Lithium plus antipsychotics or anticonvulsants for bipolar disorder: Comparing clinical response and metabolic changes

Ole Köhler-Forsberg; Louisa G. Sylvia; Michael Thase; Joseph R. Calabrese; Mauricio Tohen; Charles L. Bowden; Melvin McInnis; Dan V. Iosifescu; James H. Kocsis; Edward S. Friedman; Terence A. Ketter; Susan L. McElroy; Richard C. Shelton; Vicki Fung; Michael J. Ostacher; Andrew A. Nierenberg

doi:10.1177/00048674221077619

Lithium plus antipsychotics or anticonvulsants for bipolar disorder: Comparing clinical response and metabolic changes

Ole Köhler-Forsberg^*, Louisa G. Sylvia, Michael Thase, Joseph R. Calabrese, Mauricio Tohen, Charles L. Bowden, Melvin McInnis, Dan V. Iosifescu, James H. Kocsis, Edward S. Friedman, Terence A. Ketter, Susan L. McElroy, Richard C. Shelton, Vicki Fung, Michael J. Ostacher, Andrew A. Nierenberg

^*Corresponding author for this work

Department of Clinical Medicine - Psychosis Research Unit

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

4 Citations (Scopus)

Abstract

Objective: Patients with bipolar disorder treated with lithium often require additional antipsychotics or anticonvulsants. However, the comparative effectiveness and safety of these agents as add-on to lithium has not been studied. Methods: This secondary analysis combined two similar 24-week trials on outpatients with bipolar disorder randomized to lithium (target serum level 0.4–0.6 mEq/L). Guideline-based adjunctive antipsychotics (Li+AP) and anticonvulsants (Li+AC) could be used if clinically indicated and was assessed at every study visit. Response was measured on the Clinical Global Impression scale and we performed adjusted mixed effects linear regression analyses. Analysis of variance tests compared metabolic measures including a binary diagnosis of metabolic syndrome before and after 24 weeks of treatment. Results: Among 379 outpatients (57% female, mean age 38 years, mean Clinical Global Impression 4.4), users of Li+AP (N = 50, primarily quetiapine and aripiprazole) improved to a similar degree (mean Clinical Global Impression improvement = 1.6, standard deviation = 1.5) as those using lithium-only (i.e. without adjunctive antipsychotics or anticonvulsants, N = 149, mean Clinical Global Impression improvement = 1.7, standard deviation = 1.4) (p = 0.59). Users of Li+AC (N = 107, primarily lamotrigine and valproate, mean Clinical Global Impression improvement = 1.2, standard deviation = 1.3) and users of Li+AP+AC (N = 73, mean Clinical Global Impression improvement = 1.1, standard deviation = 1.3) showed worse response compared to lithium-only users (all p < 0.01). When comparing Li+AP to Li+AC, users of Li+AP improved slightly better on general (p = 0.05) and manic symptoms (p = 0.01), but showed a worse development of glucose, triglycerides, and metabolic syndrome. Conclusion: Despite treatment-by-indication confounding, these findings are relevant for real-world treatment settings and emphasize the need for randomized trials on this clinically important topic.

Original language	English
Journal	Australian and New Zealand Journal of Psychiatry
Volume	57
Issue	1
Pages (from-to)	93-103
Number of pages	11
ISSN	0004-8674
DOIs	https://doi.org/10.1177/00048674221077619
Publication status	Published - Jan 2023

Keywords

anticonvulsant
antipsychotic
bipolar depression
Bipolar disorder
lithium

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Köhler-Forsberg, O., Sylvia, L. G., Thase, M., Calabrese, J. R., Tohen, M., Bowden, C. L., McInnis, M., Iosifescu, D. V., Kocsis, J. H., Friedman, E. S., Ketter, T. A., McElroy, S. L., Shelton, R. C., Fung, V., Ostacher, M. J., & Nierenberg, A. A. (2023). Lithium plus antipsychotics or anticonvulsants for bipolar disorder: Comparing clinical response and metabolic changes. Australian and New Zealand Journal of Psychiatry, 57(1), 93-103. https://doi.org/10.1177/00048674221077619

@article{37922e84a7d4438db1a0e06e1e8c6870,

title = "Lithium plus antipsychotics or anticonvulsants for bipolar disorder: Comparing clinical response and metabolic changes",

abstract = "Objective: Patients with bipolar disorder treated with lithium often require additional antipsychotics or anticonvulsants. However, the comparative effectiveness and safety of these agents as add-on to lithium has not been studied. Methods: This secondary analysis combined two similar 24-week trials on outpatients with bipolar disorder randomized to lithium (target serum level 0.4–0.6 mEq/L). Guideline-based adjunctive antipsychotics (Li+AP) and anticonvulsants (Li+AC) could be used if clinically indicated and was assessed at every study visit. Response was measured on the Clinical Global Impression scale and we performed adjusted mixed effects linear regression analyses. Analysis of variance tests compared metabolic measures including a binary diagnosis of metabolic syndrome before and after 24 weeks of treatment. Results: Among 379 outpatients (57% female, mean age 38 years, mean Clinical Global Impression 4.4), users of Li+AP (N = 50, primarily quetiapine and aripiprazole) improved to a similar degree (mean Clinical Global Impression improvement = 1.6, standard deviation = 1.5) as those using lithium-only (i.e. without adjunctive antipsychotics or anticonvulsants, N = 149, mean Clinical Global Impression improvement = 1.7, standard deviation = 1.4) (p = 0.59). Users of Li+AC (N = 107, primarily lamotrigine and valproate, mean Clinical Global Impression improvement = 1.2, standard deviation = 1.3) and users of Li+AP+AC (N = 73, mean Clinical Global Impression improvement = 1.1, standard deviation = 1.3) showed worse response compared to lithium-only users (all p < 0.01). When comparing Li+AP to Li+AC, users of Li+AP improved slightly better on general (p = 0.05) and manic symptoms (p = 0.01), but showed a worse development of glucose, triglycerides, and metabolic syndrome. Conclusion: Despite treatment-by-indication confounding, these findings are relevant for real-world treatment settings and emphasize the need for randomized trials on this clinically important topic.",

keywords = "anticonvulsant, antipsychotic, bipolar depression, Bipolar disorder, lithium",

author = "Ole K{\"o}hler-Forsberg and Sylvia, {Louisa G.} and Michael Thase and Calabrese, {Joseph R.} and Mauricio Tohen and Bowden, {Charles L.} and Melvin McInnis and Iosifescu, {Dan V.} and Kocsis, {James H.} and Friedman, {Edward S.} and Ketter, {Terence A.} and McElroy, {Susan L.} and Shelton, {Richard C.} and Vicki Fung and Ostacher, {Michael J.} and Nierenberg, {Andrew A.}",

note = "Publisher Copyright: {\textcopyright} The Royal Australian and New Zealand College of Psychiatrists 2022.",

year = "2023",

month = jan,

doi = "10.1177/00048674221077619",

language = "English",

volume = "57",

pages = "93--103",

journal = "Australian and New Zealand Journal of Psychiatry",

issn = "0004-8674",

publisher = "SAGE Publications Ltd",

number = "1",

}

Köhler-Forsberg, O, Sylvia, LG, Thase, M, Calabrese, JR, Tohen, M, Bowden, CL, McInnis, M, Iosifescu, DV, Kocsis, JH, Friedman, ES, Ketter, TA, McElroy, SL, Shelton, RC, Fung, V, Ostacher, MJ & Nierenberg, AA 2023, 'Lithium plus antipsychotics or anticonvulsants for bipolar disorder: Comparing clinical response and metabolic changes', Australian and New Zealand Journal of Psychiatry, vol. 57, no. 1, pp. 93-103. https://doi.org/10.1177/00048674221077619

Lithium plus antipsychotics or anticonvulsants for bipolar disorder: Comparing clinical response and metabolic changes. / Köhler-Forsberg, Ole; Sylvia, Louisa G.; Thase, Michael et al.
In: Australian and New Zealand Journal of Psychiatry, Vol. 57, No. 1, 01.2023, p. 93-103.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Lithium plus antipsychotics or anticonvulsants for bipolar disorder

T2 - Comparing clinical response and metabolic changes

AU - Köhler-Forsberg, Ole

AU - Sylvia, Louisa G.

AU - Thase, Michael

AU - Calabrese, Joseph R.

AU - Tohen, Mauricio

AU - Bowden, Charles L.

AU - McInnis, Melvin

AU - Iosifescu, Dan V.

AU - Kocsis, James H.

AU - Friedman, Edward S.

AU - Ketter, Terence A.

AU - McElroy, Susan L.

AU - Shelton, Richard C.

AU - Fung, Vicki

AU - Ostacher, Michael J.

AU - Nierenberg, Andrew A.

PY - 2023/1

Y1 - 2023/1

N2 - Objective: Patients with bipolar disorder treated with lithium often require additional antipsychotics or anticonvulsants. However, the comparative effectiveness and safety of these agents as add-on to lithium has not been studied. Methods: This secondary analysis combined two similar 24-week trials on outpatients with bipolar disorder randomized to lithium (target serum level 0.4–0.6 mEq/L). Guideline-based adjunctive antipsychotics (Li+AP) and anticonvulsants (Li+AC) could be used if clinically indicated and was assessed at every study visit. Response was measured on the Clinical Global Impression scale and we performed adjusted mixed effects linear regression analyses. Analysis of variance tests compared metabolic measures including a binary diagnosis of metabolic syndrome before and after 24 weeks of treatment. Results: Among 379 outpatients (57% female, mean age 38 years, mean Clinical Global Impression 4.4), users of Li+AP (N = 50, primarily quetiapine and aripiprazole) improved to a similar degree (mean Clinical Global Impression improvement = 1.6, standard deviation = 1.5) as those using lithium-only (i.e. without adjunctive antipsychotics or anticonvulsants, N = 149, mean Clinical Global Impression improvement = 1.7, standard deviation = 1.4) (p = 0.59). Users of Li+AC (N = 107, primarily lamotrigine and valproate, mean Clinical Global Impression improvement = 1.2, standard deviation = 1.3) and users of Li+AP+AC (N = 73, mean Clinical Global Impression improvement = 1.1, standard deviation = 1.3) showed worse response compared to lithium-only users (all p < 0.01). When comparing Li+AP to Li+AC, users of Li+AP improved slightly better on general (p = 0.05) and manic symptoms (p = 0.01), but showed a worse development of glucose, triglycerides, and metabolic syndrome. Conclusion: Despite treatment-by-indication confounding, these findings are relevant for real-world treatment settings and emphasize the need for randomized trials on this clinically important topic.

AB - Objective: Patients with bipolar disorder treated with lithium often require additional antipsychotics or anticonvulsants. However, the comparative effectiveness and safety of these agents as add-on to lithium has not been studied. Methods: This secondary analysis combined two similar 24-week trials on outpatients with bipolar disorder randomized to lithium (target serum level 0.4–0.6 mEq/L). Guideline-based adjunctive antipsychotics (Li+AP) and anticonvulsants (Li+AC) could be used if clinically indicated and was assessed at every study visit. Response was measured on the Clinical Global Impression scale and we performed adjusted mixed effects linear regression analyses. Analysis of variance tests compared metabolic measures including a binary diagnosis of metabolic syndrome before and after 24 weeks of treatment. Results: Among 379 outpatients (57% female, mean age 38 years, mean Clinical Global Impression 4.4), users of Li+AP (N = 50, primarily quetiapine and aripiprazole) improved to a similar degree (mean Clinical Global Impression improvement = 1.6, standard deviation = 1.5) as those using lithium-only (i.e. without adjunctive antipsychotics or anticonvulsants, N = 149, mean Clinical Global Impression improvement = 1.7, standard deviation = 1.4) (p = 0.59). Users of Li+AC (N = 107, primarily lamotrigine and valproate, mean Clinical Global Impression improvement = 1.2, standard deviation = 1.3) and users of Li+AP+AC (N = 73, mean Clinical Global Impression improvement = 1.1, standard deviation = 1.3) showed worse response compared to lithium-only users (all p < 0.01). When comparing Li+AP to Li+AC, users of Li+AP improved slightly better on general (p = 0.05) and manic symptoms (p = 0.01), but showed a worse development of glucose, triglycerides, and metabolic syndrome. Conclusion: Despite treatment-by-indication confounding, these findings are relevant for real-world treatment settings and emphasize the need for randomized trials on this clinically important topic.

KW - anticonvulsant

KW - antipsychotic

KW - bipolar depression

KW - Bipolar disorder

KW - lithium

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U2 - 10.1177/00048674221077619

DO - 10.1177/00048674221077619

M3 - Journal article

C2 - 35164524

AN - SCOPUS:85125043566

SN - 0004-8674

VL - 57

SP - 93

EP - 103

JO - Australian and New Zealand Journal of Psychiatry

JF - Australian and New Zealand Journal of Psychiatry

IS - 1

ER -

Lithium plus antipsychotics or anticonvulsants for bipolar disorder: Comparing clinical response and metabolic changes

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