Original Author: Paul Perry, Ph.D, BCPP
Latest Revisers: Paul Perry, Ph.D, BCPP, Dan Smith, Pharm.D.,
BCPP
Creation Date: 1996
Peer Review Status: Internally Peer Reviewed
This handout will discuss the acute (versus prophylactic) management of depression. Maintenance and prophylactic treatment is reviewed in a subsequent monograph. The use of the term "depression" will be used generically unless otherwise specified (i.e., bipolar disorder, depression; major depression, single episode; dysthymia; atypical depression).
Antidepressant classification include "first-and second-generation" compounds, monoamine oxidase inhibitors (MAOI), lithium, carbamazepine, CNS stimulants, and 5-hydroxytryptophan. The first generation antidepressants are the tricyclic antidepressants (TCA). Second generation antidepressants currently marketed include maprotiline, trazodone, amoxapine, bupropion, and fluoxetine. The second generation or newer antidepressants were introduced in the late 1970s and the 1980s. Fluoxetine was marketed in February 1988 and is discussed in detail in a separate article in this text. Bupropion, which is a second generation agent, was removed from the U.S. market in 1986 because of seizures. It was marketed in July 1989 with a reduction in maximum dose and is discussed in detail in a subsequent monograph.
MAOIs currently available include phenelzine, tranylcypromine, and isocarboxazid. A fourth MAOI, pargyline, is marketed as an antihypertensive drug, not as an antidepressant.
FIRST GENERATION ANTIDEPRESSANTS
Morris and Beck extensively reviewed the literature in 1974 regarding the efficacy of TCAs in depression. This review compared imipramine, amitriptyline, nortriptyline, desipramine, protriptyline, and doxepin. Trimipramine, which was introduced after 1974, was the last TCA to be introduced in the U.S. Their extensive review concluded there is no difference in the efficacy of the six TCAs surveyed. Though trimipramine has not been compared to all six TCAs, a similar conclusion is reached because of reports of similar efficacy to imipramine and amitriptyline (Anon 1980).
TCA are effective treatment for 60-70% of moderately to severely depressed patients (Rogers and Clay 1975). By contrast, 30-40% of such patients improve with placebo. Thus, one third of patients have a specific drug response (the drug-placebo difference), one third improve with nonspecific treatment (the placebo response), and one third do not respond to a given antidepressant.
Prediction of antidepressant drug response remains an active research topic. The ability to predict drug response based on clinical information (i.e., family history, presenting symptoms, etc.) and/or biological markers (i.e., DST, TRH) would be a significant advance in the pharmacologic management of the depressed patient. A review by Bielski and Friedel in 1976 based on prospective, double-blind controlled studies with amitriptyline and imipramine indicated that the predictors of a positive response were as follows: upper socioeconomic class, insidious onset, anorexia, weight loss, middle and late insomnia, and psychomotor disturbance. Predictors of poor response to these two TCA were the following: neurotic, hypochondriocal, and hysterical traits, multiple prior episodes, and delusions.
Roose et al (1986) in a retrospective report of unipolar, nondelusional depression tried to identify characteristics of TCA responders. Seventeen patients who failed to respond were compared to a group of TCA responders with respect to demographic and phenomenologic variables. No distinguishing characteristics could be identified.
That low levels of urinary metabolites of NE or serotonin might be a key to preferential response to "primary" noradrenergic or serotonin antidepressants has been suggested but not conclusively demonstrated (Extein 1984).
The enthusiasm which led to widespread clinical use of the DST as a depression marker is fading because of reports of the test's lack of specificity. However, research is focusing on the utility of combining the results of the DST and the thyroid releasing hormone (TRH) test. Though some reports indicate that a positive DST or TRH test predicts antidepressant response the data is too limited to reach a conclusion. Likewise, there is no evidence to date that either test predicts preferential response to an individual antidepressant (Extein et al 1984).
Three recently reported studies have suggested that orthostatic hypotension may be a predictor of antidepressant response. Jarvik et al (1983) found in patients 55 years and older who had major depression and who were treated with imipramine or doxepin pretreatment orthostatic hypotension predicted treatment response: 11 of 13 (85%) of those who improved on TCAs had a blood pressure fall of at least 12 mm Hg; of nine nonresponders, eight (89%) had decreases of 10 mm Hg or less. Schneider et al (1986) prescribed nortriptyline, 50 to 125 mg/d, to outpatients 60 years of age or older with major depression. They found a positive correlation between pretreatment orthostatic hypotension and improvement in depression. Davidson and Turnbull (1986) reported that pretreatment postural blood pressure decrease predicted clinical improvement with isocarboxazid. All eight patients with a drop of at least 10 mm Hg responded favorably to the drug, as compared to only 15 of 26 (57%) whose blood pressure dropped less (p<.02).
SECOND GENERATION ANTIDEPRESSANTS
Most double-blind, placebo-controlled trials demonstrate that amoxapine has a similar efficacy and onset of action as the TCAs. Although most direct comparison studies lack a placebo control, maprotiline is considered as effective an antidepressant as the reference TCAs.
The clinical efficacy of trazodone in the treatment of depression has been tested in about two dozen double-blind, placebo-controlled studies in Europe and the U.S. These studies concluded that trazodone is consistently superior to placebo and is not significantly different from standard TCAs in regards to efficacy. When administered in equivalent doses (i.e., 300-600 mg/d) its onset of action does not differ from the first generation antidepressants.
However, some clinicians have observed that sleep may improve with trazodone but the core symptoms of depression remain. It is important to note, with the exception of one multicenter trial, most trazodone studies would be unlikely to detect a difference between it and the reference drug because of relatively small numbers of patients in each treatment group. Shopsin (1980) has cited several unpublished well-controlled trials conducted at different institutions that found trazodone to have very low response rates (i.e., 10-20%).
Fluoxetine and bupropion has been demonstrated to be more effective than placebo, but equal in efficacy to standard TCAs in the treatment of major depressive disorder. See handouts in this text for details.
MONOAMINE OXIDASE INHIBITORS
Efficacy - Placebo and TCAs
Morris and Beck in a 1974 review of the literature reported phenelzine (Nardil®) more effective than placebo in five of nine (56%) controlled studies while tranylcypromine (Parnate®) was more effective than placebo in three of four studies. When compared to the TCAs, all three studies reported tranylcypromine as effective as imipramine. Imipramine was more effective than phenelzine in five of nine (56%) studies, while in four studies no difference was noted between the two antidepressants. Prior to 1974, MAOIs were considered less effective than TCAs.
There is evidence to suggest that early recommended doses of MAOIs were too low (Pare 1985). Between 1973 and 1984 nine of ten placebo-controlled studies of phenelzine in depression demonstrated a positive outcome for phenelzine (Zisook 1985). Similar findings have been reported with isocarboxazid (2 studies) and tranylcypromine (3 studies) (Zisook 1985).
Subtypes of depression
Since the late 1950s, the MAOI group of antidepressants has been suggested to be specially effective in treating "atypical depression." West and Dally in 1959 conducted an uncontrolled, open study involving 101 consecutively treated, depressed patients receiving variable doses of iproniazid. Fifty-eight patients showed a good response to the drug. Analysis of the symptoms of the responders and nonresponders showed iproniazid to be effective in the group of "atypical or hysterical" depressions. The characteristics of this group included somatic overactivity, such as tremulousness, and getting more depressed in the evening. Marked self-reproach, early morning waking, and weight loss were not seen in this type of patient. Also, in this type of patient improvement occurred usually from the fifth to the eighth day after treatment. Although patients with more classical endogenous depression could be helped by iproniazid, improvement was rarely as quick and as complete.
Since this report, there have been other descriptive studies and anecdotal reports claiming that MAOIs are effective in "atypical" depression. Recently one research group has defined "atypical depression" by the following criteria (Nies 1984):
Several studies have divided patients based on endogenous vs nonendogenous symptoms. A sample of studies follow discussing response of "atypical patients to MAOIs.
Controlled studies were not performed until the 1973 when Robinson et al carried out a double-blind, controlled trial using phenelzine versus placebo. In this study involving 60 outpatients, 33 were treated with phenelzine 45-75 mg/d, and 27 were treated with placebo for six weeks. The dosage of phenelzine was adjusted to achieve 80% inhibition of platelet MAO activity. The result, based on the Hamilton Rating Scale for Depression (HRSD), showed that overall improvement was higher in the phenelzine group (p < 0.01). When examining individual symptoms, those symptoms showing statistically significant improvement involved a motor component, such as retardation, anxiety, agitation, and irritability, or were somatic complaints, such as anxiety. Those symptoms which were not significantly improved were subjective and ideational, such as depressed mood, guilt, suicidal ideation, nihilistic ideation, psychic anxiety, or "worrying" symptoms of typical endogenous depression.
A similar study was done by the same group of authors in 1978 (Robinson et al 1978). In this second study, 49 patients were treated for six weeks with either phenelzine 60 mg/d (N = 14), 30 mg/d (N = 16), or placebo (N = 19). The results showed that 71% (10/14), of the patients in the high-dose phenelzine group showed definite improvement, but only 6% (1/16) in the low-dose phenelzine group and 21% (4/19) of the placebo group did so. The high-dose phenelzine group was significantly superior to the other two groups, which did not differ significantly from each other. A comparison between the phenelzine 60 mg group and the placebo group on individual symptom improvement also showed that subjective or ideational symptoms generally did not improve with phenelzine, but that objective symptoms such as agitation and anxiety did improve.
Ravaris et al in 1980 compared phenelzine 60 mg/d to amitriptyline 150 mg/d in 105 patients labeled as nonendogenous or endogenous on basis of a Standard Depression Interview. Of the nonendogenous group, 60% of those treated with phenelzine improved substantially or were symptom-free at the end of treatment, compared with 45% of amitriptyline patients. In the endogenous patients, 40% of the phenelzine patients made such progress, compared with 67% of amitriptyline patients. The authors concluded that phenelzine may be the drug of choice in patients with the following characteristics: reactivity of mood, anxiety manifestations, and the absence of terminal insomnia and weight loss. Amitriptyline was thought to be preferred in patients with absence of mood reactivity, relative absence of anxiety symptoms, terminal insomnia, and weight loss.
Davidson et al (1981) treated 43 depressed inpatients for 3 weeks with a mean phenelzine dose of 81 mg/day or imipramine 144 mg/day. Both drugs produced similar declines in depression ratings (Quitkin et al 1981). The only significant difference between the two drugs was the improvement produced by imipramine in the anger subscale. Hostility and paranoia ratings increased in six patients taking phenelzine. The authors suggested phenelzine should be used with caution in patients with poor impulse control.
Liebowitz et al (1984) reported a well conducted trial in 1984 on 60 patients who were selected because a predominance of atypical symptoms. The patients showed a 67% response rate to phenelzine, at a dose of 60-90 mg/d, over four to six weeks, which contrasted with a 43% response to imipramine in a dose of 200-300 mg/d, which was not significantly different from placebo.
Five additional studies comparing phenelzine and amitriptyline or imipramine could not demonstrate differences based on subtyping symptomatology (Pare 1985). In conclusion, the literature is not convincing that MAOI are superior to TCAs in the population discussed. In RDC-diagnosed patients MAOIs are equal in efficacy to TCAs. Dietary restrictions limit these drugs as first-line treatment for depression, however.
TCA-refractory patients
Quitkin et al (1981) reported, retrospectively, that 76% of 40 patients with bipolar depression treated with first or second generation agents responded favorably to treatment. The authors indicated that 6 of 8 non-responders to standard antidepressants responded to an MAOI. They recommended MAOI, not another type of "cyclic" antidepressant, be used as second-line treatment when ECT is deemed unsuitable in non-responders. A study by Nolen supported this recommendation (Pare 1985). He reported that 15/26 (58%) DSM III diagnosed depressives who had failed successive four week trials of a first and second generation antidepressant, respectively, responded to a trial of tranylcypromine. Roose's study mentioned earlier reported all patients who failed to respond to an adequate trial of TCAs responded to MAOIs or ECT (Roose et al 1986).
Subtype - Bipolar depression
Several clinicians have suggested that bipolar depressed patients may respond preferentially to a MAOI as compared to a TCA. These findings, if replicated, have important research and clinical implications (Davidson and Turnbull 1986).
MAOI Response - Sex and Personality Disorder Diagnoses
Davidson and Pelton (1986) recently reviewed several double-blind studies with respect to response of three subtypes of atypical depressives to MAOIs or TCAs. They concluded there was no difference in response between the two drugs in the categories of depression with associated panic, depression secondary to a diagnosis of anxiety, and depression with reverse vegetative change. However, when gender was taken into account, MAOIs were superior to TCAs in depressed women with panic attacks, whereas TCAs were superior to MAOIs in depressed men with panic attacks.
Shawcross and Tyrer (1985) investigated the role of personality diagnoses on response to MAOIs and TCAs. Those patients who failed to respond to either treatment were significantly more likely to have an abnormal personality diagnosis than those who did not respond.
MAOI Efficacy - Antidepressant Tolerance
The report of several patients treated long term (i.e., > 6 weeks) with MAOIs developing tolerance to the antidepressant effect is disturbing (Mann 1983). Despite increases in daily doses of MAOI and stable MAOI inhibition the patients HRSD scores returned to pretreatment levels. The number of patients who develop tolerance to MAOIs is not known nor are appropriate management guidelines available.
LITHIUM
Unipolar Depression
The antidepressant effect of lithium in unipolar depressive illness has been investigated in 14 controlled studies (Doyal and Morton 1984, Kahn et al 1987). Eleven of the studies reported significant antidepressant effects. The remaining three studies revealed little or no antidepressant effect. Seven of eleven positive reports had a range of response of 21-75%, with a mean of 49%. It is recommended that lithium remain a second-line treatment behind standard antidepressants in unipolar depression.
Bipolar Depression
An analysis by Ramsey and Mendels (1980) showed a trend for bipolar patients to respond more frequently (i.e., 75% response rate) than patients diagnosed as having recurrent unipolar depression (i.e., 50% response rate).
The bipolar depressed patients who were most likely to respond to lithium usually have a positive family history of bipolar illness and present with typical affective features without evidence of 'schizoid' features. The patient with recurrent unipolar illness who was most likely to respond to lithium had the following features: a positive bipolar family history, mood lability (cyclothymia), history of post-partum depression, hypersomnia and/or hyperphagia during depression, early age of onset, and an endogenous symptom pattern associated with one or more of the preceding features.
BENZODIAZEPINES
Non-triazolobenzodiazepines
Schatzberg and Cole (1978) reviewed 20 double-blind, controlled studies involving more than 1,000 subjects, in which a benzodiazepine was compared to an antidepressant (TCA or MAOI). A placebo was also included in some studies. In most of these studies the subjects were being treated for endogenous depression, neurotic depressive reaction, or psychoneurotic reaction with depression.
Ten studies concluded the antidepressant was superior to the benzodiazepine. In nine additional studies statistically significant superiority was not established for either group. However, five of nine of the latter studies demonstrated a trend for the antidepressant to be more effective than the benzodiazepine. The 20th study produced inconclusive results. Only one study showed a trend for the benzodiazepine to be superior to a TCA. A more recent study reported no difference between diazepam and placebo in depressed outpatients (Rickels et al 1987).
Although benzodiazepines appeared to be less effective than antidepressants, benzodiazepines did exert an effect on a number of commonly occurring depressive symptoms, including insomnia, tension, and anxiety. It appears that benzodiazepines are not effective in combating symptoms of endogenous depression, which is more responsive to antidepressants. Thus, traditional benzodiazepines do not appear to have a specific antidepressant action, nor do they enhance the antidepressant effect of tricyclics when combined. The benzodiazepines may be useful in depression with an anxiety and agitation component, but a fixed-dose combination with a tricyclic is not rational. The dose of benzodiazepine and antidepressant should be individualized if they are required.
ALPRAZOLAM
Nine studies have compared alprazolam, a triazolobenzodiazepine, to imipramine, amitriptyline, desipramine, or doxepin in outpatients with mild to moderate depression. These suggest that alprazolam may have some antidepressant activity (Fawcett et al 1987, Overall et al 1987, Rickels et al 1987, Warner et al 1988, ). A criticism of these studies involve the use of less depressed outpatients for a study population.
In study published in German but reviewed in the paper by Rickels et al (1987) the authors concluded in depressed outpatients alprazolam and amitriptyline were equally effective in mildly (HAM-D, 15) and moderately (HAM-D, 22) depressed patients (Rickels et al 1987). However, in severely depressed patients (HAM-D, 32), amitriptyline was more effective than alprazolam.
Several recent articles have studied inpatients. One study compared alprazolam and amitriptyline in both inpatients and outpatients with RDC- diagnosed depression (Rush et al 1985). In addition, these patients had a shortened REM latency, which is being investigated as a laboratory marker of endogenous depression. The author's concluded that amitriptyline significantly exceeded the effects of alprazolam by the HAM-D, Beck Depression Index, and induced a more complete degree of symptom remission in more patients.
Goldberg et al 1986 demonstrated imipramine was more effective than alprazolam in patients with neurovegetative signs (i.e., sleep disturbance, loss of appetite, weight loss, motor agitation or retardation, and insidious onset).
A 1987 study by Eriksson et al in DSM III-diagnosed MDD concluded amitriptyline was more effective than alprazolam in producing a complete recovery (HAM-D < 7) and complete improvement on the CGI, 87% vs 60%, respectively.
CARBAMAZEPINE
Post and Uhde (1985) reported a 54% (30/47) mild to moderate response rate in a double-blind trial of acute depression. The responders to carbamazepine demonstrated statistically significant antidepressant response only after the first week of treatment. After the four week trial patients were placed on placebo with only mild and transient exacerbation of their illness. There was no relationship between carbamazepine blood levels and therapeutic response. More studies comparing carbamazepine to other antidepressants and placebo are needed to confirm these preliminary findings.
STIMULANTS
The use of CNS stimulants in psychiatry has recently been reviewed (Chiarello and Cole 1987). The authors conclude that available information does not support the use of stimulants as first-line treatment for MDD.
5-HYDROXYTRIPTOPHAN
Initial studies suggest that 5-HTP possesses antidepressant properties (Byerly et al 1987). Until confirmatory studies are performed, this compound can not be generally recommended for the treatment of depression.
COMBINATION THERAPY
Tricyclic Antidepressant/Lithium
De Montigny et al (1983) in a non-blinded study reported on 39 patients with unipolar depression who did not respond to three weeks of TCA therapy. In 74% of the observations the patients demonstrated >50% improvement within 48 hours of adding lithium at a dose of 900 mg/d. The patients required the presence of both lithium and the TCA to respond and removal of lithium from the therapy usually resulted in relapse. Heninger et al (1983) noted similar findings in a double-blind placebo controlled study utilizing 15 depressed patients (14 UAD, 1 BAD) according to DSM III criteria who were refractory to at least 21 days of TCA therapy. Lithium doses of 900-1200 mg/d which produced serum levels of 0.5-1.1 mEq/L produced "significant and clinically meaningful improvement" by the 7-12th day of lithium augmentation of the TCA treatment. There was no correlation between serum lithium levels and treatment response.
Louie and Meltzer in an open study reported nine cases of lithium addition to an antidepressant drug regimen in nonresponding depressed patients (Louie and Meltzer 1984). The response to lithium addition was more variable than the previously described reports. Two patients showed sustained improvement, two showed transient improvement but then relapsed, two other cases with bipolar histories became manic, and three did not respond at all. Kushnir (1986) recently reported the combination of low-dose lithium and antidepressants produced rapid, lasting remission of depression in five physically-ill geriatric patients.
However, a recent double-blind study by Kantor et al (1986) could not demonstrate a lithium augmentation effect. Seven patients who did not respond to at least 21 days of antidepressant treatment were randomly assigned to lithium or placebo added to their standard treatment. Four patients received lithium and three received placebo. The combination was continued for 48 hours. After this time, six of the seven patients showed no significant improvement. The remaining patient, who had received lithium, improved markedly over the 48 hour period. However, the patient relapsed within one week. They concluded that no evidence exists for a consistent therapeutic effect of lithium adjunct in antidepressant-resistant depression.
Tricyclic Antidepressant/Antipsychotic
In the 1960s and early 1970s the rationale for using antidepressant- antipsychotic combinations in the treatment of mixed anxiety depressive states was based on the "belief" that the combination could produce a more rapid onset of action than the antidepressant alone. Another purported advantage was that the antipsychotic in the combination would control the anxiety or hostility of the patient while the antidepressant component treated the depressive symptom thereby providing a "blanket" for all symptomatology. Although this sounded reasonable theoretically, conclusive evidence for a definite superiority of the combination over an antidepressant alone was lacking.
Morris and Beck's (1974) survey noted that four out of five randomized, double- blind, controlled studies found amitriptyline-perphenazine combination to be superior to placebo in non-delusional depression. However, among studies comparing the combination with other individual tricyclics, four out of six showed that the combination was equivalent in efficacy to tricyclics alone. One study showed that the combination was superior, while the other showed it was inferior to amitriptyline alone.
The preferred treatment of psychotic depression is still controversial. Early literature indicated a poor response to TCAs alone in depression accompanied by delusions. Indeed, some reports indicated that patients deteriorated on TCAs alone. A review of the literature published prior to 1979 reveals a combined response rate of 22% for TCA alone and 83% for the combination (Nelson et al 1986). Three studies treated these patients with antipsychotics alone and reported a 96% response.
However, two recent studies involving 56 delusional depressives and 58 non-delusional depressives concluded that response was not significantly different between single antidepressant treatment and the antidepressant- antipsychotic combination (Lykouras et al 1986, Nelson et al 1986). One study, in fact, reported that delusional depressives were more likely to respond to an antidepressant alone than non-delusional depressive patients, although they required twice as long to respond (i.e., > 3 weeks).
Antidepressant/Antipsychotic/Lithium
Price et al (1983) reported that 5/6 DSM III diagnosed patients with MDD or BAD and mood-congruent psychotic features who had failed treatment with a TCA/AP combination responded to lithium addition. Three of the five responders had a moderate to marked improvement within 7 days. The remaining two responded after three weeks.
Nelson and Mazure (1986) reported a retrospective study of 21 psychotically depressed patients who had failed treatment with a combined antidepressant- antipsychotic drug regimen who received lithium augmentation treatment. The results with these patients was compared to the response rate of 15 patients treated with ECT. Lithium augmentation was effective in 8/9 bipolar patients but in only 3/12 patients with unipolar depression. ECT was effective in 9/15 with unipolar depression. They concluded that lithium augmentation was the treatment of choice in non-responding psychotic depression in patients with bipolar illness, but ECT was indicated in non-responding unipolar patients.
Tricyclic Antidepressant/Anxiolytic
A combination product recommended in the treatment of depression is amitriptyline-chlordiazepoxide (Limbitrol). Greenblatt and Shader (1974) reviewed seven studies comparing the antidepressant-benzodiazepine combination with antidepressants alone. Overall, the combination was no more effective than the single antidepressant in six studies. Only one study demonstrated that amitriptyline-chlordiazepoxide combination was superior to amitriptyline alone.
Tricyclic Antidepressant/MAOI (Stern and Mendels 1981, Murphy et al 1984)
The use of MAOIs in combination with TCAs was common 20 years ago. However, because of a number of case reports of toxicities and fatalities, warnings against this practice were issued. Prescribing of the combination then declined. However, uncontrolled trials appeared later suggesting the combination was useful in patients unresponsive to either drug alone. Recent controlled trials, however, do not demonstrate any increase in efficacy for combined treatment vs. single drug treatment in unselected depressed patient populations. A controlled investigation of combined treatment in TCA or MAOI non-responding patients is not available. Currently, there are no criteria indicating which patients should receive combined TCA-MAOI treatment. If the combination is going to be used, it is recommended that the MAOI and TCA be started simultaneously or the MAOI a few days after the TCA and that lower doses be used then when the drugs are used individually. It is suggested that amitriptyline and either phenelzine or isocarboxazid may be the safest combination.
Tricyclic Antidepressants/Triiodothyronine (T3)
In women, but apparently not in men, T3 will accelerate the onset of the therapeutic action of a TCA when started simultaneously at the start of treatment (Prange 1985). In both men and women, T3 will convert the majority of TCA "failures" to responders within four to fourteen days according to 4 studies (Lykouras et al 1986). Doses of T3 in these studies ranged from 20 to 50 µg/day. Three of the 4 studies reported that more than half of the patients who did not respond to previous TCA therapy responded to the combination. In the fourth study, which involved 12 patients and was performed double-blind, eight patients unresponsive to previous TCA therapy responded to the combination.
Schwarcz et al in a 1984 report converted 4/8 desipramine nonresponders to responders after the addition of T3 in an open study. All patients had received 6 weeks of TCA and had normal TRH stimulation tests. Patients were reported to improve within 1 week and had moderate improvement within 2 weeks. Four weeks after the start of T3 all responders were asymptomatic.
Tricyclic Antidepressants/Methylphenidate
Wharton et al treated seven patients with delusional unipolar depression who were refractory to TCA with methylphenidate 20 mg/day and either imipramine 150 to 225 mg/day (six cases) or nortriptyline 75 mg/day (one case) (Prange 1985). Five of the seven showed marked improvement on the combination. In three of the patients, TCA blood levels were measured and were found to increase significantly after methylphenidate was added. This interaction was believed to be due to inhibition of TCA liver hydroxylating enzymes. However, the exact mechanism of the combination effectiveness is unknown.
In an uncontrolled case series, Feighner et al (1985) reported the successful treatment of "treatment resistant" depression with the addition of a CNS stimulant (i.e., d-amphetamine, methylphenidate) to a MAOI or to a combination of TCA and MAOI. The literature on combination of CNS stimulants and MAOIs indicates that hypertensive and hyperthermic crises may occur when high doses are given. Feighner's group states, "Our clinical experience is that these hypertensive crises are, at most, infrequent, and that this combination is often effective." It would appear that with many pharmacologic and non-pharmacologic treatment options available, this combination would be infrequently and carefully considered.
Tricyclic Antidepressants/L-tryptophan
L-tryptophan in combination with TCAs did not have any added benefit in three of four studies (Stern and Mendels 1981).
Tricyclic Antidepressants/Reserpine
Reserpine 2.5-10 mg administered parenterally in one to two doses was added to existing treatment in TCA nonresponders in 3 reports (Stern and Mendels 1981). Improvement was noted in 24 of 30 patients. It was reported some patients relapsed within days to months after the reserpine treatment.
Monoamine Oxidase Inhibitor/Lithium
Nineteen of 24 patients treated with this combination from the start of treatment demonstrated a very good response in two non-blinded studies (Stern and Mendels 1981). In neither study had the patients been treated with an MAOI alone.
Nelson and Byck (1982) reported that all three patients who had not responded to phenelzine 75-90 mg/d had a significant improvement within two to four days after the addition of lithium 600 to 900 mg/d.
Monoamine Oxidase Inhibitors/L-tryptophan
Four groups have conducted double-blind trials of MAOIs plus L- or DL- tryptophan compared to an MAOI alone (Stern and Mendels 1981). All four studies found the combination better than the MAOI, although in one trial six of 14 patients taking the combination had to stop because of side effects: four with drowsiness and nausea and two with muscular twitching.
Monoamine Oxidase Inhibitor/Antipsychotic/ Triiodothyronine
A woman with psychotic unipolar depression responded with the addition of T3 to phenelzine in combination with thiothixene (Hullett and Bidder 1983). She responded within 2 weeks after having been hospitalized or institutionalized for 3 years. She was a DST suppresser but responded subnormally to TRH.
L-tryptophan/Allopurinol
It has been suggested L-tryptophan alone is not an effective antidepressant because it stimulates its own liver metabolism (Stern and Mendels 1981). Allopurinol, a tryptophan pyrrolase enzyme inhibitor, when administered with L-tryptophan 4-6 gm/day produced improvement in 7 of 8 endogenously depressed male patients.
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