0
December 1983, Vol 40, No. 12 >
Article | December 1983

Lithium Carbonate Augmentation of Antidepressant Treatment: Title and subTitle BreakAn Effective Prescription for Treatment-Refractory Depression

George R. Heninger, MD; Dennis S. Charney, MD; David E. Sternberg, MD
[+] Author Affiliations

Accepted for publication June 10, 1983.

Read in part before the American Psychiatric Association, Toronto, May 20, 1982.

Reprint requests to 34 Park St, New Haven, CT 06508 (Dr Heninger).


Arch Gen Psychiatry. 1983;40(12):1335-1342. doi:10.1001/archpsyc.1983.01790110077013
Text Size: A A A
Published online
Article
References
Comments

• To assess whether lithium carbonate augments antidepressant effects of long-term antidepressant treatment in nonresponding patients, 15 treatment-refractory patients were studied using a placebo-controlled, double-blind design. After at least 21 days of antidepressant drug therapy, and while continuing to receive the same daily dose of antidepressant drug, eight patients received lithium carbonate and seven received placebo. In comparison with placebo, lithium carbonate produced a small but statistically significant improvement in the mean daily nursing ratings of depression during the first two days of treatment. The beneficial effects of lithium carbonate were more variable during the next four days, but by the seventh through 12th day of the trial, the drug produced a significant and clinically meaningful improvement. When the seven placebo-treated patients received active lithium carbonate on the 13th day of the study, their rate of improvement was similar to that of the eight patients who had received active lithium carbonate initially. This augmentation of the antidepressant effect was seen in patients treated with desipramine hydrochloride, amitriptyline hydrochloride, or mianserin hydrochloride. Although in five of the 15 patients, the improvement appeared as early as 24 to 48 hours after the first lithium carbonate dose, the remaining patients did not show a clear improvement until approximately five to eight days later. We concluded that lithium carbonate does augment the antidepressant effect when added to the long-term antidepressant treatment of nonresponding patients.

REFERENCES

1 +
Cade JGJ:  Lithium salts in the treatment of psychiatric excitement . Med J Aust 1949;;36:349-352.
2 +
Noack DH, Trautner EM:  The lithium treatment of maniacal psychosis . Med J Aust 1951;;38:219-222.
3 +
Vojtechovsky M, quoted by Schou M:  Lithium in psychiatric therapy and prophylaxis . J Psychiatr Res 1968;;5:67-95.
4 +
Andreani G, Caselli G, Martelli G:  Ritievi clinici ed electro encefalografici durante il trattemento con sali dilito in malati psichiatrici . G Psychiatr Neuropatol 1958;;86:273-328.
5 +
Dyson WL, Mendels J:  Lithium and depression . Curr Ther Res 1968;;10:601-608.
6 +
Van der Velde CD:  Effectiveness of lithium-carbonate in the treatment of manic-depressive illness . Am J Psychiatry 1970;;127:345-351.
7 +
Nahuneck K, Svestka J, Rodova A:  Zur Stellung des Lithiums in der Gruppe der Antidepressiva in der Behandlung von akuten endogenen und Involutions-Depressionen . Int Pharmacopsychiatry 1970;;5:249-257.
8 +
Noyes R Jr, Ringdahl JC, Andreasen NJ:  Effect of lithium citrate on adrenocortical activity in manic depressive illness . Compr Psychiatry 1971;;12:337-347.
9 +
Bennie EH:  Lithium in depression . Lancet 1975;;1:216.
10 +
Neubauer H, Bermingham P:  A depressive syndrome responsive to lithium: An analysis of 20 cases . J Nerv Ment Dis 1976;;163:276-281.
11 +
Cox JR, Pearson RE, Brand HL:  Lithium in depression: A biochemical study . Gerontology 1977;;23:219-235.
12 +
Schou M:  Lithium in psychiatric therapy and prophylaxis . J Psychiatr Res 1968;;5:67-95.
13 +
Goodwin FK, Murphy DL, Bunney WE Jr:  Lithium carbonate treatment in depression and mania: A longitudinal double-blind study . Arch Gen Psychiatry 1969;;21:486-496.
14 +
Stokes PE, Shamoian CA, Stoll PM, et al:  Efficacy of lithium as acute treatment of manic-depressive illness . Lancet 1971;;1:1319-1325.
15 +
Goodwin FK, Murphy DL, Dunner DL, et al;  Lithium response in unipolar versus bipolar depression . Am J Psychiatry 1972;;129:44-47.
16 +
Noyes R Jr, Dempsey GM, Blum A, et al:  Lithium treatment of depression . Compr Psychiatry 1974;;15:187-193.
17 +
Johnson G:  Antidepressant effect of lithium . Compr Psychiatry 1974;; 15:43-47.
18 +
Baron M, Gershon ES, Rudy V, et al:  Lithium carbonate response in depression: Prediction by unipolar/bipolar illness, average-evoked response, catechol-O-methyl transferase, and family history . Arch Gen Psychiatry 1975;;32:1107-1111.
19 +
Mendels J:  Lithium in the treatment of depression . Am J Psychiatry 1976;;133:373-378.
20 +
Arieli A, Lepkifker E:  The antidepressant effect of lithium . Curr Dev Psychopharmacol 1981;;6:165-190.
21 +
Fieve RR, Platman SR, Plutchik RR:  The use of lithium in affective disorders: I. Acute endogenous depression . Am J Psychiatry 1968;;125:487-491.
22 +
Mendels J, Secunda SK, Dyson WL:  A controlled study of the antidepressant effects of lithium . Arch Gen Psychiatry 1972;;26:154-157.
23 +
Watanabe S, Ishino H, Optsuki S:  Double-blind comparison of lithium carbonate and imipramine in treatment of depression . Arch Gen Psychiatry 1975;;32:659-668.
24 +
Worrall EP, Moody JP, Peet M, et al:  Controlled studies of the acute antidepressant effects of lithium . Br J Psychiatry 1979;;135:255-262.
25 +
Khan MC:  Lithium carbonate in the treatment of acute depressive illness . Bibl Psychiatr 1981;;161:244-248.
26 +
De Montigny C, Grunbert F, Mayer A, et al:  Lithium induces rapid relief of depression in tricyclic antidepressant drug non-responders . Br J Psychiatry 1981;;138:252-256.
27 +
Grahame-Smith DG, Green AR:  The role of brain 5-hydroxytryptamine in the hyperactivity produced by lithium and monoamine oxidase inhibition . Eur J Pharmacol 1974;;52:19-26.
28 +
De Montigny C, Aghajanian G:  Tricyclic antidepressants: Long-term treatment increases responsivity of rat forebrain neurons to serotonin . Science 1978;;202:1303-1306.
29 +
Hartigan GP:  The use of lithium salts in affective disorders . Br J Psychiatry 1963;;109:810-814.
30 +
Zall H:  Lithium carbonate and isocarboxazid: An effective drug approach in severe depressions . Am J Psychiatry 1971;;127:1400-1403.
31 +
Himmelhoch JM, Detre T, Kupfer DJ, et al:  Treatment of previously intractable depressions with tranylcypromine and lithium . J Nerv Ment Dis 1971;;155:216-220.
32 +
Nelson CJ, Byck R:  Rapid response to lithium in phenelzine nonresponders . Br J Psychiatry 1982;;141:85-86.
33 +
Honore P, Moller SE, Jorgensen A:  Lithium+L-tryptophan compared with amitriptyline in endogenous depression . J Affective Disord 1982;; 4:79-82.
34 +
O'Flanagan PM:  Clomipramine infusion and lithium carbonate: A synergistic effect? Lancet 1973;;11:974.
35 +
Lingjaerde O:  Synergistic effect of tricyclic antidepressants and lithium carbonate in endogenous depression . Lancet 1973;;11:1260.
36 +
Lingjaerde O, Edlund AH, Gormsen CA, et al:  The effect of lithium carbonate in combination with tricyclic antidepressants in endogenous depression . Acta Psychiatr Scand 1974;;50:233-242.
37 +
Heninger GR, French NH, Slavinsky AT, et al:  A short clinical rating scale for use by nursing personnel: II. Reliability, validity, and application . Arch Gen Psychiatry 1970;;23:241-248.
38 +
De Montigny C:  Enhancement of the 5-HT neurotransmission by antidepressant treatments . J Physiol 1981;;77:455-461.
39 +
Knapp S, Mandell AJ:  Effects of lithium chloride on parameters of biosynthetic capacity for 5-hydroxytryptamine in rat brain . J Pharmacol Exp Ther 1975;;193:812-823.
40 +
Schubert J:  Effect of chronic lithium treatment on monoamine metabolism in rat brain . Psychopharmacologia 1973;;32:301-312.
41 +
Poitov P, Guerinot F, Buhvon C:  Effect of lithium on central metabolism of 5-hydroxytryptamine . Psychopharmacologia 1974;;38:75-82.
42 +
Sangdee C, Franz DN:  Lithium enhancement of central 5-HT transmission induced by 5-HT precursors . Biol Psychiatry 1980;;15:59-75.
43 +
Friedman E, Dallob A:  Enhanced serotonin receptor activity after chronic treatment with imipramine or amitriptyline . Commun Psychopharmacol 1979;;3:89-92.
44 +
Jones RSG:  Enhancement of 5-hydroxytryptamine-induced behavioral effects following chronic administration of antidepressant drugs . Psychopharmacology 1980;;69:307-311.
45 +
Peroutka SJ, Snyder SH:  Regulation of serotonin2 (5-HT2) receptors labeled with 3H-spiroperidol by chronic treatment with the antidepressant amitriptyline . J Pharmacol Exp Ther 1980;;215:582-587.
46 +
Peroutka SJ, Snyder SJ:  Chronic antidepressant treatment decreases spiroperidol-labeled serotonin receptor binding . Science 1980;;210:88-90.
47 +
Astrachan DJ, Davis M, Gallager DW:  Behavior and binding: Correlations between alpha-1-adrenergic stimulation of acoustic startle and alpha-1-adrenoceptor occupancy and number in rat lumbar spinal cord . Brain Res 1983;;260:81-90.
48 +
Menkes DB, Kehne JH, Gallager DW, et al:  Functional supersensitivity of CNS alpha-1 adrenoceptors following chronic antidepressant treatment . Life Sci 1983;;33:181-188.
49 +
Fillion G, Fillion MP:  Modulation of affinity of postsynaptic serotonin receptors by antidepressant drugs . Nature 1981;;292:349-351.
50 +
Charney DS, Menkes DB, Heninger GR:  Receptor sensitivity and the mechanism of action of antidepressant treatment . Arch Gen Psychiatry 1981;;38:1160-1180.
51 +
Heninger GR, Charney DS:  The monoamine receptor sensitivity hypothesis of antidepressant drug action . Psychopharmacol Bull 1982;;18:130-135.
52 +
Seeger TF, Gardner EL, Bridger WF:  Increase in mesolimbic electrical self-stimulation after chronic haloperidol: Reversal by L-dopa or lithium . Brain Res 1981;;215:404-409.
53 +
Siggins GR, Schultz JE:  Chronic treatment with lithium or desipramine alters discharge frequency and norepinephrine responsiveness of cerebellar Purkinje cells . Proc Natl Acad Sci USA 1979;;76:5987-5991.
54 +
Belmaker RH, Kon M, Ebstein RP, et al:  Partial inhibition by lithium of the epinephrine-stimulated rise in plasma cyclic GMP in humans . Biol Psychiatry 1980;;15:3-8.
55 +
Mendels J, Ramsey TA, Dyson WL, et al:  Lithium as an antidepressant . Arch Gen Psychiatry 1979;;36:845-846.

First Page Preview

First page PDF preview

Figures

Tables

Interactive Graphics

Video

Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Cade JGJ:  Lithium salts in the treatment of psychiatric excitement . Med J Aust 1949;;36:349-352.
2 +
Noack DH, Trautner EM:  The lithium treatment of maniacal psychosis . Med J Aust 1951;;38:219-222.
3 +
Vojtechovsky M, quoted by Schou M:  Lithium in psychiatric therapy and prophylaxis . J Psychiatr Res 1968;;5:67-95.
4 +
Andreani G, Caselli G, Martelli G:  Ritievi clinici ed electro encefalografici durante il trattemento con sali dilito in malati psichiatrici . G Psychiatr Neuropatol 1958;;86:273-328.
5 +
Dyson WL, Mendels J:  Lithium and depression . Curr Ther Res 1968;;10:601-608.
6 +
Van der Velde CD:  Effectiveness of lithium-carbonate in the treatment of manic-depressive illness . Am J Psychiatry 1970;;127:345-351.
7 +
Nahuneck K, Svestka J, Rodova A:  Zur Stellung des Lithiums in der Gruppe der Antidepressiva in der Behandlung von akuten endogenen und Involutions-Depressionen . Int Pharmacopsychiatry 1970;;5:249-257.
8 +
Noyes R Jr, Ringdahl JC, Andreasen NJ:  Effect of lithium citrate on adrenocortical activity in manic depressive illness . Compr Psychiatry 1971;;12:337-347.
9 +
Bennie EH:  Lithium in depression . Lancet 1975;;1:216.
10 +
Neubauer H, Bermingham P:  A depressive syndrome responsive to lithium: An analysis of 20 cases . J Nerv Ment Dis 1976;;163:276-281.
11 +
Cox JR, Pearson RE, Brand HL:  Lithium in depression: A biochemical study . Gerontology 1977;;23:219-235.
12 +
Schou M:  Lithium in psychiatric therapy and prophylaxis . J Psychiatr Res 1968;;5:67-95.
13 +
Goodwin FK, Murphy DL, Bunney WE Jr:  Lithium carbonate treatment in depression and mania: A longitudinal double-blind study . Arch Gen Psychiatry 1969;;21:486-496.
14 +
Stokes PE, Shamoian CA, Stoll PM, et al:  Efficacy of lithium as acute treatment of manic-depressive illness . Lancet 1971;;1:1319-1325.
15 +
Goodwin FK, Murphy DL, Dunner DL, et al;  Lithium response in unipolar versus bipolar depression . Am J Psychiatry 1972;;129:44-47.
16 +
Noyes R Jr, Dempsey GM, Blum A, et al:  Lithium treatment of depression . Compr Psychiatry 1974;;15:187-193.
17 +
Johnson G:  Antidepressant effect of lithium . Compr Psychiatry 1974;; 15:43-47.
18 +
Baron M, Gershon ES, Rudy V, et al:  Lithium carbonate response in depression: Prediction by unipolar/bipolar illness, average-evoked response, catechol-O-methyl transferase, and family history . Arch Gen Psychiatry 1975;;32:1107-1111.
19 +
Mendels J:  Lithium in the treatment of depression . Am J Psychiatry 1976;;133:373-378.
20 +
Arieli A, Lepkifker E:  The antidepressant effect of lithium . Curr Dev Psychopharmacol 1981;;6:165-190.
21 +
Fieve RR, Platman SR, Plutchik RR:  The use of lithium in affective disorders: I. Acute endogenous depression . Am J Psychiatry 1968;;125:487-491.
22 +
Mendels J, Secunda SK, Dyson WL:  A controlled study of the antidepressant effects of lithium . Arch Gen Psychiatry 1972;;26:154-157.
23 +
Watanabe S, Ishino H, Optsuki S:  Double-blind comparison of lithium carbonate and imipramine in treatment of depression . Arch Gen Psychiatry 1975;;32:659-668.
24 +
Worrall EP, Moody JP, Peet M, et al:  Controlled studies of the acute antidepressant effects of lithium . Br J Psychiatry 1979;;135:255-262.
25 +
Khan MC:  Lithium carbonate in the treatment of acute depressive illness . Bibl Psychiatr 1981;;161:244-248.
26 +
De Montigny C, Grunbert F, Mayer A, et al:  Lithium induces rapid relief of depression in tricyclic antidepressant drug non-responders . Br J Psychiatry 1981;;138:252-256.
27 +
Grahame-Smith DG, Green AR:  The role of brain 5-hydroxytryptamine in the hyperactivity produced by lithium and monoamine oxidase inhibition . Eur J Pharmacol 1974;;52:19-26.
28 +
De Montigny C, Aghajanian G:  Tricyclic antidepressants: Long-term treatment increases responsivity of rat forebrain neurons to serotonin . Science 1978;;202:1303-1306.
29 +
Hartigan GP:  The use of lithium salts in affective disorders . Br J Psychiatry 1963;;109:810-814.
30 +
Zall H:  Lithium carbonate and isocarboxazid: An effective drug approach in severe depressions . Am J Psychiatry 1971;;127:1400-1403.
31 +
Himmelhoch JM, Detre T, Kupfer DJ, et al:  Treatment of previously intractable depressions with tranylcypromine and lithium . J Nerv Ment Dis 1971;;155:216-220.
32 +
Nelson CJ, Byck R:  Rapid response to lithium in phenelzine nonresponders . Br J Psychiatry 1982;;141:85-86.
33 +
Honore P, Moller SE, Jorgensen A:  Lithium+L-tryptophan compared with amitriptyline in endogenous depression . J Affective Disord 1982;; 4:79-82.
34 +
O'Flanagan PM:  Clomipramine infusion and lithium carbonate: A synergistic effect? Lancet 1973;;11:974.
35 +
Lingjaerde O:  Synergistic effect of tricyclic antidepressants and lithium carbonate in endogenous depression . Lancet 1973;;11:1260.
36 +
Lingjaerde O, Edlund AH, Gormsen CA, et al:  The effect of lithium carbonate in combination with tricyclic antidepressants in endogenous depression . Acta Psychiatr Scand 1974;;50:233-242.
37 +
Heninger GR, French NH, Slavinsky AT, et al:  A short clinical rating scale for use by nursing personnel: II. Reliability, validity, and application . Arch Gen Psychiatry 1970;;23:241-248.
38 +
De Montigny C:  Enhancement of the 5-HT neurotransmission by antidepressant treatments . J Physiol 1981;;77:455-461.
39 +
Knapp S, Mandell AJ:  Effects of lithium chloride on parameters of biosynthetic capacity for 5-hydroxytryptamine in rat brain . J Pharmacol Exp Ther 1975;;193:812-823.
40 +
Schubert J:  Effect of chronic lithium treatment on monoamine metabolism in rat brain . Psychopharmacologia 1973;;32:301-312.
41 +
Poitov P, Guerinot F, Buhvon C:  Effect of lithium on central metabolism of 5-hydroxytryptamine . Psychopharmacologia 1974;;38:75-82.
42 +
Sangdee C, Franz DN:  Lithium enhancement of central 5-HT transmission induced by 5-HT precursors . Biol Psychiatry 1980;;15:59-75.
43 +
Friedman E, Dallob A:  Enhanced serotonin receptor activity after chronic treatment with imipramine or amitriptyline . Commun Psychopharmacol 1979;;3:89-92.
44 +
Jones RSG:  Enhancement of 5-hydroxytryptamine-induced behavioral effects following chronic administration of antidepressant drugs . Psychopharmacology 1980;;69:307-311.
45 +
Peroutka SJ, Snyder SH:  Regulation of serotonin2 (5-HT2) receptors labeled with 3H-spiroperidol by chronic treatment with the antidepressant amitriptyline . J Pharmacol Exp Ther 1980;;215:582-587.
46 +
Peroutka SJ, Snyder SJ:  Chronic antidepressant treatment decreases spiroperidol-labeled serotonin receptor binding . Science 1980;;210:88-90.
47 +
Astrachan DJ, Davis M, Gallager DW:  Behavior and binding: Correlations between alpha-1-adrenergic stimulation of acoustic startle and alpha-1-adrenoceptor occupancy and number in rat lumbar spinal cord . Brain Res 1983;;260:81-90.
48 +
Menkes DB, Kehne JH, Gallager DW, et al:  Functional supersensitivity of CNS alpha-1 adrenoceptors following chronic antidepressant treatment . Life Sci 1983;;33:181-188.
49 +
Fillion G, Fillion MP:  Modulation of affinity of postsynaptic serotonin receptors by antidepressant drugs . Nature 1981;;292:349-351.
50 +
Charney DS, Menkes DB, Heninger GR:  Receptor sensitivity and the mechanism of action of antidepressant treatment . Arch Gen Psychiatry 1981;;38:1160-1180.
51 +
Heninger GR, Charney DS:  The monoamine receptor sensitivity hypothesis of antidepressant drug action . Psychopharmacol Bull 1982;;18:130-135.
52 +
Seeger TF, Gardner EL, Bridger WF:  Increase in mesolimbic electrical self-stimulation after chronic haloperidol: Reversal by L-dopa or lithium . Brain Res 1981;;215:404-409.
53 +
Siggins GR, Schultz JE:  Chronic treatment with lithium or desipramine alters discharge frequency and norepinephrine responsiveness of cerebellar Purkinje cells . Proc Natl Acad Sci USA 1979;;76:5987-5991.
54 +
Belmaker RH, Kon M, Ebstein RP, et al:  Partial inhibition by lithium of the epinephrine-stimulated rise in plasma cyclic GMP in humans . Biol Psychiatry 1980;;15:3-8.
55 +
Mendels J, Ramsey TA, Dyson WL, et al:  Lithium as an antidepressant . Arch Gen Psychiatry 1979;;36:845-846.

Correspondence

Submit a Letter
CME Course for:


You need to register in order to view this quiz.


To understand the clinical management of acute heart failure syndromes.
Accreditation Information The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
To view and print your certificate and access a summary of your CME courses go to My CME.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s “Cited By” API will populate this tab (http://www.crossref.org/citedby.html).
Compression-Only CPR: Pushing the Science Forward
Cone
AAM 2010;304:1493-1495.
All you need to read in the other general journals
BMJ 2010;341:c5893-c1494.
Submit a Comment

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

© 2012 American Medical Association. All Rights Reserved.
Powered bySilverchair Information Systems