Clomipramine augmentation in treatment-resistant depression

Amsterdam et al.
Jay D. Amsterdam, M.D.,* Felipe García-España, Ph.D., and Martin Rosenzweig, M.D.
In depression that is resistant to tricyclic antidepressant (TCA) therapy, the
substitution of a selective serotonin re-uptake inhibitor (SSRI), clomipramine,
or a monoamine oxidase (MAO) inhibitor has been recommended. However,
adding an additional antidepressant medication from a different drug class
may produce even more rapid efficacy. In this regard, the combination of a
MAO inhibitor or a SSRI plus a TCA has been shown to be of value in treat-
ment-resistant depression (TRD).

In this report, we examined the efficacy of clomipramine augmentation in
20 patients who failed to respond to either a MAO inhibitor or fluoxetine
therapy for at least a 6-week period, and compared this to a third group given
MAO inhibitor plus a conventional TCA.

Two out of 9 (22%) MAO inhibitor/clomipramine patients and 4 out of 11
(36%) fluoxetine/clomipramine patients improved (Fisher’s Exact test, P =
ns), compared to 3 out of 7 (43%) patients taking MAO inhibitor/TCA (
P =
ns). However, the MAO inhibitor/clomipramine group experienced signifi-
cantly more adverse events which necessitated stopping treatment (56%) when
compared to the fluoxetine/clomipramine (9%) and compared to the MAO in-
hibitor/TCA group (0%) (
c2 = 8.9, df = 2, P < 0.05). These adverse events
included several cases of serotonin syndrome of mild to moderate severity.
These observations indicate that clomipramine augmentation of a failed MAO
inhibitor trial is of marginal efficacy (compared to augmentation with a con-
ventional TCA) and should be employed with extreme caution. Depression
and Anxiety 5:84–90, 1997. 1997 Wiley-Liss, Inc.

Key words: clomipramine; MAO inhibitor; tricyclic antidepressant;
refractory depression; serotonin syndrome; drug interaction

Hornig-Rohan, 1996). Unfortunately, there is a pau-city of systematic data available to compare between Advances is psychopharmacologic treatment of mood
the bewildering number of drug combinations and disorders have contributed to improved response rates augmentation strategies. While there are some data to in patients with treatment-resistant depression suggest that particular antidepressants may demon- (TRD). Using currently accepted strategies of anti- strate a preferential response in patients with specific depressant drug combinations and augmentations, diagnostic subtypes of major depression (Liebowitz et as many as 85% of patients with major depression al., 1984; Himmelhoch et al., 1991; Nierenberg et al., will demonstrate a satisfactory treatment outcome.
1994), comparative antidepressant efficacy rates in There remains, however, a significant number of treatment-refractory depression are rare. In this patients (15%) who have persistent, treatment-refrac- context, we (Nierenberg and Amsterdam, 1990; Am- tory depression. Even after controlling for importantfactors such as duration of treatment, medication dos-age, diagnostic issues (e.g., co-morbid diagnoses), and Depression Research Unit, Department of Psychiatry, Univer-
sity of Pennsylvania School of Medicine, Philadelphia, PA

pharmacokinetic issues (e.g., plasma drug concentra-tions, variance in drug metabolism, etc.), a substantial *Correspondence to: Jay D. Amsterdam, M.D., Depression Re- percentage of patients still fail to respond to what ap- search Unit, University Science Center, 8th Floor, 3600 Market pears to be an ‘‘adequate’’ antidepressant drug trial. A variety of treatment algorithms have been proposedusing drug combinations and augmentation strategies Received for publication 23 February 1996; Revised 22 Novem- (Nierenberg and Amsterdam, 1990; Amsterdam and 1997 WILEY-LISS, INC.
Research Article: Clomipramine Augmentation
sterdam and Hornig-Rohan, 1996) and others (Him- has recently been shown to be of value in patients with melhoch et al., 1991; Thase et al., 1992) have sug- TRD (Trimble, 1990). In fact, some investigators have gested that some TRD patients with unipolar or suggested that augmentation with clomipramine may re- bipolar depression may demonstrate a preferential re- sult in an enhanced efficacy of the existing antidepressant sponse to either a MAO inhibitor or a mixed seroto- nin/noradrenalin re-uptake inhibitor. Although there In the present report, we examined the comparative are some data to support the contention that these efficacy and safety of adding clomipramine to a failed drug classes may be superior to conventional TCAs trial of either (1) a MAO inhibitor or (2) fluoxetine in (Quitkin et al., 1979; Himmelhoch et al., 1991; Thase patients with TRD, and compared this treatment to et al., 1992; Nierenberg et al., 1994), there is less in- (3) augmentation of a failed MAO inhibitor with a formation available on comparative efficacy of combi- nation drug therapy (e.g., the addition of a TCA) ineither MAO inhibitor or SSRI treatment failure.
In TRD patients for whom standard antidepressant therapy has failed, and in whom there is a substantial SUBJECTS
likelihood of morbidity and/or mortality from suicide, Twenty outpatients with TRD from the Depression it is justified for physicians to take cautiously mea- Research Unit at the Hospital of the University of sured risks. In this context, the risk-to-benefit ratio Pennsylvania received clomipramine augmentation for patients with treatment-resistant depression must therapy: 14 women and 6 men with a mean (±SD) age extend beyond the issue of efficacy vs. side effects to of 42 ± 12 years (range 23 to 69 years). All patients include factors such as the risk of suicide and the rela- met DSM-III-R criteria (American Psychiatric Asso- tive risk of ‘‘therapeutic decrement’’ after repeated ciation, 1988) for major depression and had moderate treatment failures (Amsterdam and Maislin, 1994; to severe symptoms with a Hamilton Depression Amsterdam and Hornig-Rohan, 1996). While the use Rating Scale (HDRS) (Hamilton, 1960) score ≥21 of drug combinations and augmentation strategies in on the 20-item scale prior to initiating clomi- TRD is not without potential risks, a more comprehen- pramine augmentation. Demographic features are dis- sive understanding of the relative risk-to-benefit ratio of played in Table 1. All patients had previously failed to specific treatment strategies can result in an enhanced respond to at least a 6-week prospective trial of either therapeutic outcome with fewer adverse events.
a MAO inhibitor or fluoxetine (Amsterdam and Clomipramine is a unique TCA which differs from Hornig-Rohan, 1996) immediately prior to clomi- conventional TCAs, and possesses substantial inhibition pramine augmentation (Table 1). Patients with psy- of serotonin (5HT) re-uptake (Carlsson et al., 1969). It chotic features or a diagnosis of schizophrenia, organic TABLE 1. Patient characteristics and outcome for clomipramine (CMI) augmentationa
aMAOI = monoamine oxidase inhibitor; FLU = fluoxetine; + = full response as defined in text; – = no or minimal response; s.e. = side effects necessitatingcessation of trial. 86
Amsterdam et al.
affective disorder, dysthymia, or characterologic disor- Seven additional patients (3 women and 4 men) EFFICACY
with a mean age of 41 ± 14 years (range 26 to 69 years) ANOVAs demonstrated no difference in age (F = who had failed to respond to a previous MAO inhibitor 0.46, df = 2,26; P = ns) or the number of prior drug trial, and who received augmentation with a conven- trials (F = 0.69, df = 2,26; P = ns) across the three tional TCA, were also examined for comparison with the treatment groups. Two out of 9 patients (22%) taking clomipramine augmentation groups (Table 2).
a MAO inhibitor, and 4 out of 11 patients (36%) tak- All patients had received a complete medical evalua- ing fluoxetine, responded to clomipramine augmenta- tion prior to augmentation therapy, and all were tion (Fisher’s Exact test, P = ns). Similarly, 3 out of 7 physically healthy and without meaningful laboratory MAO inhibitor patients (43%) responded to augmen- tation with a conventional TCA (vs. 2 of 9 receivingclomipramine augmentation) (Fisher’s Exact test, P = PROCEDURES
ns) (Tables 1 and 2). The mean daily clomipramine aug- A retrospective review of treatment outcome was mentation dose was 150 ± 90 mg (range 50 to 250 mg) in conducted on patients who had either (1) clomip- the responders and 136 ± 113 mg (range 25 to 300 mg) ramine augmentation of a failed MAO inhibitor trial in the nonresponders (t = 0.28, df = 18, P = ns).
(n = 9) or (2) clomipramine augmentation of a failedfluoxetine trial (n = 11). These groups were then com- ADVERSE EVENTS
pared to (3) patients who received conventional TCA While most patients experienced some mild side ef- augmentation of a failed MAO inhibitor trial (n = 7).
fects from the addition of clomipramine to their exist- All patients were treated in an open, naturalistic fash- ing drug therapy, only those adverse events that were ion. Clomipramine augmentation was initiated at 25 severe enough to warrant cessation of treatment were mg daily and was gradually titrated upward (as toler- considered for the purposes of statistical analysis ated) to a maximum daily dose of 300 mg. Patients (Table 3). Overall, 6 out of 9 patients (67%) receiving who tolerated clomipramine augmentation remained clomipramine augmentation experienced severe side on combination MAO inhibitor/clomipramine effects. Five of these patients (56%) were taking a therapy for at least 4 additional weeks for assess- MAO inhibitor and received a mean daily clomip- ment of treatment outcome. Clinical ratings were ramine dose of 50 ± 31 mg (range 25 to 100 mg). Side obtained for efficacy (Hamilton, 1960) with ‘‘re- effects were usually characterized by symptoms of se- sponse”’ defined as a ≥50% reduction in the base- rotonin syndrome (e.g., restlessness, agitation, anxiety, line HDRS score and a final HDRS score ≤9. In nervousness, diaphoresis, muscle fasiculations and those cases where severe side effects necessitated myoclonic discharge, hyperreflexia, tremor, and occa- discontinuation of treatment, appropriate documen- sionally mental confusion). One patients had symp- tation was obtained in order to determine the na- toms severe enough to require hospitalization, while ture of the treatment-emergent adverse events.
two others required immediate medical attention at ahospital emergency room. Serotonin-related side ef- STATISTICAL PROCEDURES
fects typically occurred within 4 to 48 h of adding clo- Because the data were derived from an open, unran- mipramine to the MAO inhibitor treatment, and in domized, naturalistic setting, we considered the sample one subject symptoms began within 2 h of receiving a to include all 27 subjects. Categorical variables were as- single 25-mg clomipramine tablet (Table 3). In con- sessed using the chi-square or Fisher’s Exact test (where trast, only one of 11 patients (9%) receiving the appropriate). ANOVAs and unpaired t-tests were used to combination of fluoxetine and clomipramine devel- examine continuous variables. Statistical significance was oped severe side affects (Fisher’s Exact test, P = 0.05). Significantly, none of the patients who re- TABLE 2. Patient characteristics and outcome for tricyclic-MAOI augmentationa
aDMI = desipramine; NTP = nortriptylene; IMI = imipramine; + = full reponse as defined in text; – = no or minimal response. Research Article: Clomipramine Augmentation
TABLE 3. Characteristics of patients who discontinued due to side effectsa
aTCP = tranylcypromine; ISO = isocarboxide; PLZ = phenelzine; FLU = fluoxetine. ceived TCA augmentation of their MAO inhibitor de- were substantial (about 20–30%) with causes variously veloped severe side effects or needed to discontinue attributed to sub-optimal dosing and treatment length the trial (Fisher’s Exact test, P < 0.05).
(Keller et al., 1982), variability in TCA metabolism Finally, a chi-square analysis was performed among (Glassman et al., 1977; Amsterdam et al., 1979), or in- the three augmentation treatment groups by the cat- adequate drug concentrations (Asberg, 1976; Amster- egories of (1) response, (2) nonresponse, and (3) se- dam et al., 1980). This scenario has not substantially vere side effects (χ2 = 9.0, df = 4, P < 0.06) (Table 4).
changed with the introduction of SSRIs (Fava et al., While there did not appear to be a significant differ- 1994). While some clinicians have advocated switch- ence in efficacy among the three treatment groups, ing from the failed antidepressant to another agent in there was a significant difference in the rate of severe a different chemical class (e.g., a TCA to a SSRI or side effects with substantially more events observed in MAO inhibitor), the empirical justification for this the MAO inhibitor/clomipramine treatment group (χ2 strategy is limited (Nystrom and Hallstrom, 1987; Nolen et al., 1988a,b). Moreover, there is also evi-dence that the use of high-dose therapy with some an- DISCUSSION
tidepressants may reverse what appears to be TRDwithout the necessity of switching to a new antide- As many as 30% of depressed patients fail to re- pressant (Amsterdam et al., 1979; Amsterdam, 1991; spond to treatment with a tricyclic antidepressant (TCA) and at least 60–75% may fail to achieve com- More recently, SSRIs have been used in the treat- plete remission (Roose et al., 1986). In its broadest ment of TRD (Tyrer et al., 1987; Amsterdam and form, TRD may characterize the majority of de- Maislin, 1994), and as adjunctive therapy in patients pressed patients in therapy and substantially contrib- who have failed to respond to a TCA (Rosenthal et al., ute to the overwhelming morbidity and mortality 1991). However, even after an adequate trial of fluox- associated with this syndrome (Keller et al., 1982, etine at 20 mg daily for up to 3 months, remission rates 1986; Keller, 1988). The paucity of attention given to (final HDRS score ≤7) were only 56% in patients with a the systematic treatment of TRD has led to inconsis- prior history of TRD (Amsterdam and Maislin, 1994).
tent and haphazard treatment approaches. Moreover, In lieu of TCAs and SSRIs for the treatment of treatment algorithms suggesting the step-wise selec- TRD, some investigators have reported MAO inhibi- tion of medication with optimal dosage and duration tors to be superior in many patients resistant to other of administration have often led to confusion regard- antidepressants (McGrath et al., 1987; Nolen et al., ing what constitutes ‘‘adequate’’ therapy for TRD.
1988a; Amsterdam, 1991; Thase et al., 1992). But Thus, prior to the advent of SSRIs, treatment of what does one do when a MAO inhibitor fails? In pa- MDD usually began with a TCA. Non-response rates tients who do not respond to MAO inhibitor therapy, TABLE 4. Rates of response and adverse events during CMI and TCA augmentationa (%)
aCMI = clomipramine; FLU = fluoxetine; TCA= tricyclic antidepressant; χ2 = 9.0, df = 4, P < 0.06. 88
Amsterdam et al.
some investigators have suggested augmenting with an been reported with clomipramine (Insel et al., 1982) additional antidepressant like lithium, (Nelson and and fluoxetine (Beasley et al., 1993). Therefore, when Byck, 1982), L-tryptophan (Pare, 1963), or the cau- assessing treatment options in TRD, the risk-to-ben- tious administration of a TCA (Davidson, 1982; efit ratio of clomipramine augmentation should be Amsterdam and Hornig-Rohan, 1996). However, con- carefully analyzed before adding clomipramine with cerns over drug interactions have limited the use of extreme caution to an existing MAO inhibitor trial.
MAO inhibitor augmentation strategies.
Several caveats should be considered in the inter- In the present study, we examined the relative safety pretation of the present results. The use of MAO and efficacy of augmenting a failed fluoxetine or MAO inhibitor/CMI combination in the present report inhibitor trial with adjunctive clomipramine, a potent was undertaken before the extreme dangers of this re-uptake site inhibitor of 5HT (as well as NA). We drug combination were generally appreciated. Al- then compared these treatment groups to a separate though case reports of 5HT syndrome had been re- group of TRD patients receiving a MAO inhibitor, ported as early as the 1970s (Beaumont, 1973; which was augmented with a conventional TCA (ex- Marley and Wozniak, 1984; Blackwell, 1991; Stern cluding clomipramine). We observed no overall dif- et al., 1992), there have been no systematic com- ference in efficacy among the three treatment groups parisons of patients treated with the combination of (χ2 = 0.83, P = ns), although there were significantly an MAO inhibitor plus CMI vs. an MAO inhibitor more serious side effects observed in the MAO inhibi- tor/clomipramine group (56%) compared to the fluox- Additionally, there are obvious limitations to the etine/clomipramine group (9%) (Fisher’s Exact test, P naturalistic, retrospective design of this study. This < 0.05). Interestingly, there were no serious adverse factor, together with the lack of a comparable patient events necessitating cessation of treatment in the group receiving placebo augmentation places con- MAO inhibitor/TCA group. Thus, we observed a sub- straints upon the conclusions that can be drawn about stantial risk-to-benefit ratio for MAO inhibitor/ the relative clomipramine efficacy of the three treat- clomipramine combination compared to that of MAO ments for TRD. The use of a placebo control group inhibitor/TCA combination to such an extent (Table might have enhanced the present study design, as a 4) that we would suggest dropping clomipramine aug- modest reduction in depressive symptomatology can mentation of a failed MAO inhibitor trial from treat- be expected in some depressed patients treated with ment algorithms for TRD. In contrast, to the high placebo. However, the use of a placebo control might side effect rate with MAO inhibitor/clomipramine raise ethical concerns in patients with TRD (Stanley, therapy, we observed no adverse events severe enough 1988). In addition, the limited sample size of each to warrant treatment cessation with the MAO inhibi- treatment cell detracts from the ability to distinguish tor/TCA combination. This observation comports statistical significance and limits the inferences that well with earlier reports documenting the relative can be drawn from the present results.
safety of this drug combination in TRD. In this re- The assessment of prior drug non-response, al- gard, several investigators reported similar rates of though made prospectively, was naturalistic in side effects in patients taking a combination of MAO context and not part of a controlled drug trial. Con- inhibitor/TCA compared to 150 patients receiving ei- sequently, documentation of the ‘‘adequacy’’ of ther a MAO inhibitor or TCA alone (Spiker and prior drug therapy with either fluoxetine, a TCA or Pugh, 1976; Davidson et al., 1987). On the other had, a MAO inhibitor must be considered as questionable the substantial number of potentially serious seroto- in the absence of a prospective treatment study. Thus, nin-related side effects resulting from clomipramine it is possible that some of the patients characterized as augmentation of a MAO inhibitor strengthens prior TRD might have responded if they had prospectively observations indicating that clomipramine is pharma- received treatment. In the present study, we defined cologically distinct from other TCAs and should not an ‘‘adequate’’ prior treatment to be at least 6 weeks.
be viewed as a conventional TCA with relatively weak However, this time frame may have been too short to 5HT re-uptake inhibition (Insel et al., 1982). Reports truly estimate a TRD status (Greenhouse et al., 1987).
of similar side effects as those experienced in the In this regard, prior studies (Georgotas et al., 1987; MAO inhibitor/clomipramine group have been re- Greenhouse et al., 1987; Schweizer et al., 1990) suggest ported with the addition of L-tryptophan (Glassman that a proportion of patients thought to have TRD may and Plattman, 1969) and, more recently, with fluoxe- actually be responders with ‘‘pseudo-TRD.’’ tine (Beasley et al., 1993). These similarities in side In summary, we found no statistically significant effects between clomipramine and other 5HT enhanc- difference in efficacy among the three treatment TRD ing compounds strongly suggest that the adverse groups. However, the combination of MAO inhibitor/ events observed in the present study with MAO in- clomipramine caused significantly more serious ad- hibitor/clomipramine augmentation result from en- verse events necessitating treatment cessation (56%) hancement of 5HT neurotransmission. Moreover, we when compared to the fluoxetine/clomipramine (9%) observed this effect after a single, low dose of clomip- (Fisher’s Exact test, P < 0.05) or MAO inhibitor/TCA ramine in one patient, and similar observations have combination (0%). Finally, we observed a marginally Research Article: Clomipramine Augmentation
significant association (P < 0.06) between response and Davidson J, Raft D, Pelton S (1987) An outpatient evaluation of side effects among the three treatment groups, indi- phenelzine and imipramine. J Clin Psychiatry 48:143–146.
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