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Lithium Antidepressant Augmentation in TCA-refractory Depression in Adolescents
CASE STUDY Lithium Antidepressant Augmentation in TeA-refractory Depression in Adolescents NEAL D. RYAN, M.D., VIVECA MEYER, M.D., SUSAN DACHILLE, R.N., RS.N., DEBORAH MAZZIE, R.N., M.S.N., AND JOAQUIM PUIG-ANTICH, M.D. Abstract. The few existing studies on the pharmacological treatment of major depression in adolescents indicate that most patients respond partially or not at all to a tricyclic antidepressant (TCA). Information from a retrospective chart review of 14adolescents diagnosed with nonbipolar depression who were treated openly with a TCA/lithium combination after an inadequate response to a TCA alone is presented here. The clinical course, including TCAchoice and dosage, lithiumdosage and serum levels, clinical response, and sideeffects, is detailed. Six of the 14 patients achieved a good response on this combination. All patients tolerated the TCA/lithium combination well. Results are contrasted with those presented in the adult literature, which is reviewed. J. Am. Acad. Child Adolesc. Psychiatry, 1988,27,3:371-376. Key Words: major depression, tricyclic antidepressants, lithium,adolescence. Over the past decade, the validity of the diagnosis of major depressive disorder (MOD) in children and adolescents using DSM-III criteria has received increasing support. Significant long-term morbidity, including psychosocial deficits and impaired interpersonal relationships, has been shown to be associated with the illness (Puig-Antich et aI., 1985 a, b). Although the long-term outcome of child and adolescent depression is not yet known, preliminary evidence from current longitudinal studies in children and adolescents strongly suggests that juvenile depression is continuous with young adult depression, with evidence that the rates of recovery from major depression and the risk of relapse or recurrence are similar across all age groups (Keller et aI., 1982; Kovacs et al., 1984 a, b; Strober, 1983). These studies provide the most convincing argument for the systematic exploration of pharmacological and psychotherapeutic treatments in children and adolescents with major depressive disorder. The response of adults with unipolar depression to treatment with tricyclic antidepressants (TCA) is well established (Klein and Davis, 1969; Morris and Beck, 1974; Rogers and Clay, 1975). Treatment studies in the adolescent population are few and have yielded less promising results. Kramer and Feiguine (1981), using a double-blind placebo-controlled design, did not clearly demonstrate superior effectiveness of amitriptyline over placebo in adolescents with major depression, although one instrument suggested a greater improvement in the actively treated group than in the placebo group. The study, however, has methodological problems, and results should be considered tentative at best (Ryan et al., 1986). In a study by Ryan et at. (1986), examining imipramine plasma levels and response, only 44% of the adolescents studied improved to the level of no or only slight depressed mood or anhedonia, despite evidence of good compliance, reasonable doses of imipramine, and monitoring for plasma levels over a 6-week period. There was no relationship between plasma level and response.
Alternative strategies for the pharmacological treatment of depression in adolescents are needed and deserve study. Despite studies establishing the effectiveness of TCAs in the treatment of adults with unipolar depression, some adults with depressive illness remain unresponsive to TCAs alone (Klein et aI., 1980). Decreased effectiveness has been reported in a "atypical" nonendogenous depressives, and several, but not all, studies have found one TCA, imipramine, less effective in younger adults compared with older adults (Kiloh et aI., 1962; Liebowitz et aI., 1984; Raskin, 1975). Alternative treatments in adults have included the use of monoamine oxidase inhibitors (MAOIs), MAOI/TCA combinations, and TCAs combined with various agents, including triiodothyronine, t-tryptophan, and lithium. Several authors have reported on the use of lithium with a TCA in the treatment of unipolar depression unresponsive to a TCA alone. In 1976, Neubauer and Bermingham reported on nine patients diagnosed with unipolar depression, all past treatment failures (TCA, MAOI, electroconvulsive treatment in some cases), who evidenced clinical improvement after lithium was added to treatment with a TCA. DeMontigny et at. (1981, 1983), reported on the open treatment with lithium augmentation in a total of 42 TCAresistant depressed patients, about two thirds of whom evidenced clinical improvements within 48 hours after the lithium was added. They key to this was thought to be at least 3 weeks of previous treatment with a TCA at adequate blood levels. In a smaller study, DeMontigny (1983) added lithium to 10 patients pretreated with and unresponsive to 3 weeks of random double-blind treatment with amitriptyline or placebo. All five patients pretreated with amitriptyline showed improvement at 48 hours after lithium was added, whereas only one of the placebo patients evidenced significant improvement. Heninger et aI. (1983), added lithium or placebo to 15 adult patients with unipolar depression unresponsive to a 2 I-day trial of a TCA. With 12 days of treatment, the eight patients receiving lithium evidenced improvement in their depression. The seven placebo treated patients, when given active lithium, improved at a rate paralleling that of the eight patients initially receiving lithium. In recent years, there has been an increasing number of reports in the literature on lithium potentiation of
Accepted February I, 1988. The authors are affiliated with the Western Psychiatric Institute and Clinic, Pittsburgh. Pennsylvania. Correspondence to Dr. Ryan, Western Psychiatric Institute and Clinic. 3811 O'Hara St., Pittsburgh. PA 15213. Reprints not available. 0890-8567/88/2703-O371$2.00/0© 1988 by the American Acad-
emy of Childand Adolescent Phychiatry. 371
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antidepressant treatment in unipolar depression (Garbutt et al., 1986; Louie and Meltzer, 1984; Price et al., 1986; Schrader and Levien. 1985). All reports on the antidepressive efficacy of the TCA/ lithium combination have been conducted with adults. There are no controlled studies on the use of lithium in non bipolar depression in adolescents. In reviewing the literature on the use of lithium in children and adolescents, minimal side effects are noted in this population when serum levels are appropriately monitored (Campbell et al., 1984; DeLong and Aldershof, 1987; DeLong and Nieman, 1983; Jefferson, 1982; Khandelwal et al., 1984; Youngerman and Canino, 1976). This article wiIl report on 14 adolescents with non bipolar depression who did not respond satisfactorily to an adequate trial of a TCA and were then openly treated with lithium while the TCA was continued. Based on clinical experience that a number of these patients improved, the authors have attempted to quantify this in a retrospective chart review, with the resultant findings presented here. Method Subjects
Adolescents were accepted for evaluation at the Child and Adolescent Depression Service (CADS) of Western Psychiatric Institute and Clinic if their presenting complaints were suggestive of an affective disorder. Patients were initiaIly evaluated by a psychiatric research nurse and child psychiatrist using the Schedule for Affective Disorders and Schizophrenia for Children-Present Episode (K-SADS-P) (Chambers et al., 1985). The K-SADS-P was administered first to the parent and then the patient, assessing onset, chronology, and severity of iIlness during the present episode. From this evaluation, a Research Diagnostic Criteria diagnosis was made. If a patient met criteria for the diagnosis of major depression, he or she was seen I to 2 weeks after the initial evaluation to reassess the affective symptoms before starting pharmacological treatment. The initial evaluation also included a thorough medical history, physical exam, EKG, and baseline lab tests, including complete blood count, serum electrolytes and creatinine, BUN, and thyroid and liver function tests. AIl patients were free of thyroid, cardiac, hepatic, renal, or central nervous system disease. Procedure
Charts were reviewed of consecutive adolescent patients (Tanner stage III to 19 years of age) diagnosed with a major depressive disorder without evidence of mania or hypomania who, over the course of their clinical treatment, received a combination of a TCA and lithium for the treatment of their depression. Hypomania, mania, or psychosis during or after treatment excluded a subject from this report. In all cases, treatment began with a TCA, and lithium was added based on the absence of or only partial clinical response (persistent symptoms resulting in ongoing functional impairment) following the trial of a TCA alone. Patients were seen weekly for medication adjustment, necessary serum levels, and response monitoring. Lithium serum levels were done weekly during dosage adjustment, with the goal of maintaining the level in the 0.5 to 1.2 mEq/L range.
All subjects except two received at least 6 weeks (usually more) of TCA treatment before the addition of lithium. The two exceptions (patients 2 and 12) were treated for 4 weeks with a TCA, and lithium was added sooner because of persistently severe symptoms and, in one case (patient 2) the patient having had several previous trials with TCAs and MAOIs. The length of the treatment trial with a TCA before the addition of lithium ranged from 3 weeks to 4 months. Lengthier trials were caused by partial response or patient ambivalence about the addition of another medication. In retrospect, no further improvement occurred in any patient after the eighth week of TCA treatment. The TCAs used in combination with lithium were amitriptyline (AMI), desipramine (DMI), and nortriptyline (NT). The length of the combination TCA/lithium treatment trial was at least 6 weeks, with three exceptions. Two trials (patients 5 and 12) were stopped after 3 weeks because of no response at all. The third (patient II) stopped her lithium on her own at 4 weeks after sustaining a good response, which began during the first week of combination treatment. If a good response was achieved, medication was continued for at least 4 months before discontinuation. Demographic Data
There were II females (79%) and three males (21%) in this group. The mean age was 16.9 years with a range of 14 to 19 years. All were diagnosed with non bipolar major depression, with 64% meeting Research Diagnostic Criteria for endogenous subtype. Two patients ( 14%) were diagnosed with major depression superimposed on dysthymic disorder ("double depression "), and one of these had coexisting panic attacks. Five patients (36%) required hospitalization over the course of their illness. Seven patients (50%) exhibited suicidal ideation to the extent that they had a plan, and four of these made attempts. Family history was positive for major depressive disorder in 64% and alcoholism in 50%. Results Response was assessed retrospectively (by chart review) by two CADs research nurses (S. D. and D. M.) not blind to treatment, using the Clinical Global Impressions Checklist (CGI), which generates ratings of both iIlness severity (I to 7 scale, I being not at all iII, and 7 being extremely ill), and clinical improvement (I to 7 scale, I being very much improved, 4 being no change, and 7 being very much worse). The charts were completed by CADS personnel and contain detailed information from each patient visit on symptomatic changes and improvement during treatment. The mean of the two assessments of severity and improvement for each clinic visit was used in determining overaIl response. Patients were rated at initial presentation, at the end of the TCA trial (that visit at which the decision was made to add lithium), at 4 weeks, and at 6 weeks (when available) after the addition of lithium. Based on the CGI ratings, the mean severity of illness at initial presentation for the entire group was 4.8 ± 0.7. This dropped to 4.0 ± 0.6 after the TCA trial and decreased further to 3.3 ± 1.0 6 weeks after the addition of lithium to the TCA. Using the paired t test, improvement in the mean severity
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LITHIUM ANTIDEPRESSANT AUGMENTATION TABLE I. Clinical Course with Lithium Augmentation Diagnosis
First Trial
Second Trial
Third Trial
Comment Stable response for 4 months, then stopped medications on own
I MOO-EO anxious features hx of panic attacks Sev: 4.5"
OMI 250 mg/q.d, level = 168 8-week trial Sev: 3.5 Glob: 3"
OMI 250 rng/q.d. Li 900 mg-I ,200 mg/q.d. levels 0.5-0.8 16 weeks Sev: 3 Glob: 2.5
2 MOO-EO suicidality Sev: 5.5
Several TCAs MAOI in series over 9 months without response
OMI 250 mg 4 weeks Sev: 5 Glob: 4
OMI 250 mg Li 600 mg levels 0.68-1.03 6 weeks Sev: 5 Glob: 4.5
Subsequently placed on trazodone with partial response
3 MOD-NEO Sev: 4
NT75 mg level 125 II weeks Sev: 3.5 Glob: 3
NT 75 mg Li 900 mg level 0.78-1.0 3 weeks
OMI 250 mg Li 900 mg 2 months Sev:4 Glob: 3
Change to OMI because of side effects on NT
4 MOO-EO dysthymia Sev:4
NT 75-100 mg level 141 8 weeks Sev: 3.5 Glob: 3
NT 75 mg Li 1200 mg level 0.5-0.8 8 weeks Sev: 3 Glob: 4
OMI 150 mg Li 1,200 mg Sev: 2 Glob: 2
NT, OMI doses limited by EKG changes
5 MOO-EO suicidality Sev: 4.5
IMI 250 mg 12 weeks Change to OMI because of side effects on imipramine
OMI 275 mg 4 weeks Sev: 4.5 Glob: 4
OMI 275 mg Li 900 mg level 0.5-0.9 4 weeks Sev: 4.5 Glob: 4
Presently on AMI, Li, and phenelzine with partial response
6 MOO-EO suicidality Sev: 5
AMI 200 mg level 186 8 weeks Sev: 5 Glob: 3.5
AMI 200 mg Li 600 rng level 0.6-0.7 16 weeks Sev: 3.5 Glob: 2
NT/TRAN no response
7 MOO-NEO Sev:4
AMI 350 mg 12 weeks Sev: 3 Glob: 3
AMI 350 mg Li 900 mg level 0.22-0.58 4 weeks Sev: 3 Glob: 2
Li 900 mg 16 weeks sustained response
AMI discontinued following seizure
8 MOO-EO Sev:4
NT 100-125 mg level 226 10 weeks Sev:4 Glob: 4.5
NT 50 mg Li 900 mg levels 0.57-0.84 5 weeks Sev: 4 Glob: 4
NT 50 mg TRAN 20 mg full response
NT decreased following high level
9 MOO-NEO Sev: 5
OMI 250 mg 8 weeks Sev:4 GLOB: 3.5
OMI 200 mg Li 900-1200 mg q.o.d. level 0.44-0.73 II weeks Sev: 3 Glob: 2.5
OMI 200 mg 10 weeks mild deterioration
Patient stopped Li and OMI on own
(continued on p. 374)
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RYAN ET AL. TABLE I. Clinical Course with Lithium Augmentation
Second Trial
Third Trial
Comment
10 MDD-NED suicidality Sev: 4
NT75 mg level 96 6 weeks Sev: 3.5 Glob: 3.5
NT 75 mg Li 900 mg level 0.28-0.54 8 weeks Sev: 3 Glob: 2.5
DMI 250 mg Li 1,200-1,500 mg q.o.d. levels 0.5-1.0 7 months Sev: 2 Glob: I
Dose of NT limited by side effects
II MDD-ED suicidality Sev: 6
NT 75 mg level 108 6 weeks Sev: 4.5 Glob: 3.5
NT 100 mg level 122 Li 600 mg level 0.62-0.63 4 weeks Sev: 2 Glob: I
NT 100 mg 12 weeks sustained response
Patient stopped Li on own after 4 weeks
12 MDD-ED suicidality Sev: 6
AMI 300 mg 4 weeks Sev: 4.5 Glob: 3.5
AMI 300 mg Li 600 mg level 0.33-0.89 3 weeks Sev: 4.5 Glob: 4
13 MDD-NED dysthymia panic attacks Sev: 5
NT 100 mg 12 weeks Sev: 4 Glob: 4
NT 100 mg Li 900 mg level 0.6-0.7 6 weeks Sev: 2 Glob: 2
14 MDD-ED suicidality
AMI 250 mg 16 weeks Sev:4 Glob: 3
AMI 300 mg Li 900-1,200 rng/ q.o.d. levels 0.7-0.83 6 weeks Sev: 3 Glob: 2
Diagnosis
Sev: 5
a h
First Trial
Eventually responded to NT and phenelzine combination
Severity of illness from CGI: I, not at all ill; 4, moderately ill; 7, extremely ill. Global improvement from CGI: I, very much improved; 4, no change; 7, very much worse.
rating was significant between baseline and the end of the TCA trial (1 = 5.26, p < 0.0002), with continued improvement between the end of the TCA trial and 6 weeks after lithium addition (1 = 3.22, p < 0.007). Table I and Figure I present the severity of illness at four points over the course of treatment for all patients. Responders were defined as patients improved to the point of being no more than mildly symptomatic or better. Clinically, these patients were no longer functionally impaired by their illness. Six patients (43%) were considered responders, rated much to very much improved and borderline to mildly ill following the addition of lithium to their treatment regimen. Three other patients (patients I, 6, and 7) evidenced some additional global improvement with the addition of lithium but continued to be functionally impaired. Five patients (36%) had little or no improvement at all over the course of their treatment. As a group, responders did not differ significantly in the initial severity of illness (4.8 ± 0.8) when compared with nonresponders (4.7 ± 0.8). Both groups had evidenced partial response following a TCA trial, and the severity of illness in the lithium responders (3.9 ± 0.4) did not differ from that of lithium nonresponders (4.1 ± 0.7) at that point in treatment.
There was no difference between male and female patients in lithium response. Most responders experienced a gradual improvement in symptoms over the first month of lithium treatment. This contrasts with earlier reports from the adult literature of rapid improvement within 24 to 48 hours after the addition of lithium but is more consistent with later reports that in fact suggest that in most patients, a minimum of 3 weeks on the combination of lithium and a TCA may be necessary to evaluate response. In the population of this study, severity ratings from the forth to the sixth week of lithium addition improved in six patients and worsened in only one (see Fig. 1). The group mean severity rating at 4 weeks, 3.6 ± 0.8, improved significantly to 3.3 ± 1.0 at 6 weeks following lithium addition (paired 1 test, 1 = 2.39, p < 0.03). One responder (patient 11) experienced significant improvement over the first week of combination treatment, subsequently discontinued the lithium after only 1 month, but sustained her improvement on the TCA alone. DeMontigny et aJ. (1981) reported a similar pattern with some patients while noting a deterioration in others when lithium was stopped. Response, with the addition of lithium, did not differ based
375
LITHIUM ANTIDEPRESSANT AUGMENTATION
7-.-----------------------------,
Extremely in II
6
3
2
Not at all ill
Baseline
Post TCA Trial
4 Week Post Lithium Addition
6 Week Post Lithium Addition
FIG. I. Lithium augmentation in adolescent MDD (N = J4).
on the TCA used (AMI, NT, DMI), consistent with DeMontigny et al.'s findings. The mean serum lithium level for the responders (0.65 ± 0.06 mEq/L) did not differ from that of nonresponders (0.64 ± 0.13 rnfiq/L), Early adult studies found no correlation between lithium levels and the efficacy oflithium augmentation. Again consistent with adult studies, there was no significant difference in the mean duration of prior treatment with a TCA in responders (9.3 ± 4 weeks) versus nonresponders (9.0 ± 4 weeks). Side effects on TCAs alone and in combination with lithium are shown in Table 2. In general, if the TCA was tolerated. the addition of lithium was also well tolerated. Threshold for the onset of side effects during the combination treatment varied greatly in this patient group , with no consistent correlation with serum levels, and frequently , persistent side effects
TABLE
TCA Alone Anticholineric Dizziness Hand tremors Urinary hesitancy Widened QRS or PR Lethargy/fatigue Nausea Headache Irritability Palpitations Weight gain
" N = 15.
Patient
(N) 12 10 4 4 3 3 2 2 I I I
were managed by adjustment of the TCA. Onl y one patient (patient 8) experienced no side effects during the combination treatment. In no case did side effects from lithium necessitate its discontinuation. Discussion Given the limited number of patients in this report as well as the open and uncontrolled nature of the treatment trial, conclusions that may be drawn are only tentative. The clinical experience with these patients suggests that, as in adults, certain adolescents may respond to the addition of lithium to a TCA if previously unresponsive to an adequate trial of a TCA alone. The duration of prior treatment with a TCA was longer with these patients (6 to 8 weeks) than that in most studies with adults (3 weeks). Together with the lack of further
2. S ide Effe cts"
Lithium with TCA Hand tremors Dizziness Nausea Dry mouth Fat igue Polydysia/polyuria Blurred vision Palpitations/chest pain Hypersomnia Headaches Constipation Weight gain Confusion
Patient (N)
8 5 5 5 3 3 3 3 2 2 2 I
1
Serum Level (dose range 600-1.500 mg/day) 0.50-1 .32 mEq/L 0.50-0.90 0.58-1 .25 0.50-0.90 0.66-0.99 0.33-1.03 0.68-1 .03 0.28-0.91 0.66-0.99 0.20-0.70 0.66-0.91 0.69-0.89 0.16
376
RYAN ET AL.
improvement found after the eighth week of TCA treatment, this makes the positive response to lithium addition unlikely to be caused by late effects of the TCA alone (Quitkin et aI., 1984). Additionally, the duration of lithium augmentation necessary to effect a positive clinical response in these patients was longer than that reported in the adult literature, and it is of interest that seven patients continued to improve up to 6 weeks after lithium was added. These data, however, do not preclude the possibility that some patients improved with just time alone, because of the fluctuating nature of the illness. The Question of medication versus time effect deserves further study in a controlled treatment trial. Although no significant differences in plasma levels between lithium responders and nonresponders were found, it is still possible that a higher dose or plasma level of lithium may induce a higher rate of response, as the plasma level threshold for lithium response may vary from one non bipolar individual to another. This variability should be tested in further research. The elimination of any patients treated with lithium augmentation who had past or drug-induced mania or hypomania was an effort to make this group more clinically homogeneous. In this review, however, there were no clinical predictors found that separated responders from nonresponders. Studies which indicate that a substantial minority of adolescent depressions have a bipolar outcome over the short term (I to 4 years) argue for greater consideration of this combination treatment in this population, especially when psychotic symptoms or a family history of bipolar disorder are present (Strober and Carlson, 1982). Despite the limitations of this treatment trial, the results of this study suggest a possible therapeutic effect of a TCAI lithium combination in some TCA resistent adolescent depressions. These results, along with the relative safety of the treatment regimen, support the need for controlled studies in TCA resistent adolescent depression. References Campbell, M., Perry, R. & Green, w. H. (1984), Use of lithium in children and adolescents. Psychosomatics, 25:95-106. Chambers, W. J., Puig-Antich, J., Hirsch, M., et al. (1985), The assessment of affective disorders in children and adolescents by semistructured interview: test-retest reliability of the K-SADS-P. Arch. Gen. Psychiatry, 42:696-701. Delong, G. R. & Aldershof, A. L. (1987), Long term experience with lithium treatment in childhood: correlation with clinical diagnoses. J. Am. Acad. Child Adolesc. Psychiatry, 26:389-394. - - Nieman, G. W. (1983), Lithium-induced behavior changes in children with symptoms suggesting manic-depressive illness. Psychopharmacol. Bull., 19:258-265. deMontigny, C; Cournoyer, G., Morissette, R., Langlois, R. & Caille, G. (1983), Lithium carbonate addition in tricyclic antidepressantresistant unipolar depression. Arch.Gen. Psychiatry, 40:1327-1334. - - Grunberg, F., Mayer, A. & Deschenes, J. P. (1981), Lithium induces rapid relief of depression in tricyclic antidepressant drug nonresponders. Br. J. Psychiatry, 138:252-256. Garbutt, J. c., Mayo, J. P., Gillette, G., Little, K. & Mason, G. (1986), Lithium potentiation of tricyclic antidepressants following lack ofT3 potentiation. Am. J. Psychiatry, 143:1038-1039. Heninger, G. R., Charney, D. S. & Sternberg, D. E. (1983), Lithium
carbonate augmentation of antidepressant treatment. Arch. Gen. Psychiatry, 40:1336-1342. Jefferson, J. W., (1982), The use of lithium in childhood and adolescents: an overview. J. Clin. Psychiatry, 43:174-177. Keller, M. B., Shapiro, R. W., Lavori, P. W. et al. (1982), Recovery and relapse in major depressive disorder. Arch. Gen. Psychiatry, 39:905-915. Khandelwah, S. K., Varma, V. K. & Murthy, R. S. (1984), Renal function in children receiving long-term lithium prophylaxis. Arch. Gen. Psychiatry, 141:278-279. Kiloh, L. G., Ball, J. R. B. & Garside, R. F. (1962), Prognostic factors in treatment of depressive states with imipramine. Br. Med. J., 1:1225-1227. Klein, D. F. & Davis, J. M. (1969), Diagnosis and Drug Treatment ofPsychiatric Disorders. Baltimore: William & Wilkins. - - Gittleman, R., Quitkins, F. & Rifkin, A. (1980)., Diagnosis and Drug Treatment of Psychiatric Disorders: Adults and Children. Baltimore: Williams & Wilkins. Kovacs, M., Feinberg, T. L., Crouse, M. A., Paulaskas, S. & Finkelstein, R. (1984a), Depressive disorders in childhood I. Arch. Gen. Psychiatry, 41:229-237. - - Feinberg, T. L., Crouse, M. A., Paulaskas, S. & Finkelstein, R. (1984b), Depressive disorders in childhood II. Arch. Gen. Psychiatry, 41:643-649. Kramer, E. & Feiguine, R. (1981), Clinical effects of amitriptyline in adolescent depression. J. Am. Acad. Child Adolesc. Psychiatry, 20:636-644. Liebowitz, M. R., Quitkin, F. M., Stewart, J. W. et al. (1984), Phenelzine vs imipramine in atypical depression. Arch. Gen. Psychiatry, 41:669-677. Louie, A. K. & Meltzer, H. Y. (1984), Lithium potentiation of antidepressant treatment. J. Clin. Psychopharmacol., 4:316-321. Morris, J. B. & Beck, A. T. (1974), The efficacy of antidepressant drugs. Arch. Gen. Psychiatry, 30:667-674. Neubauer, H. & Bermingham, P. (1976), A depressive syndrome responsive to lithium. J. Nerv. Ment. Dis., 163:276-281. Price, L. H., Charney, D. S. & Heninger, G. R. (1986), Variability of response to lithium augmentation in refractory depression. Am. J. Psychiatry, 143:1387-1392. Puig-Antich, J., Lukens, E., Davies, M., Goetz, D., Brennan-Quattrock, J. & Todak, G. (l985a), Psychosocial functioning in prepubertal major depressive disorders I. Arch. Gen. Psychiatry, 42:500507. . - - Lukens, E., Davies, M., Goetz, D., Brennan-Quattrock, J. & Todak, G. (l985b), Psychosocial functioning in prepubertal major depressive disorders II. Arch. Gen. Psychiatry, 42:511-517. Quitkin, F. M., Rabkin, J. G., Ross, D. & McGrath, P. J. (1984), Duration of antidepressant drug treatment: what is a good trial? Arch. Gen. Psychiatry, 41:238-245. Raskin, A. (1975), Age-sex differences in response to antidepressant drugs. J. Nerv. Ment. Dis., 159:120-130. Rogers, S. C. & Clay, P. M. (1975), A statistical review of controlled trials of imipramine and placebo in the treatment of depressive illness. Br. J. Psychiatry, 127:599-603. Ryan, N., Puig-Antich, J., Cooper, T. & Rabinovich, H. et al. (1986), Imipramine in adolescent major depression: plasma level and clinical response. Acta Psychiatr. Scand., 73:275-288. Schrader, G. D. & Levien, H. E. M. (1985), Response to sequential administration of clomipramine and lithium carbonate in treatment-resistant depression. Br. J. Psychiatry, 147:573-575. Strober, M. (1983), Natural history of major depressive disorder in adolescence. Paper presented at the annual meeting of the American Psychiatric Association, New York. - - Carlson, G. (1982), Bipolar illness in adolescents with major depression: clinical, genetic, and"psychopharmacologic predictors in a three-to four-year prospective follow-up investigation. Arch. Gen. Psychiatry, 39:549-555. Youngerman, J. & Canino, I. A. (1976), Lithium carbonate use in children and adolescents. Arch. Gen. Psychiatry, 35:216-224.
Alternative strategies for the pharmacological treatment of depression in adolescents are needed and deserve study. Despite studies establishing the effectiveness of TCAs in the treatment of adults with unipolar depression, some adults with depressive illness remain unresponsive to TCAs alone (Klein et aI., 1980). Decreased effectiveness has been reported in a "atypical" nonendogenous depressives, and several, but not all, studies have found one TCA, imipramine, less effective in younger adults compared with older adults (Kiloh et aI., 1962; Liebowitz et aI., 1984; Raskin, 1975). Alternative treatments in adults have included the use of monoamine oxidase inhibitors (MAOIs), MAOI/TCA combinations, and TCAs combined with various agents, including triiodothyronine, t-tryptophan, and lithium. Several authors have reported on the use of lithium with a TCA in the treatment of unipolar depression unresponsive to a TCA alone. In 1976, Neubauer and Bermingham reported on nine patients diagnosed with unipolar depression, all past treatment failures (TCA, MAOI, electroconvulsive treatment in some cases), who evidenced clinical improvement after lithium was added to treatment with a TCA. DeMontigny et at. (1981, 1983), reported on the open treatment with lithium augmentation in a total of 42 TCAresistant depressed patients, about two thirds of whom evidenced clinical improvements within 48 hours after the lithium was added. They key to this was thought to be at least 3 weeks of previous treatment with a TCA at adequate blood levels. In a smaller study, DeMontigny (1983) added lithium to 10 patients pretreated with and unresponsive to 3 weeks of random double-blind treatment with amitriptyline or placebo. All five patients pretreated with amitriptyline showed improvement at 48 hours after lithium was added, whereas only one of the placebo patients evidenced significant improvement. Heninger et aI. (1983), added lithium or placebo to 15 adult patients with unipolar depression unresponsive to a 2 I-day trial of a TCA. With 12 days of treatment, the eight patients receiving lithium evidenced improvement in their depression. The seven placebo treated patients, when given active lithium, improved at a rate paralleling that of the eight patients initially receiving lithium. In recent years, there has been an increasing number of reports in the literature on lithium potentiation of
Accepted February I, 1988. The authors are affiliated with the Western Psychiatric Institute and Clinic, Pittsburgh. Pennsylvania. Correspondence to Dr. Ryan, Western Psychiatric Institute and Clinic. 3811 O'Hara St., Pittsburgh. PA 15213. Reprints not available. 0890-8567/88/2703-O371$2.00/0© 1988 by the American Acad-
emy of Childand Adolescent Phychiatry. 371
372
RYAN ET AL.
antidepressant treatment in unipolar depression (Garbutt et al., 1986; Louie and Meltzer, 1984; Price et al., 1986; Schrader and Levien. 1985). All reports on the antidepressive efficacy of the TCA/ lithium combination have been conducted with adults. There are no controlled studies on the use of lithium in non bipolar depression in adolescents. In reviewing the literature on the use of lithium in children and adolescents, minimal side effects are noted in this population when serum levels are appropriately monitored (Campbell et al., 1984; DeLong and Aldershof, 1987; DeLong and Nieman, 1983; Jefferson, 1982; Khandelwal et al., 1984; Youngerman and Canino, 1976). This article wiIl report on 14 adolescents with non bipolar depression who did not respond satisfactorily to an adequate trial of a TCA and were then openly treated with lithium while the TCA was continued. Based on clinical experience that a number of these patients improved, the authors have attempted to quantify this in a retrospective chart review, with the resultant findings presented here. Method Subjects
Adolescents were accepted for evaluation at the Child and Adolescent Depression Service (CADS) of Western Psychiatric Institute and Clinic if their presenting complaints were suggestive of an affective disorder. Patients were initiaIly evaluated by a psychiatric research nurse and child psychiatrist using the Schedule for Affective Disorders and Schizophrenia for Children-Present Episode (K-SADS-P) (Chambers et al., 1985). The K-SADS-P was administered first to the parent and then the patient, assessing onset, chronology, and severity of iIlness during the present episode. From this evaluation, a Research Diagnostic Criteria diagnosis was made. If a patient met criteria for the diagnosis of major depression, he or she was seen I to 2 weeks after the initial evaluation to reassess the affective symptoms before starting pharmacological treatment. The initial evaluation also included a thorough medical history, physical exam, EKG, and baseline lab tests, including complete blood count, serum electrolytes and creatinine, BUN, and thyroid and liver function tests. AIl patients were free of thyroid, cardiac, hepatic, renal, or central nervous system disease. Procedure
Charts were reviewed of consecutive adolescent patients (Tanner stage III to 19 years of age) diagnosed with a major depressive disorder without evidence of mania or hypomania who, over the course of their clinical treatment, received a combination of a TCA and lithium for the treatment of their depression. Hypomania, mania, or psychosis during or after treatment excluded a subject from this report. In all cases, treatment began with a TCA, and lithium was added based on the absence of or only partial clinical response (persistent symptoms resulting in ongoing functional impairment) following the trial of a TCA alone. Patients were seen weekly for medication adjustment, necessary serum levels, and response monitoring. Lithium serum levels were done weekly during dosage adjustment, with the goal of maintaining the level in the 0.5 to 1.2 mEq/L range.
All subjects except two received at least 6 weeks (usually more) of TCA treatment before the addition of lithium. The two exceptions (patients 2 and 12) were treated for 4 weeks with a TCA, and lithium was added sooner because of persistently severe symptoms and, in one case (patient 2) the patient having had several previous trials with TCAs and MAOIs. The length of the treatment trial with a TCA before the addition of lithium ranged from 3 weeks to 4 months. Lengthier trials were caused by partial response or patient ambivalence about the addition of another medication. In retrospect, no further improvement occurred in any patient after the eighth week of TCA treatment. The TCAs used in combination with lithium were amitriptyline (AMI), desipramine (DMI), and nortriptyline (NT). The length of the combination TCA/lithium treatment trial was at least 6 weeks, with three exceptions. Two trials (patients 5 and 12) were stopped after 3 weeks because of no response at all. The third (patient II) stopped her lithium on her own at 4 weeks after sustaining a good response, which began during the first week of combination treatment. If a good response was achieved, medication was continued for at least 4 months before discontinuation. Demographic Data
There were II females (79%) and three males (21%) in this group. The mean age was 16.9 years with a range of 14 to 19 years. All were diagnosed with non bipolar major depression, with 64% meeting Research Diagnostic Criteria for endogenous subtype. Two patients ( 14%) were diagnosed with major depression superimposed on dysthymic disorder ("double depression "), and one of these had coexisting panic attacks. Five patients (36%) required hospitalization over the course of their illness. Seven patients (50%) exhibited suicidal ideation to the extent that they had a plan, and four of these made attempts. Family history was positive for major depressive disorder in 64% and alcoholism in 50%. Results Response was assessed retrospectively (by chart review) by two CADs research nurses (S. D. and D. M.) not blind to treatment, using the Clinical Global Impressions Checklist (CGI), which generates ratings of both iIlness severity (I to 7 scale, I being not at all iII, and 7 being extremely ill), and clinical improvement (I to 7 scale, I being very much improved, 4 being no change, and 7 being very much worse). The charts were completed by CADS personnel and contain detailed information from each patient visit on symptomatic changes and improvement during treatment. The mean of the two assessments of severity and improvement for each clinic visit was used in determining overaIl response. Patients were rated at initial presentation, at the end of the TCA trial (that visit at which the decision was made to add lithium), at 4 weeks, and at 6 weeks (when available) after the addition of lithium. Based on the CGI ratings, the mean severity of illness at initial presentation for the entire group was 4.8 ± 0.7. This dropped to 4.0 ± 0.6 after the TCA trial and decreased further to 3.3 ± 1.0 6 weeks after the addition of lithium to the TCA. Using the paired t test, improvement in the mean severity
373
LITHIUM ANTIDEPRESSANT AUGMENTATION TABLE I. Clinical Course with Lithium Augmentation Diagnosis
First Trial
Second Trial
Third Trial
Comment Stable response for 4 months, then stopped medications on own
I MOO-EO anxious features hx of panic attacks Sev: 4.5"
OMI 250 mg/q.d, level = 168 8-week trial Sev: 3.5 Glob: 3"
OMI 250 rng/q.d. Li 900 mg-I ,200 mg/q.d. levels 0.5-0.8 16 weeks Sev: 3 Glob: 2.5
2 MOO-EO suicidality Sev: 5.5
Several TCAs MAOI in series over 9 months without response
OMI 250 mg 4 weeks Sev: 5 Glob: 4
OMI 250 mg Li 600 mg levels 0.68-1.03 6 weeks Sev: 5 Glob: 4.5
Subsequently placed on trazodone with partial response
3 MOD-NEO Sev: 4
NT75 mg level 125 II weeks Sev: 3.5 Glob: 3
NT 75 mg Li 900 mg level 0.78-1.0 3 weeks
OMI 250 mg Li 900 mg 2 months Sev:4 Glob: 3
Change to OMI because of side effects on NT
4 MOO-EO dysthymia Sev:4
NT 75-100 mg level 141 8 weeks Sev: 3.5 Glob: 3
NT 75 mg Li 1200 mg level 0.5-0.8 8 weeks Sev: 3 Glob: 4
OMI 150 mg Li 1,200 mg Sev: 2 Glob: 2
NT, OMI doses limited by EKG changes
5 MOO-EO suicidality Sev: 4.5
IMI 250 mg 12 weeks Change to OMI because of side effects on imipramine
OMI 275 mg 4 weeks Sev: 4.5 Glob: 4
OMI 275 mg Li 900 mg level 0.5-0.9 4 weeks Sev: 4.5 Glob: 4
Presently on AMI, Li, and phenelzine with partial response
6 MOO-EO suicidality Sev: 5
AMI 200 mg level 186 8 weeks Sev: 5 Glob: 3.5
AMI 200 mg Li 600 rng level 0.6-0.7 16 weeks Sev: 3.5 Glob: 2
NT/TRAN no response
7 MOO-NEO Sev:4
AMI 350 mg 12 weeks Sev: 3 Glob: 3
AMI 350 mg Li 900 mg level 0.22-0.58 4 weeks Sev: 3 Glob: 2
Li 900 mg 16 weeks sustained response
AMI discontinued following seizure
8 MOO-EO Sev:4
NT 100-125 mg level 226 10 weeks Sev:4 Glob: 4.5
NT 50 mg Li 900 mg levels 0.57-0.84 5 weeks Sev: 4 Glob: 4
NT 50 mg TRAN 20 mg full response
NT decreased following high level
9 MOO-NEO Sev: 5
OMI 250 mg 8 weeks Sev:4 GLOB: 3.5
OMI 200 mg Li 900-1200 mg q.o.d. level 0.44-0.73 II weeks Sev: 3 Glob: 2.5
OMI 200 mg 10 weeks mild deterioration
Patient stopped Li and OMI on own
(continued on p. 374)
374
RYAN ET AL. TABLE I. Clinical Course with Lithium Augmentation
Second Trial
Third Trial
Comment
10 MDD-NED suicidality Sev: 4
NT75 mg level 96 6 weeks Sev: 3.5 Glob: 3.5
NT 75 mg Li 900 mg level 0.28-0.54 8 weeks Sev: 3 Glob: 2.5
DMI 250 mg Li 1,200-1,500 mg q.o.d. levels 0.5-1.0 7 months Sev: 2 Glob: I
Dose of NT limited by side effects
II MDD-ED suicidality Sev: 6
NT 75 mg level 108 6 weeks Sev: 4.5 Glob: 3.5
NT 100 mg level 122 Li 600 mg level 0.62-0.63 4 weeks Sev: 2 Glob: I
NT 100 mg 12 weeks sustained response
Patient stopped Li on own after 4 weeks
12 MDD-ED suicidality Sev: 6
AMI 300 mg 4 weeks Sev: 4.5 Glob: 3.5
AMI 300 mg Li 600 mg level 0.33-0.89 3 weeks Sev: 4.5 Glob: 4
13 MDD-NED dysthymia panic attacks Sev: 5
NT 100 mg 12 weeks Sev: 4 Glob: 4
NT 100 mg Li 900 mg level 0.6-0.7 6 weeks Sev: 2 Glob: 2
14 MDD-ED suicidality
AMI 250 mg 16 weeks Sev:4 Glob: 3
AMI 300 mg Li 900-1,200 rng/ q.o.d. levels 0.7-0.83 6 weeks Sev: 3 Glob: 2
Diagnosis
Sev: 5
a h
First Trial
Eventually responded to NT and phenelzine combination
Severity of illness from CGI: I, not at all ill; 4, moderately ill; 7, extremely ill. Global improvement from CGI: I, very much improved; 4, no change; 7, very much worse.
rating was significant between baseline and the end of the TCA trial (1 = 5.26, p < 0.0002), with continued improvement between the end of the TCA trial and 6 weeks after lithium addition (1 = 3.22, p < 0.007). Table I and Figure I present the severity of illness at four points over the course of treatment for all patients. Responders were defined as patients improved to the point of being no more than mildly symptomatic or better. Clinically, these patients were no longer functionally impaired by their illness. Six patients (43%) were considered responders, rated much to very much improved and borderline to mildly ill following the addition of lithium to their treatment regimen. Three other patients (patients I, 6, and 7) evidenced some additional global improvement with the addition of lithium but continued to be functionally impaired. Five patients (36%) had little or no improvement at all over the course of their treatment. As a group, responders did not differ significantly in the initial severity of illness (4.8 ± 0.8) when compared with nonresponders (4.7 ± 0.8). Both groups had evidenced partial response following a TCA trial, and the severity of illness in the lithium responders (3.9 ± 0.4) did not differ from that of lithium nonresponders (4.1 ± 0.7) at that point in treatment.
There was no difference between male and female patients in lithium response. Most responders experienced a gradual improvement in symptoms over the first month of lithium treatment. This contrasts with earlier reports from the adult literature of rapid improvement within 24 to 48 hours after the addition of lithium but is more consistent with later reports that in fact suggest that in most patients, a minimum of 3 weeks on the combination of lithium and a TCA may be necessary to evaluate response. In the population of this study, severity ratings from the forth to the sixth week of lithium addition improved in six patients and worsened in only one (see Fig. 1). The group mean severity rating at 4 weeks, 3.6 ± 0.8, improved significantly to 3.3 ± 1.0 at 6 weeks following lithium addition (paired 1 test, 1 = 2.39, p < 0.03). One responder (patient 11) experienced significant improvement over the first week of combination treatment, subsequently discontinued the lithium after only 1 month, but sustained her improvement on the TCA alone. DeMontigny et aJ. (1981) reported a similar pattern with some patients while noting a deterioration in others when lithium was stopped. Response, with the addition of lithium, did not differ based
375
LITHIUM ANTIDEPRESSANT AUGMENTATION
7-.-----------------------------,
Extremely in II
6
3
2
Not at all ill
Baseline
Post TCA Trial
4 Week Post Lithium Addition
6 Week Post Lithium Addition
FIG. I. Lithium augmentation in adolescent MDD (N = J4).
on the TCA used (AMI, NT, DMI), consistent with DeMontigny et al.'s findings. The mean serum lithium level for the responders (0.65 ± 0.06 mEq/L) did not differ from that of nonresponders (0.64 ± 0.13 rnfiq/L), Early adult studies found no correlation between lithium levels and the efficacy oflithium augmentation. Again consistent with adult studies, there was no significant difference in the mean duration of prior treatment with a TCA in responders (9.3 ± 4 weeks) versus nonresponders (9.0 ± 4 weeks). Side effects on TCAs alone and in combination with lithium are shown in Table 2. In general, if the TCA was tolerated. the addition of lithium was also well tolerated. Threshold for the onset of side effects during the combination treatment varied greatly in this patient group , with no consistent correlation with serum levels, and frequently , persistent side effects
TABLE
TCA Alone Anticholineric Dizziness Hand tremors Urinary hesitancy Widened QRS or PR Lethargy/fatigue Nausea Headache Irritability Palpitations Weight gain
" N = 15.
Patient
(N) 12 10 4 4 3 3 2 2 I I I
were managed by adjustment of the TCA. Onl y one patient (patient 8) experienced no side effects during the combination treatment. In no case did side effects from lithium necessitate its discontinuation. Discussion Given the limited number of patients in this report as well as the open and uncontrolled nature of the treatment trial, conclusions that may be drawn are only tentative. The clinical experience with these patients suggests that, as in adults, certain adolescents may respond to the addition of lithium to a TCA if previously unresponsive to an adequate trial of a TCA alone. The duration of prior treatment with a TCA was longer with these patients (6 to 8 weeks) than that in most studies with adults (3 weeks). Together with the lack of further
2. S ide Effe cts"
Lithium with TCA Hand tremors Dizziness Nausea Dry mouth Fat igue Polydysia/polyuria Blurred vision Palpitations/chest pain Hypersomnia Headaches Constipation Weight gain Confusion
Patient (N)
8 5 5 5 3 3 3 3 2 2 2 I
1
Serum Level (dose range 600-1.500 mg/day) 0.50-1 .32 mEq/L 0.50-0.90 0.58-1 .25 0.50-0.90 0.66-0.99 0.33-1.03 0.68-1 .03 0.28-0.91 0.66-0.99 0.20-0.70 0.66-0.91 0.69-0.89 0.16
376
RYAN ET AL.
improvement found after the eighth week of TCA treatment, this makes the positive response to lithium addition unlikely to be caused by late effects of the TCA alone (Quitkin et aI., 1984). Additionally, the duration of lithium augmentation necessary to effect a positive clinical response in these patients was longer than that reported in the adult literature, and it is of interest that seven patients continued to improve up to 6 weeks after lithium was added. These data, however, do not preclude the possibility that some patients improved with just time alone, because of the fluctuating nature of the illness. The Question of medication versus time effect deserves further study in a controlled treatment trial. Although no significant differences in plasma levels between lithium responders and nonresponders were found, it is still possible that a higher dose or plasma level of lithium may induce a higher rate of response, as the plasma level threshold for lithium response may vary from one non bipolar individual to another. This variability should be tested in further research. The elimination of any patients treated with lithium augmentation who had past or drug-induced mania or hypomania was an effort to make this group more clinically homogeneous. In this review, however, there were no clinical predictors found that separated responders from nonresponders. Studies which indicate that a substantial minority of adolescent depressions have a bipolar outcome over the short term (I to 4 years) argue for greater consideration of this combination treatment in this population, especially when psychotic symptoms or a family history of bipolar disorder are present (Strober and Carlson, 1982). Despite the limitations of this treatment trial, the results of this study suggest a possible therapeutic effect of a TCAI lithium combination in some TCA resistent adolescent depressions. These results, along with the relative safety of the treatment regimen, support the need for controlled studies in TCA resistent adolescent depression. References Campbell, M., Perry, R. & Green, w. H. (1984), Use of lithium in children and adolescents. Psychosomatics, 25:95-106. Chambers, W. J., Puig-Antich, J., Hirsch, M., et al. (1985), The assessment of affective disorders in children and adolescents by semistructured interview: test-retest reliability of the K-SADS-P. Arch. Gen. Psychiatry, 42:696-701. Delong, G. R. & Aldershof, A. L. (1987), Long term experience with lithium treatment in childhood: correlation with clinical diagnoses. J. Am. Acad. Child Adolesc. Psychiatry, 26:389-394. - - Nieman, G. W. (1983), Lithium-induced behavior changes in children with symptoms suggesting manic-depressive illness. Psychopharmacol. Bull., 19:258-265. deMontigny, C; Cournoyer, G., Morissette, R., Langlois, R. & Caille, G. (1983), Lithium carbonate addition in tricyclic antidepressantresistant unipolar depression. Arch.Gen. Psychiatry, 40:1327-1334. - - Grunberg, F., Mayer, A. & Deschenes, J. P. (1981), Lithium induces rapid relief of depression in tricyclic antidepressant drug nonresponders. Br. J. Psychiatry, 138:252-256. Garbutt, J. c., Mayo, J. P., Gillette, G., Little, K. & Mason, G. (1986), Lithium potentiation of tricyclic antidepressants following lack ofT3 potentiation. Am. J. Psychiatry, 143:1038-1039. Heninger, G. R., Charney, D. S. & Sternberg, D. E. (1983), Lithium
carbonate augmentation of antidepressant treatment. Arch. Gen. Psychiatry, 40:1336-1342. Jefferson, J. W., (1982), The use of lithium in childhood and adolescents: an overview. J. Clin. Psychiatry, 43:174-177. Keller, M. B., Shapiro, R. W., Lavori, P. W. et al. (1982), Recovery and relapse in major depressive disorder. Arch. Gen. Psychiatry, 39:905-915. Khandelwah, S. K., Varma, V. K. & Murthy, R. S. (1984), Renal function in children receiving long-term lithium prophylaxis. Arch. Gen. Psychiatry, 141:278-279. Kiloh, L. G., Ball, J. R. B. & Garside, R. F. (1962), Prognostic factors in treatment of depressive states with imipramine. Br. Med. J., 1:1225-1227. Klein, D. F. & Davis, J. M. (1969), Diagnosis and Drug Treatment ofPsychiatric Disorders. Baltimore: William & Wilkins. - - Gittleman, R., Quitkins, F. & Rifkin, A. (1980)., Diagnosis and Drug Treatment of Psychiatric Disorders: Adults and Children. Baltimore: Williams & Wilkins. Kovacs, M., Feinberg, T. L., Crouse, M. A., Paulaskas, S. & Finkelstein, R. (1984a), Depressive disorders in childhood I. Arch. Gen. Psychiatry, 41:229-237. - - Feinberg, T. L., Crouse, M. A., Paulaskas, S. & Finkelstein, R. (1984b), Depressive disorders in childhood II. Arch. Gen. Psychiatry, 41:643-649. Kramer, E. & Feiguine, R. (1981), Clinical effects of amitriptyline in adolescent depression. J. Am. Acad. Child Adolesc. Psychiatry, 20:636-644. Liebowitz, M. R., Quitkin, F. M., Stewart, J. W. et al. (1984), Phenelzine vs imipramine in atypical depression. Arch. Gen. Psychiatry, 41:669-677. Louie, A. K. & Meltzer, H. Y. (1984), Lithium potentiation of antidepressant treatment. J. Clin. Psychopharmacol., 4:316-321. Morris, J. B. & Beck, A. T. (1974), The efficacy of antidepressant drugs. Arch. Gen. Psychiatry, 30:667-674. Neubauer, H. & Bermingham, P. (1976), A depressive syndrome responsive to lithium. J. Nerv. Ment. Dis., 163:276-281. Price, L. H., Charney, D. S. & Heninger, G. R. (1986), Variability of response to lithium augmentation in refractory depression. Am. J. Psychiatry, 143:1387-1392. Puig-Antich, J., Lukens, E., Davies, M., Goetz, D., Brennan-Quattrock, J. & Todak, G. (l985a), Psychosocial functioning in prepubertal major depressive disorders I. Arch. Gen. Psychiatry, 42:500507. . - - Lukens, E., Davies, M., Goetz, D., Brennan-Quattrock, J. & Todak, G. (l985b), Psychosocial functioning in prepubertal major depressive disorders II. Arch. Gen. Psychiatry, 42:511-517. Quitkin, F. M., Rabkin, J. G., Ross, D. & McGrath, P. J. (1984), Duration of antidepressant drug treatment: what is a good trial? Arch. Gen. Psychiatry, 41:238-245. Raskin, A. (1975), Age-sex differences in response to antidepressant drugs. J. Nerv. Ment. Dis., 159:120-130. Rogers, S. C. & Clay, P. M. (1975), A statistical review of controlled trials of imipramine and placebo in the treatment of depressive illness. Br. J. Psychiatry, 127:599-603. Ryan, N., Puig-Antich, J., Cooper, T. & Rabinovich, H. et al. (1986), Imipramine in adolescent major depression: plasma level and clinical response. Acta Psychiatr. Scand., 73:275-288. Schrader, G. D. & Levien, H. E. M. (1985), Response to sequential administration of clomipramine and lithium carbonate in treatment-resistant depression. Br. J. Psychiatry, 147:573-575. Strober, M. (1983), Natural history of major depressive disorder in adolescence. Paper presented at the annual meeting of the American Psychiatric Association, New York. - - Carlson, G. (1982), Bipolar illness in adolescents with major depression: clinical, genetic, and"psychopharmacologic predictors in a three-to four-year prospective follow-up investigation. Arch. Gen. Psychiatry, 39:549-555. Youngerman, J. & Canino, I. A. (1976), Lithium carbonate use in children and adolescents. Arch. Gen. Psychiatry, 35:216-224.