This communication reviews current literature on lithium augmentation in patients
not responding to SSRIs, giving some recommendations at the end. A significant proportion
of depressive patients do not respond to a first antidepressive treatment independently
of the class of drugs used. During the last 10 years, there have been several case
reports published about open and controlled studies on the use of lithium augmentation
in patients who were non-responders to SSRIs, including citalopram, fluoxetine, paroxetine
and sertraline. The main underlying hypothesis is a synergistic effect between SSRIs
and lithium, which both act on serotonergic neurotransmission. The available studies
vary considerably in methodology. There are insufficient results available to confirm
a rapid improvement (within 24 - 48 h) after introduction of lithium, but most studies
show substantial effects after 1 - 2 weeks, and some after 6 weeks. There is as yet
no more clear evidence for a pharmacokinetic interaction between lithium and SSRIs
with pharmacodynamic consequences. In conclusion, present evidence suggests that a
lithium augmentation in depressive patients who do not respond to SSRIs may be an
efficacious and generally well tolerated treatment, with a response rate of at least
50 % after a period lasting 1 - 2 weeks. However, special care is indicated when treating
elderly patients, where the risk of adverse effects is higher.
References
- 1
Adli M, Bschor T, Canata B, Döpfmer S, Bauer M.
Lithium in der Behandlung der akuten Depression.
Fortschr Neurol Psychiat.
1998;
66
435-441
- 2
American Psychiatric Association .
Practice guideline for major depressive disorder in adults.
Am J Psychiatry.
1993;
150
(Suppl 4)
- 3
Anderson I M.
SSRIS versus tricyclic antidepressants in depressed inpatients: a meta-analysis of
efficacy and tolerability.
Depression and Anxiety.
1998;
7
(Suppl. 1)
11-17
- 4
Aronson R, Offman H J, Joffe R T, Naylor C D.
Triiodthyronine augmentation in the treatment of refractory depression.
Arch Gen Psychiatry.
1996;
53
842-848
- 5
Austin L S, Arana G W, Melvin J A.
Toxicity resulting from lithium augmentation of antidepressant treatment in elderly
patients.
J Clin Psychiatry.
1990;
51
344-345
- 6
Barak Y, Stein D, Levine J, Ring A, Hadjez J, Elizur A, Shoshani D.
Thyroxine augmentation of fluoxetine treatment for resistant depression in the elderly.
Hum Psychopharmacol.
1996;
11
463-467
- 7
Bauer M.
The combined use of lithium and SSRIs.
J Serotonin Res.
1995;
2
69-76
- 8
Bauer M.
Adverse events and tolerability of the combination of fluoxetine/lithium compared
with fluoxetine.
J Clin Psychopharmacol.
1996;
16
130-134
- 9
Bauer M, Hellweg R, Graf K J, Baumgartner A.
Treatment of refractory depression with high dose thyroxine.
Neuropsychopharmacology.
1998;
18
444-455
- 10
Bauer M, Döpfmer S.
Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled
studies.
J Clin Psychopharmacol.
1999;
19
427-434
- 11
Bauer M, Bschor T, Kunz D, Berghöfer A, Ströhle A, Müller-Oerlinghausen B.
Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant
medication in continuation tratment of unipolar major depression.
Am J Psychiatry.
2000;
157
1429-1435
- 12
Baumann P, Nil R, Souche A, Montaldi S, Baettig D, Lambert S, et al.
A double-blind, placebo-controlled study of citalopram with and without lithium in
the treatment of therapy-resistant depressive patients: a clinical, pharmacokinetic,
and pharmacogenetic investigation.
J Clin Psychopharmacol.
1996;
16
307-314
- 13
Baumann P.
Care of depression in the elderly: comparative pharmacokinetics of SSRIs.
Int Clin Psychopharmacol.
1998a;
13
S35-S43
- 14
Blier P, Bergeron R.
The use of pindolol to potentiate antidepressant medication.
J Clin Psychiatry.
1998;
59
16-23
- 15
Bodkin J A, Lasser R A, Wines J D, Gardner D M, Baldessarini R J.
Combining serotonin reuptake inhibitors and bupropion in partial responders to antidepressant
monotherapy.
J Clin Psychiatry.
1997;
58
137-145
- 16
Breuel H P, Müller-Oerlinghausen B, Nickelsen T, Heine P R.
Pharmacokinetic interactions between lithium and fluoxetine after single and repeated
fluoxetine administration in young healthy volunteers.
Int J Clin Pharmacol Ther.
1995;
33
415-419
- 17
Byrne S E, Rothschild A J.
Loss of antidepressant efficacy during maintenance therapy: possible mechanisms and
treatments.
J Clin Psychiatry.
1998;
59
279-288
- 18
Camprubi M E, Puri B K.
The treatment of refractory depression using paroxetine with lithium augmentation.
Prog Neuropsychopharmacol Biol Psychiat.
1995;
19
515-517
- 19
De Angelis L.
Lithium treatment and the geriatric population.
Int J Clin Pharmac Ther Toxicol.
1990;
28
394-398
- 20
De Montigny C, Grunberg F, Mayer A.
Lithium induces rapid relief of depression in tricyclic antidepressant drug nonresponders.
Br J Psychiatry.
1981;
138
252-256
- 21
De Montigny C, Cournoyer G, Moriseett R.
Lithium carbonate additionin tricyclic antidepressant-resistant unipolar depression.
Arch Gen Psychiatry.
1983;
40
1327-1334
- 22
De Montigny C.
Lithium addition in treatment-resistant depression.
Int Clin Psychopharmacol.
1994;
9
31-35
- 23
Delgado P L, Price L H, Charney D S, Heninger G R.
Efficacy of fluvoxamine in treatment-refractory depression.
J Affect Disord.
1988;
15
55-60
- 24
Dietrich D E, Emrich H M.
The use of anticonvulsants to augment antidepressant medication.
J Clin Psychiatry.
1998;
59
51-58
- 25
Dinan T G.
A rational approach to the non-responding depressed patient.
Int Clin Psychopharmacol.
1993a;
8
221-223
- 26
Dinan T G.
Lithium augmentation in sertraline-resistant depression: a preliminary dose-response
study.
Acta Psychiatr Scand.
1993b;
88
300-301
- 27
Dinan T G, Lavelle E, Cooney J, Burnett F, Scott L, Dash A, Thakore J, Berti C.
Dexamethasone augmentation in treatment-resistant depression.
Acta Psychiatr Scand.
1997;
95
58-61
- 28
Ebert D, Jaspert A, Murata H, Kaschka W P.
Initial lithium augmentation improves the antidepressant effects of standard TCA treatment
in non-resistant depressed patients.
Psychopharmacology.
1995;
118
223-225
- 29
Edwards J G, Anderson I.
Systematic review and guide to selection of selective serotonin reuptake inhibitors
(review).
Drugs.
1999;
57
507-533
- 30
Egberts A CG, Lenderink A W, De Koning F HP, Leufkens H GM.
Channeling of three newly introduced antidepressants to patients not responding satisfactorily
to previous treatment.
J Clin Psychopharmacol.
1997;
17
149-155
- 31
Evans M, Marwick P.
Fluvoxamine and lithium: an unusual interaction.
Br J Psychiatry.
1990;
156
286
- 32
Fava M, Rosenbaum J F, Cohen A, Reiter S, McCarthy M, Steingard R, Clancy K.
High-dose fluoxetine in the treatment of depressed patients not responsive to a standard
dose of fluoxetine.
J Affect Disord.
1992;
25
229-234
- 33
Fava M, Rosenbaum J F, McGrath P J, Stewart J W, Amsterdam J D, Quitkin F M.
Lithium and tricyclic augmentation of fluoxetine treatment for resistant major depression:
a double-blind, controlled study.
Am J Psychiatry.
1994;
151
1372-1374
- 34
Finley P R, Warner M D, Peabody C A.
Clinical relevance of drug interactions with lithium.
Clin Pharmacokinet.
1995;
29
172-191
- 35
Flint A J, Rifat S L.
A prospective study of lithium augmentation in antidepressant-resistant geriatric
depression.
J Clin Psychopharmacol.
1994;
14
353-356
- 36
Fontaine R, Ontiveros A, Elie R, Vézina M.
Lithium carbonate augmentation of desipramine and fluoxetine in refractory depression.
Biol Psychiatry.
1991;
29
946-948
- 37
Freeman M P, Stoll A L.
Mood stabilizer combinations: a review of safety and efficacy.
Am J Psychiatry.
1998;
155
12-21
- 38
Gallinat J, Boetsch T, Padberg F, Hampel H, Herrman W M, Hegerl U.
Is the EEG helpful in diagnosing and monitoring lithium intoxication? A case report
and review of the literature.
Pharmacopsychiat.
2000;
33
169-173
- 39
Grohman R, Rüther E, Engel R R, Hippius H.
Assessment of adverse drug reactions in psychiatric inpatients with the AMSP drug
safety program: methods and first results for tricyclic antidepressants and SSRI.
Pharmacopsychiat.
1999;
32
21-28
- 40
Guscott R, Grof P.
The clinical meaning of refractory depression: a review for the clinician.
Am J Psychiatry.
1991;
148
695-704
- 41
Hadley A, Cason M P.
Mania resulting from lithium-fluoxetine combination.
Am J Psychiatry.
1989;
146
1637-1638
- 42
Hardy B G, Shulman K I, Zucchero C.
Gradual discontinuation of lithium augmentation in elderly patients with unipolar
depression.
J Clin Psychopharmacol.
1997;
17
22-26
- 43
Hawley C J, Roberts A G, Baldwin D S.
Tolerability of combined treatment with lithium and fluoxetine: 14 cases treated under
open conditions.
Int Clin Psychopharmacol.
1994a;
9
31-33
- 44
Hawley C J, Roberts A G, Walker M H.
Tolerability of combined treatment with lithium and paroxetine: 19 cases treated under
open conditions.
J Psychopharmacol.
1994b;
8
266-267
- 45
Hawley C J, Loughlin P J, Quick S J, Gale T M, Sivakumaran T, Hayes J, McPhee S. for
the Hertfordshire Neuroscience Research Group .
Efficacy, safety and tolerability of combined administration of lithium and selective
serotonin reuptake inhibitors: a review of the current evidence.
Int Clin Psychopharmacol.
2000;
15
197-206
- 46
Heit S, Nemeroff C B.
Lithium augmentation of antidepressants in treatment-refractory depression.
J Clin Psychiatry.
1998;
59
28-33
- 47
Hilton S E, Maradit H, Möller H J.
Serotonin syndrome and drug combinations: focus on MAOI and RIMA.
Eur Arch Psychiatry Clin Neurosci.
1997;
247
113-119
- 48
Hopwood S E, Bogle S, Wildgust H J.
The combination of fluoxetine and lithium in clinical practice.
Int Clin Psychopharmacol.
1993;
8
325-327
- 49
Joffe R T.
Refractory depresion: treatment strategies, with particular reference to the thyroid
axis.
J Psychiatry Neurosci.
1997;
22
327-331
- 50
Joffe R T.
The use of thyroid supplements to augment antidepressant medication.
J Clin Psychiatry.
1998;
59
26-29
- 51
Kallner G, Lindelius R, Petterson U, Stockman O, Tham A.
Mortality in 497 patients with affective disorders attending a lithium clinic or after
having left it.
Pharmacopsychiat.
2000;
33
8-13
- 52
Katona C LE.
Refractory depression: a review with particular reference to the use of lithium augmentation.
Eur Neuropsychopharmacol.
1995;
suppl
109-113
- 53
Katona C LE, Abou-Saleh M T, Harrison D A, Nairac B A, Edwards D RL, Lock T, et al.
Placebo-controlled trial of lithium augmentation of fluoxetine and lofepramine.
Br J Psychiatry.
1995;
166
80-86
- 54
Kelsey J E.
Switching drug class after initial SSRI failure.
J CLin Psychiatry.
1997;
583
26-327
- 55
Kojima H, Terao T, Yoshimura R.
Serotonin syndrome during clomipramine and lithium treatment.
Am J Psychiatry.
1993;
150
1897
- 56
Kupfer D J.
Long-term treatment of depression.
J Clin Psychiatry.
1991;
52
(Suppl. 5)
28-34
- 57
Lenox R H, McNamara R K, Papke R L, Manji H K.
Neurobiology of lithium: an update.
J Clin Psychiatry.
1998;
59
37-47
- 58
Leonard B E.
Pharmacological and biochemical aspects of therapy-resistant depression.
Int Clin Psychopharmacol.
1991;
6
13-29
- 59
McDougle C J, Price L H, Goodman W K, Charney D S, Heninger G R.
A controlled trial of lithium augmentation in fluvoxamine-refractory obsessive-compulsive
disorder: lack of efficacy.
J Clin Psychopharmacol.
1991;
11
175-184
- 60
Mekler G, Woggon B.
A case of serotonin syndrome caused by venlafaxine and lithium.
Pharmacopsychiat.
1997;
30
272-273
- 61
Montgomery S A.
Efficacy in long-term treatment of depression.
J Clin Psychiatry.
1996;
57
24-30
- 62
Moreno F A, Gelenberg A J, Bachar K, Delgado P L.
Pindolol augmentation of treatment-resistant depressed patients.
J Clin Psychiatry.
1997;
58
437-439
- 63
Muly E C, Mcdonald W, Steffens D, Book S.
Serotonin syndrome produced by a combination of fluoxetine and lithium.
Am J Psychiatry.
1993;
150
1565
- 64
Nelson J C, Price L H.
Lithium or desipramine augmentation of fluoxetine treatment.
Am J Psychiatry.
1995;
152
1538-1539
- 65
Nelson J C.
Augmentation strategies with serotonergic-noradrenergic combinations.
J Clin Psychiatry.
1998;
59
65-68
- 66
Nierenberg A A, Amsterdam J D.
Treatment-resistant depression: definition and treatment approaches.
J Clin Psychiatry.
1990;
6
39-47
- 67
Nisijima K, Shimizu M, Abe T, Ishiguro T.
A case of serotonin syndrome induced by concomitant treatment with low-dose trazodone
and amitriptyline and lithium.
Int Clin Psychopharmacol.
1996;
11
289-290
- 68
Noveske F G, Hahn K R, Flynn R J.
Possible toxicity of combined fluoxetine and lithium.
Am J Psychiatry.
1989;
146
1515
- 69
O'Connor M, Silver H.
Adding risperidone to selective serotonin reuptake inhibitor improves chronic depression.
J Clin Psychopharmacol.
1998;
18
89-91
- 70
Okamoto Y, Motohashi N, Hayakawa H, Muraoka M, Yamawaki S.
Addition of lithium to chronic antidepressant treatment potentiates presynaptic serotonergic
function without changes in serotonergic receptors in the rat cerebral cortex.
Pharmacopsychiat.
1996;
33
17-20
- 71
Öhman A, Spigset O.
Serotonin syndrome induced by fluvoxamine-lithium interaction.
Pharmacopsychiat.
1993;
26
263-264
- 72
Pope H G, McElroy S L, Noxon R A.
Possible synergism between fluoxetine and lithium in refractory depression.
Am J Psychiatry.
1988;
145
1292-1294
- 73
Price L H, Charney D S, Heninger G R.
Variability of response to lithium augmentation in refractory depression.
Am J Psychiatry.
1986;
143
1387-1392
- 74
Reynolds C F, Frank E, Perel J M, Mazumdar S, Dew M A, Begley A, Kupfer D J, et al.
High relapse rate after discontinuation of adjunctive medication for elderly patients
with recurrent major depression.
Am J Psychiatry.
1996;
153
1418-1422
- 75
Rihmer Z, Kiss G H, Kecskes I, Pestality P, György S.
SSRI supplementation of antimanic medication in dysphoric mania.
Pharmacopsychiat.
1998;
31
30-31
- 76
Rouillon F, Gorwood P.
The use of lithium to augment antidepressant medication.
J Clin Psychiatry.
1998;
59
32-39
- 77
Rush A J, Thase M E.
Strategies and tactics in the treatment of chronic depression.
J Clin Psychiatry.
1997;
58
14-22
- 78
Sacristan J A, Iglesias C, Arellano F, Lequercia J.
Absence seizures induced by lithium: possible interaction with fluoxetine.
Am J Psychiatry.
1991;
148
146-147
- 79
Salama A A, Shafey M.
A case of severe lithium toxicity induced by combined fluoxetine and lithium carbonate.
Am J Psychiatry.
1989;
146
278
- 80
Schmauss M, Erfurth A.
Kombinationstherapien bei Therapieresistenz auf Antidepressiva - eine Übersicht.
Fortschr Neurol Psychiatr.
1996;
64
390-402
- 81
Schou M.
Has the time come to abandon prophylactic lithium treatment? A review for clinicians.
Pharmacopsychiat.
1998;
31
210-215
- 82
Schöpf J.
Treatment of depression resistant to tricyclic antidepressants, related drugs or MAO-inhibits
by lithium addition: review of the literature.
Pharmacopsychiat.
1989;
22
174-182
- 83
Schöpf J, Baumann P, Lemarchand T, Rey J M.
Treatment of endogenous depressions resistant to tricyclic antidepressants or related
drugs by lithium addition: results of a placebo-controlled double-blind study.
Pharmacopsychiat.
1989;
22
183-187
- 84
Seth R, Jennings A L, Bindman J, Phillips J, Bergmann K.
Combination tratement with noradrenaline and serotonin reuptake inhibitors in resistant
depression.
Br J Psychiatry.
1992;
161
562-565
- 85
Slama M, Masmoudi K, Blanchard N, Andréjak M.
A possible case of lithium intoxication mimicking Creutzfeld-Jakob syndrome.
Pharmacopsychiat.
2000;
33
145-146
- 86
Sluzewska A, Sobieska M, Rybanowski J K.
Changes in acute-phase proteins during lithium potentiation of antidepressants in
refractory depression.
Biol Psychiatry.
1997;
35
123-127
- 87
Sobanski T, Bagli M, Laux G, Rao M L.
Serotonin syndrome after lithium add-on medication to paroxetine.
Pharmacopsychiat.
1997;
30
106-107
- 88
Sokolov S TH, Joffe R T.
Practical guidelines for combination drug therapy of treatment-resistant depression.
CNS Drugs.
1995;
4
341-350
- 89
Spoov J, Lahdelma L.
Should thyroid augmentation precede lithium augmentation - pilot study.
J Aff Disord.
1998;
49
235-239
- 90
Sprenger D.
Buspirone augmentation of a selective serotonin reuptake inhibitor: efficacy in two
depressed patients with comorbid anxiety and type I alcohol dependence.
J Clin Psychopharmacol.
1997;
17
425-426
- 91
Sternbach H.
The serotonin syndrome.
Am J Psychiatry.
1991;
148
705-713
- 92
Sussman N, Joffe R T.
Augmentation of antidepressant medication.
J Clin Psychiatry.
1998;
59
3-4
- 93
Terao T.
Rapid synergistic effects of lithium and antidepressants.
Psychopharmacology.
1995;
122
206-207
- 94
Thase M E, Blomgren S L, Birkett M A, Apter J T, Tepner R G.
Fluoxetine treatment of patients with major depressive disorder who failed initial
treatment with sertraline.
J Clin Psychiatry.
1997;
58
16-21
- 95
Thase M E, Howland R H, Friedman E S.
Treating antidepressant nonresponders with augmentation strategies: an overview.
J Clin Psychiatry.
1998;
59
5-12
- 96
Uchitomi Y, Yamawaki S.
Chronic lithium traetment enhances the postsynaptic 5-HT1A receptor mediated 5-HT behavioral syndrome induced by 8-OH-DPAT in rats via catecholaminergic
systems.
Psychopharmacology.
1993;
112
74-79
- 97
Uehlinger C, Nil R, Amey M, Baumann P, Dufour H.
Citalopram-lithium combination treatment of elderly depressed patients: a pilot study.
Int J Ger Psychiatry.
1995;
10
281-287
1 This contribution was part of an oral presentation at the ECNP meeting in Vienna,
1997 (Baumann, P. Advantages and disadvantages of lithium augmentation. Eur. Neuropsychopharmacol.
7 (suppl. 2): the S82, 1997. [Abstract])
Daniele ZullinoMD
Unité de Biochimie et
Psychopharmacologie Clinique
Département Universitaire de
Psychiatrie Adulte
1008 Prilly-Lausanne
Switzerland
