. Orthostatic symptoms were reported with similar frequency in both nortriptyline and phenelzine patients. There were no significant differences across the three groups in the frequencies of such cardiovascular side effects as palpitations, tachycardia, and dizziness. In general. although there were differences in the distr~buti~~nof side effects. neither of the antidep~ssants appeared to cause more morbidity than the other. Side effects were most often judged to be mild to moderate in severity. were well-tolerated by patients, and did not require any alterations in treatment except for a modest lowering of the dose in five phen~l7,jnc parients.
To our knowledge. this is the first comp~hensive donb~e-b~~ndFlace~~con~o~~ed study investigating the comparative efficacy and safety of nortriptyhne and phenelzine in elderiy patients suffering from the broadly defined RDC diagnosis of major depressive disorder. Insofar as these drugs are representative of their respective classes, our findings can be generalized to a con~parison of the major classes of the first generation antidepressants, the tricychcs and the mon~mine oxidase inhibitors. The results of this show that late-life depressions can be treated despite common misconceptions about their being the natural consequence of aging. It is also clear that both nortriptyline and phenelzine have a definite place as first choice treatments of affective disorders in Later life, regardless of the clinical subtype. This is demonstrated by the sj~ni~cantIy higher response rates (no~riptyline 6596, ph~nelzine 61%) of both drugs as compared to the I3% rate of the placebo group. The response rate of both antidepressants is fairly high considering that this group of patients was heterogeneous with respect to both diagnoses and severity of illness. As is usual for our clinic population, many of the patients were at the end of the road because of previous treatment failures and were willing to undergo the rigors of a pIace~-controlled design because they felt desperate. Although signs of improvement were apparent earlier, it took, under the optimal conditions of this study, at least 5 weeks to observe a significant antidepressant response. This important finding should be seriously considered in future pharmacological studies in the elderly, as the usual length of the treatment phase (around 4 weeks) is probably inadequate. This should also be kept in mind in everyday clinical practice, as clinicians frequently change medications after only a few weeks in elderly patients who are not apparentfy responding.
MAOIs vs. TCAs in
Elderly Depression
BIOL PSYCHIATRY 1986:21:1155-1166
1165
There has been a repeated emphasis on the seriousness of side effects of antidep~ssant drugs in the elderly. This has perhaps been exaggerated in several recent reports dealing with comparative trials of first- and second-generation antidepressants. Interestingly enough, in most of these trials, aside from other methodological shortcomings, the antidepressants usually chosen were almost always from the tricyclic class and were frequently tertiary amines, which are notorious for their high incidence of anticholinergic, cardiovascular, and sedative side effects. MAOIs have almost always been excluded from comp~ative studies because of the fear of orthostatic hypotension or of a hypertensive crisis. However, some recent studies have supported their efficacy and safety in elderly depressed patients (Georgotas et al. 1981; Ashford and Ford 1979; Georgotas et al. 1983a). An earlier study also showed that elderly patients responded considerably better than younger adult patients to phenelzine (Robinson 1974). This is not to say that tricyclic antidepressants or MAOIs are devoid of significant toxicity. However, as we have reported (Georgotas et al, 1983a), with a careful selection of patients and of drugs, proper dosing based on optimal levels, few readjustments of the dose, an adequate treatment time, and the elimination of unnecessary concurrent medications, both TCAs and MAOIs are easily tolerated by the elderly. This is supported by our present study, in which only 9 (5 on placebo) of 90 patients were prematurely terminated because of putative side effects. For the most part, the adverse reactions to both drugs were of mild to moderate severity and well tolerated. Most patients continued treatment while experiencing side effects and eventually had a favorable outcome. In no cases were there disastrous consequences, such as confusional states or severe injuries. Nortriptyline, as expected, seemed to have a higher anticholinergic profile than either phenelzine or placebo. On the other hand, phenelzine-fated patients reported significantly more frequent drowsiness, nasal congestion, urinary symptoms, and skin rashes than both the nortriptyline and placebo patients, more tremor than placebo patients, and more diarrhea than nortriptyline-treated patients. Despite the overstated fear of potentially fatal hypertensive crises associated with MAOIs, none of our phenelzine patients experienced one. This is consistent with other studies in younger populations, where the incidence of hy~~ensive reactions to phenelzine were found to be almost negligible (Raskin 1972; Nies and Robinson 1980). The ability of our population to tolerate these drugs is made clear by the high degree of compliance and the low dropout rate throughout the study. It should also be noted that MAO dietary restrictions were not a significant deterrent for the majority of our patients. The results of the present investigation elucidate the success with which depression in later life can be treated with ph~acothe~py. The results also clarify the comparative efficacy and safety of representatives of the two major classes of first-generation antidepressants. It should be emphasized, however, that neither of these drugs is a panacea for depression in the elderly. There is still work to be done regarding the identification of subtypes of depression in the elderly, their response patterns to pharmacotherapy, and the development of novel antidepressants with distinct advantages in terms of efficacy and side effects. These issues remain an important challenge for current research.
The authorswish to thank Ms. EthelFdelstein for her excellent secretarial assistance. We would also like to acknowledge the expert technica assistance of Mr. David Allen, Ms. Audrey Meister, Brenda Katos, and Rhoda Imow for no~ptyiine assays, as well as Ms. Mary Armour and Joan Kuster for MAO assays.
1166
BIOL PSYCHIATRY 198~21:1155-1 lhh
4. tieorgotas
et ;ri
References 8, Sjoqvist F, Tuck D (1971): Relationship therapeutic effect of nortriptyline. ff r Med J 3:33 1-334.
Asberg M, Cr~~~lrn
Ashford JW, Ford VC (1979): Use of MAO inhibitors 136:1466-1467. tllazer D, Williams CD (1980): Epide~ology Am .I Psychiatq 137:439-444. Georgotas A (1983): Affective Age Age&g lZ:I-10.
disorders
between
in elderly patients.
plasma level and Am J Pxyychiutt~
of dysphoria and depression in an elderly population.
in the elderly: Diagnostic
and research considerations.
Georgotas A, Mann J, Friedman E (1981): Platelet mono~ine oxidase inhibition as a potential indicator of favorable response to MAOIs in geriatric depression. Biol Psychiarry l6:997-1001. Georgotas A, Cooper T, Kim M. Hapworth W ( 1983a): The treatment of affective disorders in the elderly. P.~y~hophurmaco~Brrll 19:226-237. Georgotas A. Friedman E, McCarthy M, Mann J, Krakowski M, Siege1 R, Ferris S (1983b): Resistant geriatric depressions and therapeutic response to monoamine oxidase inhibitors. Biol Psychiatry 18:195-205. Guriand B (1980): The epidemiology of depression and dementia in the elderly: The use of multiple indicators of these conditions. In Cole, Barrett feds), P.~chopa?hology in the Aged. New York: Raven Press, pp 37-60. Jarvik LS, Gerson S (1985): Outcome of drug treatment in depressed patients over the age of fifty. in Shamoian (ed), Treatment of Affective Disorders in the elderly. Washington, DC: APA Press. pp 29-36. Kragh-Sdrensen P, Asberg M, Christian depression. Lancer i:ll3-115.
EH (1973): Plasma-nortriptyline
levels in endogenous
Montgomery SA. Braithwaite R, Dawling S, McAuley R (1978): High plasma nortriptyline in the ~eatment of depression. Clin P~r~col Ther 23:309-314. Nies A, Robinson DS (1980): Monoamine oxidase inhibitors. Affective Disorders. Edinburgh: Churchill Livingstone.
levels
In Paykel ES (ed). Handbook q/
Nies A, Robinson DS, Friedman MJ, Green R, Cooper TB, Ravaris CL, Ives JO (1977): Relationship between age and tricyclic antidepressant plasma levels. Am J P~ch~uf~ 134:790-793. Raskm A (1972): Adverse reactions to phenelzine: Clin Pharmacol 12:22-25.
Results of a nine-hospital
Reisberg B, Ferris SH, de Leon MJ, Crook T (1982): The giobal deterioration of primary degenerative dementia. Am J Psy~hiafry 139:1136-l 139.
depression
study. J
scale for assessment
Robinson DS ( 1974): Age-related factors affecting antidepressant drug metabolism and clinical response. In Nancy K (ed), Geriatric Psychopharmacology. New York: Elsevier-North Holland. Robinson DS, Nies A, Ravaris L. Ives JO, Bartlett D (1978): Clinical pharmacofogy Arch Gcn Psy~hiut~ 35:629-635.
of phenelzine.
Roose S, Classman AH, Siris S, et al (198 1): Comparison of imipramine- and nottriptyline-induced orthostatic hypotension: A meaningful difference. J Clin Psychopharmacol I:3 16-321. Sll(rensen B, Kragh-SBrensen P. Larsen NE, Hvidberg EF (1978): The practical significance of no~p~iine plasma control. A prospective evaluation under routine conditions in endogenous depression. Psychopharmucoiogy (Bed) 59:35-39. Spitzer RD, Endicott J, Robins E (1978): Research Diagnostic Criteria. Rationale and reliability. Arch Gen Psychiarry 35:773-782. Walker JI, Cogin~on TR f 1982): Diagnosis and ph~acological elderly. J Clin Exp Gerontol 4: I-39.
m~agement
Ziegler VE, Clayton PJ, Taylor JR, Co BT, Biggs JT (1976): Nortriptyline therapeutic response. Clin Pharmucol Ther 20:458-463.
of depression
in the
plasma levels and
1155
Comparative Efficacy and Safety of MAOIs versus TCAs in Treating Depression in the Elderly Anastasios Georgotas, Robert E. McCue, William Hapworth, Eitan Friedman, 0. Mary Kim, Joan Welkowitz, Irene Chang, and Thomas B. Cooper
This comprehensive study investigated both the role of antidepressant drugs in the treatment of affective disorders of later life and their safety with careful clinical and pharmacological monitoring. A 7-week double-blind comparison was made of the eficacy and safety of nortriptyline (a tricyclic), phenelzine (a monoamine oxidase inhibitor), and placebo. The results indicated a response rate of approximately 60% for both nortriptyline and phenelzine versus a 1390 response rate for placebo. Anticholinergic side effects were more frequently reported in the nortriptyline group. Orthostatic symptoms were reported with similar frequency in both drug groups. Overall, both drugs were well tolerated.
Introduction Affective disorders in the elderly constitute the most commonly encountered psychiatric illness (Blazer and Williams 1980; Gurland 1980; Walker and Cogington 1982). Despite this, depression in the elderly has not been studied extensively, and there is confusion and uncertainty about both its prevalence and treatment. This is due partially to diagnostic difficulties resulting from the heterogeneity of these disorders, and to some extent, to the unidimensional focus on the dementias (Georgotas 1983), which has partly overshadowed interest in geriatric depression. In addition, the frequently exaggerated claims about the supremacy of second generation antidepressants have interfered with the study of the efficacy and safety of first generation antidepressants in the elderly. As a result, there is a paucity of well-designed studies with antidepressant drugs in the elderly (Jarvik and Gershon 1985). The depressed elderly have generally been managed under principles largely determined by anecdotal experience and by the limited information from the work of a few investigators. Furthermore, depressed elderly patients have generally been treated like younger individuals, despite certain physical, physiological, and biochemical changes
FromtheDepartmentsofPsychiatry(A.G.,R.E.McC., W.H.,E.F.,O.M.K.),Psychology(J.W.),andPharmacology(E.F.), and the Depression Studies Program (A.G., IX.), New York University School of Medicine; the Department of Clinical Psychopharmacology in Psychiatry (T.B.C.), College of Physicians and Surgeons, Columbia University; the Analytical Psychopharmacology Laboratory (T.B.C.), Nathan Kline Institute, and the New York State Psychiatric Institute (T.B.C.), New York, NY. Supported in pat by NIMH Grant MH351% (A.G.). Address reprint requests to Dr. A. Georgotas, N.Y.U. Medical Center, Department of Psychiatry, 550 First Avenue, New York, NY 10016. Received February 12, 1986; revised April 11,1986.
0 1986 Society of Biological Psychiatry
0006-3223/86/$03.50
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BIOL PSYCHIATRY 19R6:Zi:I 1% -1 ihh
that occur with aging (Nies et al. J977: Walker and Cogington f982: Georgotas et al. 1983a). Of the tricyclic antidepressants (TCAs), nortriptyline seems to be a promising drug for the treatment of the depressed elderly due to its moderately low anticholinergic protile and the accumulated evidence that suggests that it might have fewer cardiovascular side effects particularly orthostatic hypotension (Roose et al. 198l f. Data from several studies (Asberg et al. 1971; Kragh-S~rcnsen et al. 1973; ZiegIer et al. 1976: Montgomery et al. 1378; Sdrensen et al. I9781 seem to indicate that the ‘*therapeutic window” for no~~ptyIinc (NT) does apply to the elderly and falls between 50 and 180 ngimi. As to NTs efficacy, S~renscn et al. ( 19%) treated 19 older patients with good results t 16 responders}. It is also worthy of note that many of the NT responders in the six studies previously cited were above 60 years of age. ~reIimina~ results from our own open study ~Ge~~r~otasct al. 1983af showed a response rate approximating 700/n, and most of the responders had achieved NT plasma levels within the above-described therapeutic range. Monoamine oxidase inhibitors (MAOIs) have been used much less frequently in elderly depressed patients, and there is still a divergence of opinions regarding their use, despite recent findings suggesting a safety profile comparable to TCAs and a broader spectrum of antidcpr~ssant efficacy ~Robinson et al. 1978) than TCAs. These findings, as well as their low level of anticholinergic activity, have prompted some recent studies with promising results in the use of MAOIs in geriatric ~pulations (Ashford and Ford. 1979). In our piiot study (Georgotas et al. I983bf. 20 elderly patients with the Research Diagnostic Criteria IRDC) diagnosis of major depressive illness were treated with phenel2ine (PE) for 2-7 weeks. with few side effects and good results (65% response rate). This is despite the chronicity of some of the cases invoived and their resistance to previous antidepressant treatments. The present study sought to investigate if antidepressant drugs are indicated for treatment of geriatric depression and if careful clinical and pharmacological monitoring would provide an acceptable margin of safety. An additional goal was to assess the comparative efficacy and safety of no~r~ptyline and phenelzine over placebo in depressed geriatric patients.
The study was conducted at the Depression Studies Program of New York University, a research academic facility for the study and treatment of affective disorders. Men and women, 55 years of age and older, complaining of depressive symptoms, were evaluated for entry into this outpatient study. During the initial screening, the treatment plan and study requirements were fully explained and written informed consent secured. Patients inctuded in the study were independently diagnosed by two psychiatrists as suffering from a major depressive disorder as defined by the Research Diagnostic Criteria (Spitzer et al. 1978). A score of 16 or greater on the Hamilton Rating Scale for Depression was also required for inclusion. The depressive subtype (endogenous/nonendogenous) according to RDC was also ascertained. Patients were excluded if they showed evidence of moderate to severe dementia, drug or alcohol dependence as defined by DSM-III, mental re~rdat~on, serious n~urologicai disorders, other preexisting major psychiatric disorders, serious medicaf illness, urinary retention, narrow-angle glaucoma, or supersensitivity to TCAs or MAOIs. The severity
MAOIs vs. TCAs in Elderly Depression
BIOL PSYCHIATRY 1986;21:1155-1166
1157
of the d~~r~ss~onor its resistance to previous tr~atrn~~t was not a deterrent to inclusion, provided that patients were not actively suicidal and that they had a responsible friend or family member who was in frequent contact with our research team. The treatment of severely depressed patients was both feasible and safe because of optimal monitoring, which included a skilled staff exclusively involved in the study, frequent visits and telephone contact, drug levels, and medical follow-up when indicated. Following this initial phase, patients were given a complete physical examination, electr~ardiogram (ECG), and clinical laboratory evaluations to r&e out active medical problems. Patients with chronic illnesses that were under control were included provided that they met the other criteria and bad obtained clearance from their personal physician. All patients accepted for the study were placed on dietary restrictions for MAOIs.
Assessments Diagnostic evaluation was performed by experienced psychiatrists. An unstructured interview evaluating the patient’s overall psychiatric condition was followed by a more structured interview based on the RDC. Cognitive functioning was rated on the Global Dete~oration Scale (GDS) {Reisberg et ai. f982), which is based on both objective cognitive testing (Guild Memory Test) and on clinical evaluation. Patients included in the study had GDS ratings of 1, 2, or 3 (normal, very mild, mild, res~ctively). Patients with moderate or worse (GDS of 4 or more) cognitive impai~ent were excluded. Severity of depression and efficacy were assessed by the 21-item Hamilton Depression Scale and the Zung Self-Rating Scale and the Clinical Global Impression Scale. Drug safety was monitored th~ughout the trial by utilizing a standard Treatment Emergent Symptom Scale (TESS) and check list.
Study Design and Objective Patients who met the entry criteria were administered placebo during a single-blind washout period of at least 7 days. Any patient not meeting the entry criteria at the end of the washout period was not admitted to the doubIe-blind portion of the study, which lasted 7 weeks. Patients who were admitted were ~ndomly assigned to one of three treatment conditions: no~~ptyline (NT), phenelzine (PE), or placebo (PL). All three substances were in identical capsules that contained either 25 mg of NT, 15 mg of PE, or an inert substance. The initial dose of one capsule for 3 days was increased to two capsules on days 4-7. At the end of the first ~eatment week, the daily dose was increased to three capsules. Blood samples obtained at the end of week 2 were assayed for either NT plasma level or MAO platelet inhibition. Patients on NT who attained a plasma level between 50 and 180 ng/ml remained on three capsules. In patients whose levels were below this therapeutic window, the dosage was raised to four capsules, and if, on the basis of the sample taken at the end of ~eatment week 3, therapeutic levels had still not been achieved, the dose was raised to five capsules. A similar regimen was followed for patients on PE those who did not attain a 70% or greater percentage of MAO inhibition by week 2 were prescribed a dose of four capsules and the dose was raised to five capsules if the specified percent MAO inhibition had not been achieved by week 3. The dose of placebo was aiso adjusted. In the event of side effects that interfered with functioning to a significant degree, dosage was decreased, i~es~ct~ve of percent platelet MAO inhibition or NT level. During each of the seven weekly visits, the patient’s general clinical condition was
noted and the Hamilton scale, Zung scale, CGI, and TESS were completed by a physician blind to the patient’s treatment. Vital signs in both the supine and upright positions were taken. ECGs were completed at the end of the third week and at the final week. Blood samples were obtained each visit from all patients and analyzed for NT plasma level or percent MAO inhibition. Routine laboratory analysis was repeated at the end of the study ,. and a patient termination record was completed. Criteria for Including andlor Excluding Certain Patients from Final Data Analysis Patients completing less than 28 days of treatment for any reason were excluded from the final data analysis. except when signi~cant drug-related adverse reactions required wi~dmwal of medication, or when there was a signi~cant dete~orat~o~ of clinical condition in any patient treated for at least 14 days. All patients completing at least 28 days of active drug treatment were included in the iinal data analysis, unless they failed to achieve NT levels within therapeutic range (50- 180 nglml) or platelet MAO inhibition less than 70% for at least 2 weeks, or if they developed intercurrent illness or were removed from the study due to other reasons not related to psychiatric pathology or study drugs, such as evidence of noncompliance or alcohol or other drug abuse.
The Hamilton and Zung scores over the 7-week treatment period were tested using a repeated measures multiple regression analysis. The baseline score was used as a covariate. The variables of treatment, time, and treatment by time interaction were entered into the analysis. Additional analyses of Hamilton and Zung scores were performed using weekby-week Analyses of Covariance (ANCOVA) with the baseline score as the covariate. Chi-square analyses were used to compare treatment groups for each of the three CGl scales. The frequency of a side effect, the number of patients who reported it, and its mean duration over the treatment period were evaluated using an Analysis of Variance (ANOVA).
Results
Two hundred and ninety-five men and women received an initial evaluation, However, only 137 were found to meet the inclusion criteria of the study. Of these, 11 were never entered into the single-blind placebo washout period. The remaining 126 entered the single blind placebo washout phase, and of these, 36 withdrew or were discontinued prior to entry into the doubly-blind treatment phase for the following reasons: 10 could not obtain medical clearance, 5 dropped out because of subjective side effects on placebo, 3 were placebo responders, 10 could not follow the program requirements, 5 dropped out because of clinical deterioration, aod 3 could not abide by the guidelines for the washout period. Of the 90 patients entered in the double-blind treatment phase, I5 were excluded from the final data analysis for not meeting the criteria for inclusion for that analysis (inadequate levels. premature te~~nations, noncompliances.
BIOL PSYCHIATRY
MAOIs vs. TCAs in Elderly Depression
1159
1986;21:1155-1166
Table 1. Clinical Ch~acte~sti~s of Patient Sample Placebo (n = 28) Age (years, mean 2
SD)
Sex (m~e~fem~es) Race (white/black) Current medical status (significant health problems/ fair health/good health) RDC subtypes (endogen~s/ nonendogenous) GDS (mean + SD)
Nortriptyline (n = 25)
Phenelzine (n = 22)
Comparison
f 7.6 (range: 55-75) 13115
64.6 -c 6.4 (range: 55-76) 7118
65.5 k 4.4 (range: 56-72) 9113
p = 0.88
2111
24/l
2111
p = 0.98
o/17/11
2/11/6
311118
p = 0.25
19i9
2015
1715
p = 0.56
1.9 + 0.8
2.2 2 0.8
2.0 2 0.8
p = 0.58
64.1
p = 0.38
Table I shows the major demographic and clinical characteristics of the 75 patients used for the efficacy analysis. There were no significant differences, by either x2 or ANOVA, in these factors among the three treatment groups. The patients were predominantly white women, presently or previously married, who had had past depressive episodes. The average length of the present episode was around 4 months. Most patients fit RDC for endogenous depression. A clear precipitant to the present episode was variably present. The patients studied ranged from being moderately to severely ill on the CGI Severity of Illness Scale. None of the patients were delusion~ly depressed. The mean GDS score was 2 for these patients, indicating that for most, only a very mild degree of cognitive impairment was present. None of the patients had pseudodementia. Of the 75 patients who met inclusion criteria for the efficacy analysis, 56 finished 7 weeks of active treatment after 1 week of placebo washout. Of the 19 patients who terminated prematurely, 11 (57.9%) had been in the placebo treatment group and terminated because of clinical dete~oration. Five patients (one placebo, two no~ptyline, two pheneizine) had responded at the time of termination. Two patients in the nortriptyline group and two patients in the phenelzine group dropped out due to side effects. Dosage and Blood Levels The no~~ptyIine group took an average of 79.0 mgfday, whereas the phenelzine patients took an average of 53.9 mglday. The phenelzine-treated patients took significantly more capsules (p < 0.04) during weeks 2-4. After week 4, there were no significant differences in dosage among the three groups. Patients treated with nortriptyline generally reached the optimal range (50-180 t&ml) at week 1, but the phenelzine-treated patients did not reach the minimally acceptable level (>70% inhibition) until week 3. Eficacy Hamilton Depression Scale. A repeated measures analysis comparing changes over time in the total score of the Hamilton Depression Scale, while partialling out the baseline score, showed a signific~t ~eatment effect (p < 0.001). Subsequent pairwise comparisons of treatment groups using a similar repeated measures model showed significant
differences
between no~ripty~ine
and placebo {IT < 0.001) and between phene~zine and patients having s~gni~~ant~y greater reductions in their Hamilton scores than placebo-treated patients. There was no significant difference (p :> 0.10) between nortriptyiine and phenelzine in reducing patients’ totai Hamilton scores. The weekly changes in Hamilton scores were further investigated with ANCOVAS covarying for the baseline score. As shown in Table 2. an overall comparison of the treatment effect shows significant differences (p = 0.037) beginning at week 2. Pairwise ANCOVAs show this to be due to significantly lower Hamilton scores {mean 17.41) in the no~ript~~~~n~ group than in the placebo group (mean 21.65). At week 2, no s~gnj~cant differences were found in Hamilton scores between either the phenetzine (mean 20.561 and placebo patients (f’ = 0.63) or the no~r~ptyl~ne and phene~z~ne patients (p = 0.37). Phenel~jn~-treated patients had signi~cant~y lower Hamilton scores than did pfacehrttreated patients f f4.92 versus 19.79; 13 = O.K!i beginning at week 4. After this point. both the nortriptyline and phenelzine groups were significantly different from the placebo group. At no time were there significant differences in Hamilton scores in comparing no~riptyiin~ and phenelzine patients. Another way of looking at the treatment effect was to classify patients as responders or nonresponders, with a responder having a total Hamilton score of less than or equal to IO. Table 3 shows weekly y’ comparisons of the distribution of responders and nonresponders. Significant differences were found at week\ 3 and 7. The majority (>50%) of no~~pty~ine-treated patients did not respond untit week 5. whereas the majority of phene~~ine-treated patients were not responders until week 7 Of 54 patients who had Hamilton ratings at week 7. 13.3% (2) of the placebo patients. 6f .9% ( 13) of the no~r~ptyline patients. and 61.1% t I I t of the phenetzine patients were responders. fn Iookinp at ail 75 patients who were treald, 10.7% (31 of the placebo group, 60.0% (15) of the nortriptyfine group. and 59. t 54 (1.3) uf the phenelzine had responded during the 7 weeks. In summary, nortriptyline and phenelzine appeared to be signiticantly better in treating depression, as measured by decreases in the Hamilton Depression Scale, than did placebo. There was no significant difference in the treatment effect of nortriptyhne versus phenelzine over the entire 7-week period. Around 60% of patients treated with either drug were responders. Antidepressant-treated patients showed signs of improvement beginning at week 2 for the no~rjpt~lin~ group and at week 4 for the phenclzine group. Most of ptacebo fp CC.O.Wl f, with the antjd~pressant-treated
Table 2. Weekly ~~~~pa~s~~nof Adjuste& Mean T&d -Adjusted Mean Hamilton Placebo Baseline Week 1 Week 2 Week 3 Week 4 Week S Week 6 Week 7
23 .O7
21.65 21.65 19.02 19.79 20.01 19.16 20.32
Nortriptyline
Hamilton Scores Corstparison
by ANCOVA
Overall
PI_. vs. NT
PL vs. PE
NT vs. PE I__,
Scores Phenelzine
23.58 19.7.3 17.11 15.40 13.32
22.14 2I”OO 2O.xl 15.27 I*~.%
[’ -= 0.65 p -= 0.308 p ‘:- 0.037 p = 0.037 {> L= 0.014
p = O.Ol?h p = O.Ol@ p = O.004”
,> r-. 0.54 (r .L. 0.054 17 -2 O.O2h
p = 0.12 p = 0.66 p = 0.53
I l.?J
11.1.
p -= 0.001 p =. Cl.#lh
p = wot~
p = 0.7%
IDS7 10.12
10.98 9.57
,7’ = 0.001 p c 0.001
p -I- O.OO2h p cc 0.0016
p = 0.88 p = 0.80
p z= O.OOlh p < O.OOi”
MAOIs vs. TCAs in
BIOL PSYCHIATRY 1~21:~~55-~1~
Elderly Depression
1161
Table 3. Percentage of Responders”Per Treatment Group x2 Comparison
Percentage responders (n) Placebo
Nortriptyline
Phenelzine
Overall
Week I Week 2
14.3% (4) 3.7% (1)
4.0% (1) 16.7% (4)
4.5% (1) 9.1% (2)
p = 0.301 p = 0.291
Week 3
21.7% (5)
40.0% (10)
38.1% (8)
p = 0.349
Week 4 Week 5 Week 6 Week 7
10.0% (2) 16.7% (3) 18.8% (3) 13.3% (2)
44.0% 52.2% 56.5% 61.9%
27.3% 47.4% 44.4% 61.1%
p = o.O42b p = 0.051
(1 I) (12) (13) (13)
(6) (9) (8) (II)
p = 0.061 p < o.Ow
PL vs. NT
PL vs. PE
p = p = 0.04* p = p = 0.04b p = p < O.Oib p < p = 0.03h
NT vs. PE
0.10
p = 0.37 p = 1.00
0.22
p = 0.65
0.30
O.OP p = 1.oa
Total Hamilton Score 6 10 “Significant at p i 0.05.
the nortriptyline-treated patients were not responders until week 5, whereas most of the phenelzine-treated patients were not responders until week 7. It appeared that the onset of improvement was earlier for the patients treated with nortriptyline as compared to those treated with phenelzine, although there was never a statistically significant difference between these two groups. This difference may be due to the 2-week lag in achieving optimal levels in the phenelzine group. Zupig SelfiRating SC&. A repeated measures analysis comparing changes over time in Zung scores, while partialling out the baseline score, showed a significant treatment effect (p < 0.05). Pairwise comparisons of treatment groups using a similar repeated measures model showed significant differences in comparing nortriptyline to placebo (p < 0.01) as well as comparing phenelzine to placebo (p < O.Ol), with the active substances causing greater drops in Zung scores over the 7-week period. No significant difference was found (p > 0.10) in comparing nortriptyline and phenelzine. The weekly changes in Zung scores were further investigated with ANCOVAs, partialling out the baseline score. Significant differences in Zung scores across the three treatment groups appeared at week 5 (p = 0.039). From week 5 on, both the no~ptyline and phenelzine patients had significantly lower Zung scores than did the placebo patients. The Zung scores of the no~~ptyline and phenelzine groups were not significantly different at any point in time. In summary, patients treated with either nortriptyline or phenelzine had significant decreases in their Zung scores as compared to patients treated with placebo. These decreases became statistically significant at week 5. No differences were found between the two antidepressants. Clinical Global Impressions (CGI) Scales. Chi-square analyses comparing the three treatment groups on the CGI Severity of Illness Scale showed nortriptyline-treated patients beginning at week 5 and phenelzine-treated patients at week 7 to be significantly more often classified as “normal” or “mildly ill” than placebo-treated patients. There were no signific~t differences in comp~ng the no~ptyline and phenelzine groups, In both ~tidepress~t treatment groups, the majority of patients were classified as “normal” or “mildly ill” beginning at week 5. On the CGI Global Improvement Scales, weekly x2 comparisons of all three treatment groups showed a significant improvement over placebo beginning at week 5 for the
no~riptylin~ group. There were no signihcant differences between the pheneIzine and nortriptyline groups. The majority of no~~ptyline-treated patients were classified as “improved” at week 5 and the majority of phenelzine-treated patients at week 6. Weekly x7 comparisons of the three treatment groups on the CGI Efficacy Scale showed a significant difference at week 5, although none of the subsequent pairwise xL comparisons were significant. At both weeks 6 and 7, antidepressant-treated patients were significantly more often classified as *‘improved” than were placebo-treated patients. In both antidepressant treatment groups. the majority of patients were classified as “improved” at week 5. There was no significant difference between the phenelzine and the nortriptyline groups. In summary, patients classified on the basis of the CC1 were significantly more often classified as “normal” to “mildly ill” or as “improved” if they had been treated with either phenelzine or no~riptyline as compared to placebo. These treatment differences generaIly became significant at week 5.
Side Effects Side effects were evaluated by utilizing a Treatment Emergent Symptom Scale (TESS). Patients were questioned weekly about the presence of symptomatology on the TESS. A side effect was considered to be present if a symptom had not been present at baseline or had been present to a lesser degree at baseline. Table 4 shows the frequencies and duration of the more commonly reported side effects during the 7-week treatment period. Six patients in the placebo group, one in the nortriptyline group, and two in the phenelzine group reported no side effects. The most frequently reported side effect was dry mouth; it occurred significantly more often in nortriptyline patients (79 times in 56% of patients) than in phenelzine patients (44 times in 59% of patients) and placebo patients (14 times in 36% of patients) and significantly more often in phenelzine patients than in placebo patients. The second most frequently reported side effect was constipation; it was reported significantly more often in the nortriptyline group (50 times in 52% of patients) than in the other two groups. The nortriptyline patients (19 times in 32% of patients) and the phenelzine patients (26 times in 45% of patients) reported significantly more drowsiness than placebo-treated patients (4 times in 11% of patients). In addition, phenelzine patients reported drowsiness significantly more frequently than nortriptyline patients. The phenelzine group had significantly more nasal congestion (9 times in 14% of patients), urinary symptoms (24 times in 32% of patients), and de~atological problems (10 times in I8% of patients) than both the nortriptyline and placebo groups. In addition, phenelzine-treated patients reported significantly more tremor (8 times in 14% of patients) than did placebo-treated patients (0 times), and more diarrhea (11 times in 27% of patients) than nortriptyline-treated patients (2 times in 4% of patients). Dizziness was reported fairly often in all three groups (PL,: 22 times in 36% of patients; NT: 36 times in 60% of patients; PE: 28 times in 50% of patients), with no significant differences among them. Orthostatic symptoms were present in roughly equal frequency in both nortriptyline (39 times in 60% of patients) and phenelzine (33 times in 45% of patients) groups and were significantly more frequent than in the placebo group (12 times in 21% of patients). Among patients who reported side effects, comparisons were also made of the duration of the side effect. Most side effects were reported for l-3 weeks, and there were no significant differences in the duration among the three treatment groups. Only dry mouth
4 0 14 7 1 6 22 12 3
“NT > PL, PE > PL at p < 0.05. bPE>PLatp<0.05. =NT>PL,PE>PL,NT>PEatp
Drowsiness Tremor Dry mouth Constipation Micturition Diarrhea Syncope/dizziness Orthostatic effects Dermatological
3 (11%) 0 (0%) 10 (36%) 3 (11%) 1 (3%) 4 (14%) 10 (36%) 6 (21%) 2 (7%)
No. of patients affected
Placebo
of Side Effects
No. of occurrences
Table 4. Comparison
1.3 0 1.4 2.3 1 1.5 2.2 2 1.5
Mean duration (weeks) 19 6 79 50 4 2 36 39 3
No. of occurrences 8 (32%) 3 (12%) 14 (56%) 13 (52%) 3 (12%) 2 (8%) 15 (60%) 15 (60%) 3 (12%)
No. of patients affected
Nortriptyline
2.4 2 5.6 3.8 1.3 1 2.4 2.6 1
Mean duration (weeks) 26 8 44 18 24 11 28 33 10
No. of occurrences 10 (45%) 3 (14%) 13 (59%) 6 (27%) 7 (32%) 6 (27%) 11 (50%) 10 (45%) 4 (18%)
No. of patients affected
Phenelzine
2.6 2.7 3.4 3 3.4 1.8 2.5 3.3 2.5
Mean duration (weeks)
No. of occurrences/ patient
NS 0.001” 0.026 NS 0.001’ p < O.OJd 0.001’ NS 0.001~ NS NS 0.018g NS NS p = o.c!W NS n = 0.027’ NS
p < p = p < p < p i p =
No. of occurrences
Comparison
was reported signihcantly longer (mean 5.6 weeks) by no~riptyl~ne patients than by either ~hene~zine (mean 3.4 weeks) or placebo (mean 1.4 weeks) patients. One phenelzine-treated patient had to have dosage reductions secondary to dry mouth. tremor. drowsiness, and blurred vision. No patients in the nortriptyline or placebo groups had to have dosage reductions because of side effects. Four patients prematurely terminated because of putative side effects. One no~ri~ty~ine-treated patient dropped out because of palpitations~ another stopped after the occurrence of visual haiIucinations. Two phene~zinc patients prematurely terminated due to possible side effects: one patient fell (no injuries). possibly due to orthostatic hypotension; the other patient reported multiple symptoms. such as pains in the extremities. nausea, blurred vision, and dizziness. In summary, the most frequently reported side effects were anticholinergic (dry mouth and c~~nstipation)and were present si~ni~cantiy more often in no~r~~tyline-treated patients. Dry mouth was atso reported for a si~ni~cantiy longer period of time in no~~~ty~ine patients. Orthostatic symptoms were reported with similar frequency in both nortriptyline and phenelzine patients. There were no significant differences across the three groups in the frequencies of such cardiovascular side effects as palpitations, tachycardia, and dizziness. In general. although there were differences in the distr~buti~~nof side effects. neither of the antidep~ssants appeared to cause more morbidity than the other. Side effects were most often judged to be mild to moderate in severity. were well-tolerated by patients, and did not require any alterations in treatment except for a modest lowering of the dose in five phen~l7,jnc parients.
To our knowledge. this is the first comp~hensive donb~e-b~~ndFlace~~con~o~~ed study investigating the comparative efficacy and safety of nortriptyhne and phenelzine in elderiy patients suffering from the broadly defined RDC diagnosis of major depressive disorder. Insofar as these drugs are representative of their respective classes, our findings can be generalized to a con~parison of the major classes of the first generation antidepressants, the tricychcs and the mon~mine oxidase inhibitors. The results of this show that late-life depressions can be treated despite common misconceptions about their being the natural consequence of aging. It is also clear that both nortriptyline and phenelzine have a definite place as first choice treatments of affective disorders in Later life, regardless of the clinical subtype. This is demonstrated by the sj~ni~cantIy higher response rates (no~riptyline 6596, ph~nelzine 61%) of both drugs as compared to the I3% rate of the placebo group. The response rate of both antidepressants is fairly high considering that this group of patients was heterogeneous with respect to both diagnoses and severity of illness. As is usual for our clinic population, many of the patients were at the end of the road because of previous treatment failures and were willing to undergo the rigors of a pIace~-controlled design because they felt desperate. Although signs of improvement were apparent earlier, it took, under the optimal conditions of this study, at least 5 weeks to observe a significant antidepressant response. This important finding should be seriously considered in future pharmacological studies in the elderly, as the usual length of the treatment phase (around 4 weeks) is probably inadequate. This should also be kept in mind in everyday clinical practice, as clinicians frequently change medications after only a few weeks in elderly patients who are not apparentfy responding.
MAOIs vs. TCAs in
Elderly Depression
BIOL PSYCHIATRY 1986:21:1155-1166
1165
There has been a repeated emphasis on the seriousness of side effects of antidep~ssant drugs in the elderly. This has perhaps been exaggerated in several recent reports dealing with comparative trials of first- and second-generation antidepressants. Interestingly enough, in most of these trials, aside from other methodological shortcomings, the antidepressants usually chosen were almost always from the tricyclic class and were frequently tertiary amines, which are notorious for their high incidence of anticholinergic, cardiovascular, and sedative side effects. MAOIs have almost always been excluded from comp~ative studies because of the fear of orthostatic hypotension or of a hypertensive crisis. However, some recent studies have supported their efficacy and safety in elderly depressed patients (Georgotas et al. 1981; Ashford and Ford 1979; Georgotas et al. 1983a). An earlier study also showed that elderly patients responded considerably better than younger adult patients to phenelzine (Robinson 1974). This is not to say that tricyclic antidepressants or MAOIs are devoid of significant toxicity. However, as we have reported (Georgotas et al, 1983a), with a careful selection of patients and of drugs, proper dosing based on optimal levels, few readjustments of the dose, an adequate treatment time, and the elimination of unnecessary concurrent medications, both TCAs and MAOIs are easily tolerated by the elderly. This is supported by our present study, in which only 9 (5 on placebo) of 90 patients were prematurely terminated because of putative side effects. For the most part, the adverse reactions to both drugs were of mild to moderate severity and well tolerated. Most patients continued treatment while experiencing side effects and eventually had a favorable outcome. In no cases were there disastrous consequences, such as confusional states or severe injuries. Nortriptyline, as expected, seemed to have a higher anticholinergic profile than either phenelzine or placebo. On the other hand, phenelzine-fated patients reported significantly more frequent drowsiness, nasal congestion, urinary symptoms, and skin rashes than both the nortriptyline and placebo patients, more tremor than placebo patients, and more diarrhea than nortriptyline-treated patients. Despite the overstated fear of potentially fatal hypertensive crises associated with MAOIs, none of our phenelzine patients experienced one. This is consistent with other studies in younger populations, where the incidence of hy~~ensive reactions to phenelzine were found to be almost negligible (Raskin 1972; Nies and Robinson 1980). The ability of our population to tolerate these drugs is made clear by the high degree of compliance and the low dropout rate throughout the study. It should also be noted that MAO dietary restrictions were not a significant deterrent for the majority of our patients. The results of the present investigation elucidate the success with which depression in later life can be treated with ph~acothe~py. The results also clarify the comparative efficacy and safety of representatives of the two major classes of first-generation antidepressants. It should be emphasized, however, that neither of these drugs is a panacea for depression in the elderly. There is still work to be done regarding the identification of subtypes of depression in the elderly, their response patterns to pharmacotherapy, and the development of novel antidepressants with distinct advantages in terms of efficacy and side effects. These issues remain an important challenge for current research.
The authorswish to thank Ms. EthelFdelstein for her excellent secretarial assistance. We would also like to acknowledge the expert technica assistance of Mr. David Allen, Ms. Audrey Meister, Brenda Katos, and Rhoda Imow for no~ptyiine assays, as well as Ms. Mary Armour and Joan Kuster for MAO assays.
1166
BIOL PSYCHIATRY 198~21:1155-1 lhh
4. tieorgotas
et ;ri
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