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The Brown University Psychopharmacology Update December 2016

Drug-Drug Interactions
Hyperkalemia associated with valproic acid
THE BROWN UNIVERSITY PSYCHOPHARMACOLOGY UPDATE Y. W. Francis Lam, Pharm.D., FCCP
(Print ISSN: 1068-5308; Online ISSN: 1556-7532) is published

V alproic acid is widely used for the evaluation. After three weeks of hospi-
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111 River St., Hoboken, NJ 07030-5774.
Postmaster: Send all address changes to THE BROWN UNIVER- management of symptoms in pa- talization, the patient was discharged on
SITY PSYCHOPHARMACOLOGY UPDATE, John Wiley & Sons Inc., tients with mania. Although the drug has olanzapine 5 mg/day for management of
c/o The Sheridan Press, PO Box 465, Hanover, PA 17331.
Copyright and Copying (in any format): Copyright © 2016 Wiley been reported to cause hyponatremia,1 manic symptoms. No new episodes of
Periodicals Inc. All rights reserved. No part of this publication its use as a mood stabilizer in general mania were reported.
may be reproduced, stored, or transmitted in any form or by any
means without the prior permission in writing from the copyright is well-tolerated, and there has been no
holder. Authorization to photocopy items for internal and person-
al use is granted by the copyright holder for libraries and other evidence in the literature of abnormali- Discussion
users registered with their local Reproduction Rights Organisa- ties in other electrolyte levels associated Valproic acid has been associated with
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Drive, Danvers, MA 01923, USA (www.copyright.com), provided with its use. hyponatremia and syndrome of inappro-
the appropriate fee is paid directly to the RRO. This consent
does not extend to other kinds of copying such as copying for The following case described an elderly priate secretion of antidiuretic hormone.1,3
general distribution, for advertising and promotional purposes, woman who developed hyperkalemia while This case demonstrated a possible asso-
for republication, for creating new collective works, or for resale.
Permissions for such reuse can be obtained using the RightsLink receiving valproic acid monotherapy.2 ciation between acute hyperkalemia and
“Request Permissions” link on Wiley Online Library. Special
requests should be addressed to: permissions@wiley.com.
valproic acid. The onset of hyperkalemia
Information for Subscribers: The Brown University Psychophar- Clinical report2 and ECG changes in the patient correlated
macology Update is published in 12 issues per year. Subscription
prices for 2017 are: Personal Print Only: $205 (US, Canada, and A 76-year-old female was admitted with initiation of valproic acid monother-
Mexico), £130 (UK), €164 (Europe), $255 (rest of world). Personal to the psychiatric ward for evaluation of apy. The potential causality was further
Print & Online: $226 (US, Canada, and Mexico), £141 (UK), €178
(Europe), $276 (rest of world). Personal Online Only: $185 (US, mania. Her symptoms included elevated supported by resolution of laboratory and
Canada, and Mexico), £95 (UK), €119 (Europe), $185 (rest of
world). Institutional Print Only: $2038 (USA), $2092 (Canada
mood, decreased sleep, increased ten- ECG abnormalities upon discontinuation
and Mexico), £1082 (UK), €1366 (Europe), $2112 (rest of world). dency to talk, and expression of grandiose of valproic acid. In addition, the patient
Institutional Print & Online: $2446 (USA), $2511 (Canada and
Mexico), £1299 (UK), €1640 (Europe), $2535 (rest of world). Insti- thoughts. She had no significant medi- had not received any other medications
tutional Online Only: $2038 (USA, Canada, and Mexico), £1044
(UK), €1318 (Europe), $2038 (rest of world). Prices are exclusive
cal or other psychiatric history. Results before or during hospitalization. There
of tax. Asia-Pacific GST, Canadian GST/HST and European VAT of physical examinations and admission also had been no report of changes in di-
will be applied at the appropriate rates. For more information on
current tax rates, please go to www.wileyonlinelibrary.com/tax- laboratory tests, including renal function etary habits.
vat. The price includes online access to the current and all online
back files to January 1, 2013, where available. For other pricing
and electrolytes, were normal. Hyperkalemia occurring with valproic
options, including access information and terms and conditions, The patient was started on valproic acid has never been reported in the lit-
please visit www.wileyonlinelibrary.com/access.
Delivery Terms and Legal Title: Where the subscription price
acid 500 mg/day as the only medication erature. Although the cause of the patient’s
includes print issues and delivery is to the recipient’s address, delivery for managing her psychiatric symptoms. electrolyte and ECG changes during hos-
terms are Delivered at Place (DAP); the recipient is responsible for
paying any import duty or taxes. Title to all issues transfers FOB our General weakness was reported after five pitalization is unclear, there is some recent
shipping point, freight prepaid. We will endeavour to fulfil claims for
missing or damaged copies within six months of publication, within
days of therapy. Laboratory evaluations suggestion of an inhibitory effect of val-
our reasonable discretion and subject to availability. revealed hyperkalemia, with serum potas- proic acid on histone deacetylase, which
Disclaimer: The Publisher and Editors cannot be held responsible
for errors or any consequences arising from the use of information
sium of 6 mEq/L, and hyponatremia, with could result in suppression of transcrip-
contained in this journal; the views and opinions expressed do not serum sodium of 133 mEq/L. A 12-lead tional activity of the mineralocorticoid
necessarily reflect those of the Publisher and Editors, neither does
the publication of advertisements constitute any endorsement by the electrocardiogram (ECG) showed peaked receptor.4 Since potassium secretion is
Publisher and Editors of the products advertised.
T-waves. A nephrology work-up for deter- under the influence of aldosterone act-
Customer Service: For ordering information, claims, and any
enquiry concerning your journal subscription, please go to www. mining potential causes of hyperkalemia ing at the mineralocorticoid receptor, this
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included glomerular filtration rate, urine altered mineralocorticoid function could
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wiley.com. Visit our Online Customer Help available in seven
any of these tests. Regardless of the exact mechanism of
languages at www.wileycustomerhelp.com/ask. Valproic acid was immediately discon- this potential adverse effect of valproic
Wiley’s Corporate Citizenship initiative seeks to address the
environmental, social, economic, and ethical challenges faced in our
tinued. A week later, the patient’s serum acid, hyperkalemia can be fatal. Clinicians
business and which are important to our diverse stakeholder groups. potassium and sodium levels returned need to be aware of the potential for elec-
Since launching the initiative, we have focused on sharing our content
with those in need, enhancing community philanthropy, reducing to normal (3.8 mEq/L and 136 mEq/L, trolyte imbalances, especially with regard
our carbon impact, creating global guidelines and best practices for
paper use, establishing a vendor code of ethics, and engaging our
respectively). In addition, no peaked T to sodium and potassium levels, in patients
colleagues and other stakeholders in our efforts. Follow our progress waves were reported in follow-up ECG treated with valproic acid. ▪
at www.wiley.com/go/citizenship.
View this journal online at www.wileyonlinelibrary.com/journal/PU.
Editor: Lawrence H. Price, M.D. Managing Editor: Gary Enos
Editorial Correspondence: Contact Gary Enos via email:
garyenos5@gmail.com
BottomLine
For submission instructions, subscription, and all other information,
visit: www.wileyonlinelibrary.com/journal/pu. Hyperkalemia associated with valproic acid had not previously been reported in the
Printer Details: Printed in the USA by The Allied Group
research literature. Providers should remain aware of the potential for electrolyte
imbalances, which can be dangerous, in patients taking valproic acid.
 December 2016 The Brown University Psychopharmacology Update 3
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References
1. Branten AJ, Wetzels JF, Weber AM, et al. Hy-
ponatremia due to sodium valproate. J Ann Neurol
1998; 43:265–267.
What’s New in Research
Studies of lurasidone
for bipolar depression
show differing results
précis
• Researchers examined results from
two placebo-controlled studies of
lurasidone for the treatment of bipolar
depression to evaluate whether the
drug is effective and safe in patients 55
and older.
• Patients receiving lurasidone
monotherapy showed significant
improvement over patients receiving
placebo, but an adjunctive therapy
study did not find significant
differences from placebo when
lurasidone was used with lithium
or valproate. Lurasidone was well-
tolerated in both studies.
• The researchers believe that the
antidepressant effects of lithium and
valproate might have accounted for
the absence of a significant difference
between lurasidone and placebo in the
adjunctive therapy study.
A monotherapy study and an adjunc-
tive therapy study using lurasi-
done in the treatment of bipolar depres-
sion yielded differing results for patients
ages 55 and older, with the monotherapy
study showing effectiveness over pla-
cebo in reducing depressive symptoms
and the adjunctive therapy study show-
ing no significant difference from pla-
cebo when lurasidone was combined
with lithium or valproate.
The chronic nature of bipolar disor-
der results in the illness persisting past
age 50 for many patients, and a small
subset of patients also experience a late
onset of the illness in their 50s. There
are three approved medication treat-
ments for bipolar depression, but the
atypical antipsychotics used in its treat-
ment have not been tested in older adults
in randomized, placebo-controlled trials.
Because lurasidone has a favorable
safety profile in younger populations,
2. Kuo YC, Lin YC, Chen PH. Emerging hyperkale-
mia following valproic acid use in an elderly patient
with late-onset mania. J Clin Psychopharmacol
2016; 36:394–395.
3. Miyaoka T, Seno H, Itoga M, et al. Contribution
of sodium valproate to the syndrome of inappropri-
ate secretion of antidiuretic hormone. Int J Clin
it is believed that it could benefit older
patients with bipolar depressive episodes
as well. A post hoc analysis of two stud-
ies evaluated the efficacy and safety of
lurasidone in adults over age 55, exam-
ining results from studies that featured a
broader range of participant ages.
Study details
The two 6-week studies enrolled out-
patients ages 18 to 75 who met DSM-IV-
TR criteria for bipolar disorder and were
experiencing a major depressive episode
and who had a history of at least one
manic or mixed manic episode.
In the monotherapy study, partici-
pants were randomized to one of two
flexible-dose ranges of lurasidone (20–
60 mg or 80–120 mg) or placebo, with
starting doses of 20 mg/day in both
lurasidone groups. In the adjunctive
therapy study, participants were ran-
domized to lurasidone 20–120 mg/day
or placebo, with a starting dose of 20
mg/day and increases to 60 mg/day after
the first week (with adjustments upward
or downward thereafter, depending on
investigator judgment).
The primary outcome in both stud-
ies was mean change from baseline to
treatment endpoint in total score on the
Montgomery-Asberg Depression Rating
Scale (MADRS). The main secondary
outcome was mean change in depression
severity score on the Clinical Global
Impression-Bipolar Severity of Illness
depression scale (CGI-BP-S). The re-
searchers evaluated adverse events, and
a number of laboratory tests and physi-
cal examinations were conducted.
Results
A total of 142 of the 853 patients ran-
domized to treatment in the two studies
were older than 55 and were therefore
included in the post hoc analyses. Treat-
ment discontinuation rates were similar
for the lurasidone and placebo groups
in the monotherapy study, while discon-
tinuation rates were somewhat higher in
Psychopharmacol 2001; 16:59–61.
4. Kang SH, Seok YM, Song MJ, et al. Histone
deacetylase inhibition attenuates cardiac hypertro-
phy and fibrosis through acetylation of mineralocor-
ticoid receptor in spontaneously hypertensive rats.
Mol Pharmacol 2015; 87:782–791.
the lurasidone group in the adjunctive
therapy study.
In the monotherapy study, MADRS
and CGI-BP-S scores indicated signifi-
cantly greater symptom improvement for
patients in both lurasidone groups com-
pared with placebo. Response rates were
46.4% in the lurasidone groups when
looking at pooled data, compared with
14.8% in the placebo group. Response
was defined as at least a 50% reduction
in MADRS total score from baseline to
study endpoint.
In the adjunctive therapy study, there
was no significant difference between
lurasidone and placebo on the MADRS
or the CGI-BP-S. Differences in re-
sponse and remission rates slightly fa-
vored lurasidone, but the differences
were not significant.
The most frequently reported ad-
verse events in the lurasidone groups
in the monotherapy study were nausea
and somnolence. Serious adverse events
were rare in all patient groups in the
study. Akathisia and insomnia were the
most frequently reported adverse events
among lurasidone patients in the adjunc-
tive therapy study, and the incidence of
serious adverse events was low in both
the lurasidone and placebo groups. Re-
sults for vital signs and laboratory mea-
sures did not show significant between-
group differences in either study.
Implications
The researchers pointed out that while
improvement on lurasidone in the ad-
junctive therapy study was of a similar
magnitude to the improvement seen in
the monotherapy study, effect sizes in
the adjunctive therapy study were in the
small to moderate range. They explained
that the antidepressant effects of lithium
and valproate might have accounted for
this. “The design of the current adjunctive
therapy trial required patients to receive
28 days of treatment with therapeutic lev-
els of lithium or valproate,” they wrote.
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