Using_Lithium_in_Older_Age_Bip1cool.pdf

Vol.:(0123456789)

Drugs & Aging (2019) 36:147–154
https://doi.org/10.1007/s40266-018-0628-1

R E V I E W A R T I C L E

Using Lithium in Older Age Bipolar Dis : Special Considerations

Jocelyn Fotso Soh1  · Sivan Klil‑Drori1 · Soham Rej1,2

Published online: 7 January 2019
© Springer Nature Switzerland AG 2019

Abstract
Lithium is the gold-standard treatment for bipolar dis , and is effective in the management of manic, depressive, and
maintenance phases of bipolar dis treatment. Despite this, the implications of lithium use in the older population remain
less understood. This critical narrative review aims to better understand the impact of lithium in older age bipolar dis
(OABD), including tolerability and efficacy, based on up-to-date evidence. Relevant studies of efficacy, effectiveness, and
tolerability published any time prior to May 2018 were identified using the PubMed keyword search “lithium older adult
bipolar dis ” and references from recent international bipolar dis guidelines. One randomized controlled trial was
identified, the GERI-BD (Acute Pharmacotherapy in Late-Life Mania) study. This study found lithium to be effective in
late-life mania and hypomania. The remaining literature examining lithium in OABD was reviewed, comprising of a num-
ber of small open-label and retrospective studies, with special considerations highlighted. In summary, there is a small yet
increasing geriatric evidence base that lithium is effective in OABD. Although there can be adverse effects with lithium, it
is generally well tolerated, and there are methods to minimize these risks. Further research would strengthen the evidence
base for lithium therapy in OABD. In the meantime, lithium remains the gold-standard treatment for OABD.

Key Points

Lithium is the gold-standard treatment for bipolar disor-
der; however, the implications of lithium use in the older
population remain less understood.

In this review, we identified one randomized controlled
trial, the GERI-BD (Acute Pharmacotherapy in Late-
Life Mania) study, as well as other studies, which found
lithium to be effective in late-life mania and hypomania.

Although there can be adverse effects with lithium, it
is generally well tolerated in older adults, and there are
methods to minimize these risks.

1 Introduction

1.1 Epidemiology of Older Age Bipolar Dis
(OABD)

Older age bipolar dis (OABD), i.e. bipolar dis
in individuals aged 60 years and above, represents an esti-
mated 25% of bipolar dis patients worldwide [1]. This
estimate includes both individuals with early-onset bipolar
dis (onset at age < 50 years) who have aged and those with late-onset bipolar dis . With the rapidly aging population, worldwide estimates of OABD are projected to increase significantly; by 2030, over 50% of bipolar dis- patients will likely be aged 60 years and above [2]. Furthermore, compared with younger adults, older adults with bipolar dis utilize proportionately more healthcare services. Compared with patients with other mental disor- ders, OABD patients have a three to fourfold increased risk of psychiatric hospitalization [3, 4]. Similarly, compared with the general population, those with OABD have a 15- to 20-year reduced life expectancy, with a twofold increased risk of physical health conditions such as metabolic syn- drome, cardiovascular disease, stroke, endocrine dis s, renal disease, and cognitive decline [3, 5–8]. These physical comorbidities in OABD can be associated with reduced drug * Jocelyn Fotso Soh [email protected] 1 Geri-PARTy Research Group, Department of Psychiatry, Jewish General Hospital, Institute of Community and Family Psychiatry, McGill University, 4333 Cote Ste-Catherine, Montreal, QC H3T 1E4, Canada 2 Department of Psychiatry, McGill University, Montreal, QC, Canada http://orcid.org/0000-0001-9706-995X http://crossmark.crossref.org/dialog/?doi=10.1007/s40266-018-0628-1&domain=pdf 148 J. Fotso Soh et al. effectiveness and tolerability in older adults compared with younger adults [9, 10]. Despite all of this, bipolar dis in late-life remains relatively less well-studied, with only one randomized controlled trial (RCT) to date specifically investigating pharmacological treatment in older adults with bipolar dis [11]. 1.2 Pharmacologic Treatment Options for OABD There are a number of limitations of pharmacotherapy stud- ies in OABD (especially older studies), including small sam- ple sizes, lack of randomization in many studies, and some difficulty extrapolating from mixed-aged geriatric/adult bipolar dis clinical trials. Despite these limitations, a number of pharmacological treatment options for OABD have been identified by international guidelines [12, 13]. Lurasidone, lamotrigine, quetiapine, asenapine, and lithium have been effective for the treatment of depressive episodes in OABD [13–18]. Meanwhile, lithium, valproate, asenap- ine, quetiapine, and risperidone [11, 17, 19, 20] have had evidence in mania/hypomania. Lithium also has evidence to reduce the risk of suicide in patients with bipolar dis- [21]. Carbamazepine and adjunctive gabapentin are other options for mania/hypomania based on lower-quality studies [22]. Additionally, clozapine [23] and electrocon- vulsive therapy (ECT) [1] are also other agents for geriatric treatment-refractory mania and depression. An International Society of Bipolar Dis (ISBD)- led task force report was in agreement with this literature, and felt that OABD patients, like younger bipolar dis patients, had high response rates to lithium [23, 24]. Stud- ies by these investigators had identified that similar serum levels of lithium are often required for remission, however lower levels are often tolerated [22, 24]. In a recent Delphi consensus survey of OABD experts, while lamotrigine was thought to be more effective in the maintenance for depres- sion in OABD, lithium was thought to be more useful in preventing relapse of manic symptoms [24]. Lithium has been considered by the OABD research community as a first-line medication in the maintenance of OABD because of its effectiveness in both phases of the illness, considerable evidence base from the adult litera- ture, and being the agent with the most number of geriatric studies [22]. Valproate has been found to have level 1 evi- dence in treating acute mania in adults. The mixed adult/ geriatric BALANCE trial by Geddes et  al. found both lithium and valproate to be helpful in maintaining remis- sion in OABD [25]. Lamotrigine has also been found to be effective maintenance treatment in OABD [26]. Table 1 highlights the levels of evidence for OABD pharmacother- apies, based on the literature and the recent 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) bipolar dis guidelines [12]. For the remainder of this critical narrative review paper, we describe the role of lithium in the context of the OABD literature. The most relevant studies of lithium’s efficacy, effectiveness, and tolerability in OABD were identified using a PubMed keyword search (“lithium older adult bipolar dis ”), references from recent international bipolar dis and OABD guidelines [12, 13], and the senior author’s (SR) knowledge of the field. Ultimately, only one geriatric RCT of lithium in OABD was identified—the GERI-BD (Acute Pharmacotherapy in Late-Life Mania) study [11]. This landmark study is described in detail. Major studies in the remaining litera- ture examining lithium in OABD are also described, with special considerations highlighted. Table 1 Evidence for pharmacotherapies in older age bipolar dis based on geriatric data (age > 60 years)

DB database, OABD older age bipolar dis , RCT randomized controlled trial
a Post hoc analysis of two placebo-controlled RCTs found lurasidone to be superior to placebo [1, 2]
b The only geriatric RCT in OABD compared lithium and valproate (no placebo arm) for acute mania and hypomania (Young et al. [11])
c Post hoc analyses of mixed-aged adult/geriatric RCTs [23]
d Post hoc analysis of placebo-controlled RCTs in the treatment of bipolar mania and depression [13–17, 22, 27]
e Retrospective data [20]

Level of evidence Pharmacotherapies in older age bipolar dis

Level 1: > 60 subjects—two DB RCTs/meta-analyses Lurasidonea (depression)
Level 2: > 60 subjects—one DB RCT Lithiumb (mania), lithium (maintenance)c, valproateb (mania), olanzapinec, lamo-

trigine (maintenance)c, quetiapinec (depression and mania)
Level 3: prospective open-label trials with > 10 participants Lamotrigined (depression, n = 57), valproated (maintenance), asenapined (manic and

depressive symptoms), aripiprazoled (manic and depressive symptoms)
Level 4: case series/consensus Carbamazepinee, clozapined, risperidoned, gabapentind (for these four agents ‘clini-

cal improvement’ broadly defined was the endpoint)

149Lithium Use in Older Age Bipolar Dis

2 The Efficacy and Tolerability of Lithium
in OABD

2.1 Efficacy and Effectiveness of Lithium in OABD

The use of lithium as a mood stabilizer dates back to the
nineteenth century and has since been studied extensively
in the treatment and prevention of mania [27]. Lithium
remains the gold standard medication for bipolar dis
in international guidelines [12]. Clinical trial data [25]
and recent large observational studies in mixed-aged adult
populations [28, 29] seem to suggest that lithium use is
superior to other maintenance treatments for bipolar dis-
, with lower relapse rates. Furthermore, 30–40% of
patients may be preferential lithium responders [30].

This is important since up to 40% of OABD patients
may attain symptomatic remission with lithium mono-
therapy [9], whereas the typical OABD patient can be
taking an average of three psychotropic medications for
bipolar dis (e.g. mood stabilizer, antipsychotics, etc.)
[31]. As with other OABD pharmacotherapies, lithium has
similar effectiveness as in younger adults, except in OABD
lower doses may be better tolerated, even though some
OABD patients require the younger adult dose to achieve
remission [9].

Of the OABD pharmacotherapies currently available,
lithium has the most extensive evidence base for the treat-
ment of bipolar dis in older adults [13]. Two RCTs
of mixed-aged bipolar dis patients concluded that
lithium is superior to valproate [25] and placebo [26]
for bipolar dis maintenance, although these did not
include only geriatric patients. Eight geriatric studies have
examined lithium use in OABD patients with mania, with
all studies concluding that lithium is effective in treating
manic symptoms [32–39]. Other studies have concluded
that lithium is effective in reducing depressive symptoms
[32, 33, 36, 37, 39]. Pharmacotherapy research in older
adults with bipolar dis is limited as older adults are
often excluded from RCTs, with studies usually excluding
patients above 65 years of age, in part due to the increased
risk of medication adverse effects in older adults.

2.2 Tolerability of Lithium in OABD

Although tolerated well by most patients, lithium has been
prescribed with less frequency in the last three decades, in
part due adverse effects [31, 40, 41]. Although controver-
sial [42], longer-term lithium use has been associated with
a twofold increased risk of chronic kidney disease (CKD)
[43], including in OABD patients [40], although part of
this is likely related to poor lithium monitoring practices

[44]. CKD risk may be increased by two- to threefold by
the presence of nephrogenic diabetes insipidus (NDI) and
acute kidney injury (AKI) [45].

Acute elevations in lithium levels have also been associ-
ated with acute neurological toxicity, which can include
coarse tremor, altered mental status/delirium, muscle
twitching, and altered gait [46]. The risk of lithium level
elevations is increased by dehydration, lithium overdose,
AKI (which can also occur as a result of lithium), and
drug–drug interactions [45].

In patients aged 65 years and older, lithium levels and
renal function should be monitored every 3 months [47].
To prevent CKD, lithium levels of 0.4–0.8 mmol/L should
be used and risk factors such as diabetes mellitus, hyper-
tension and NDI should be minimized/managed as much
as feasible [12]. When starting a medication known to
increase serum lithium levels, such as diuretics, angio-
tensin-converting enzyme (ACE) inhibitors, angiotensin
receptor blockers (ARBs), and non-steroidal anti-inflam-
matory drugs (NSAIDs), lithium levels and renal function
should be tested 5–7  days after these medications have
been initiated [45, 48]. The National Institute for Health
and Care Excellence (NICE) UK guidelines suggest neph-
rologist consultation in the following scenarios: a base-
line estimated glomerular filtration rate (eGFR) < 60 mL/ min/1.73 m2, or a clinically important sustained decline in renal function (e.g. eGFR decrease of > 5 mL/min/1.73 m2
over 1 year or > 10 mL/min/1.73 m2 over 5 years) [49].

Older adults are vulnerable to dehydration and, par-
ticularly if they are using lithium, should be hydrated to
prevent renal or other sequelae. However, the literature
suggests that there is no clinically significant association
between environmental temperature and serum lithium
in temperate climates (e.g. daytime maximum tempera-
ture ≥ 25–30 °C) [50, 51]. That said, it is unknown whether
more extreme temperatures (e.g. > 35–40 °C) may be asso-
ciated with lithium level elevations.

The use of lithium and NSAIDS has been linked to
NDI; NDI has also been associated with a two- to threefold
increased risk of CKD [52]. Close monitoring of kidney
function through eGFR levels and 10 h water restriction
urinary osmolality values can help early diagnosis and
treatment of NDI and help prevent the occurrence and
severity of complications in kidney function [12, 53].

Lithium is associated with hyperparathyroidism and
hypercalcemia, but clinically important hypercalcemia
is not common in chronic lithium users, even in late
life (< 5%) [8, 47]. Older lithium users have a twofold increased risk of hypothyroidism compared with the general population, with a prevalence of approximately 32–40%, which is similar to rates in adult lithium users [43, 54, 55]. Lithium use has also been associated with weight gain, although this has not necessarily lead to more 150 J. Fotso Soh et al. metabolic syndrome compared with other OABD patients [56]. However, an emerging epidemiological literature sug- gests that lithium may also have positive effects on physi- cal health. Compared with other bipolar dis patients, lithium users may have lower rates of dementia [57, 58], diabetes [59], stroke [60], and cancer [61]. Basic science research is increasingly identifying the potential anti-inflam- matory, antioxidant, and endothelial effects of lithium [62, 63], as well as its effects on intracellular signalling path- ways—calcium signalling [64], glycogen synthase kinase-3 beta (GSK3Beta) inhibition [65], mammalian target of rapa- mycin (mTOR) [66], and others, which may be contributing to these effects. Further large-scale epidemiological studies and RCTs are needed to confirm whether lithium can prevent physical health conditions in OABD patients. Although lithium monotherapy can be effective in up to 30–40% of OABD patients [24], in North America it is used in a small minority of patients [31]. When lithium is used in conjunction with antipsychotics, one can pay attention to the potential for pharmacodynamic interactions, e.g. cumula- tive effects on weight gain, and sedation [10, 12]. There has been emerging data that antipsychotics may be associated with AKI [67, 68], therefore patients receiving both lithium and antipsychotics should be followed closely for their renal function, especially during medication initiation and dose adjustment. Alternatively, when used in conjunction with lithium therapy, lamotrigine does not seem to cause signifi- cant change in the pharmacokinetics of lithium [69, 70]. 2.3 Recent Data Regarding the Therapeutic Effects of Lithium in OABD: The GERI‑BD Trial In 2017, a landmark RCT of lithium for mania and hypo- mania in OABD was published [71]. Young and colleagues conducted the first double-blind RCT in OABD to exam- ine the efficacy and tolerability of two first-line treatment therapies—lithium and divalproex. Overall, 224 inpatients and outpatients aged 60 years and older with manic symp- toms were randomized to treatment of lithium carbonate or valproic acid over a 9-week period. Target serum concen- trations for lithium carbonate and valproic acid were 0.08— 0.99 mEq/L and 80–99 µm/L, respectively. Patients assessed to have an inadequate response after 3 weeks received risp- eridone as adjunct treatment to either lithium carbonate or valproic acid for the remaining 6 weeks. In this RCT for the treatment of mania and hypomania, both lithium and valproic acid were found to be efficacious [11], as assessed by a reduction on Young Mania Rating Scale (YMRS) scores at 3-week follow-up. However, lithium was found to be superior to valproic acid in reducing manic symptoms at 9 weeks follow-up [11]. These findings mir- ror the treatment outcomes in younger adults with bipolar I dis [15, 25], and extend previous literature suggesting that lithium and valproic acid are both effective in treating acute mania in older adults. Furthermore, lithium and vaproic acid were found to be equally tolerable in this population of OABD. Tolerability was primarily assessed by the presence of sedation or sleepi- ness and experienced tremors between the treatment groups during the 9-week period. These findings provide some evidence for lithium and valproic acid as potentially safe treatment options with relatively minimal adverse effects in older adults. Despite the positive outcomes, the RCT presented some limitations. First, for ethical reasons, there was no pla- cebo comparison to verify the therapy-dependent effects of lithium and valproate acid in older adults. Furthermore, as patients only received treatment over a 9-week period, further data would be needed to understand the longer-term efficacy and tolerability of lithium and valproate in OABD. 3 Special Considerations for Using Lithium in OABD Since lithium is associated with a number of physical health adverse events in OABD patients, a number of special con- siderations may be helpful. While applying the following special considerations, it is worth remembering that, given the high rates of physical health problems in OABD, most physical health problems seen in OABD may be unrelated to lithium exposure [52]. That said, most acute and chronic lithium-associated physical health problems could be pre- vented through safe lithium dosing, prescribing (including avoiding drug–drug interactions), preventing cardiovascular disease, and appropriate laboratory monitoring. The majority of international bipolar dis guidelines have no separate section on OABD pharmacotherapy, let alone lithium use in this population [72], but this is changing slowly [12]. Although general pharmacotherapy recommen- dations for treating OABD are similar to those in younger adults, special considerations should be taken for side effects due to polypharmacy and somatic comorbidity [12, 72]. However, therapeutic lithium serum levels are suggested to be lower in treating older adults with bipolar dis [12, 73, 74]. Polypharmacy and comorbidities appear to be important contributing factors to lithium toxicity in older adults with bipolar dis , as noted in 63% and 76.3% of cases, respectively [74]. An ISBD task force consensus survey reported lithium as a preferred treatment for maintenance therapy in OABD [12, 47, 75]. In maintenance therapy, it is recommended to assess lithium, thyroid and renal function at 6  months and every 12 months thereafter [26, 47]. Lithium levels of 0.4–0.8  mmol/L have recently been recommended by the 151Lithium Use in Older Age Bipolar Dis International Society for Bipolar Dis s Task Force on OABD [12]. However, the lithium serum level needed for bipolar depression and maintenance in older patients may be as low as 0.4–0.6 mmol/L [75, 76]. Depression and maintenance are the most challenging aspects of OABD [22], and lithium levels > 0.8 mmol/L have been linked to cognitive/neurologi-
cal/mood symptoms [77] and renal effects [78], which provides
part of the rationale for the 0.4–0.8 mmol/L dose range. Serum
lithium levels for bipolar mania and maintenance are indicated
at 0.4–0.8 mmol/L for ages 60–79 years and 0.4–0.7 mmol/L
recommended for adults 80 years and older [73].

It is recommended that serum lithium levels should be
monitored 5–7 days after a dose change, 3–6 months there-
after, or as clinically necessary [12, 75]. Serum calcium and
parathyroid hormone (PTH) should be assessed annually
[47]. As per the CANMAT guidelines, laboratory assess-
ment of lithium levels can be completed at 12 h following
the previous dose (trough level) [12].

In terms of dosing, it can be useful to start at 150 mg/
day, and check the 12-h trough lithium level 5–7 days later,
aiming for 0.4 mmol/L for bipolar depression/maintenance
and 0.6 mmol/L in acute mania. The dose could then be
increased as needed, as is safely tolerated and effective.
Dosing every night is usually preferred by patients to mini-
mize potential daytime somnolence. Alternate-day dosing
can sometimes be useful for targeting intermediate lithium
levels [79], e.g. alternating between 150 and 300 mg every
second day.

Drug–drug interactions can occur between lithium and
ACE inhibitors, loop diuretics [48], NSAIDs [80, 81],
cyclooxygenase 2 (COX2) inhibitors [82], and diuretics
(including thiazides) [83]. These medications, commonly
prescribed in older people (33% of OABD patients [31])
have each been associated with lithium level increases of up
to 50%. If these medications are started or adjusted while a
patient is receiving lithium, it is wise to check serum lithium
levels 5–7 days after the medication change.

Close monitoring of renal function and lithium every
3 months in geriatric patients can help prevent renal disease
[47]. Using once-daily dosing can also be helpful [52]. Mon-
itoring at least annually for thyroid-stimulating hormone
(TSH), calcium, and metabolic syndrome (fasting glucose,
HbA1C, lipid profile, waist circumference) is also beneficial
[47]. In maintenance therapy, it is recommended to assess
lithium, thyroid, and renal function at 6 months and every
12 months thereafter [47].

4 Limitations of the Literature

There are a number of limitations in the existing literature
for lithium in OABD. Aside from GERI-BD, no RCTs have
been conducted. Methodologies and outcome measures

used also differ between studies. In addition, varying age
cut-offs have been used to define OABD (e.g. ≥ 50 vs. ≥ 60
or 65 years). Moreover, studies include both late-onset and
early-onset cases in which patients have grown old.

Other limitations of pharmacotherapy studies in OABD
(especially older studies) have been identified, including
small sample sizes, lack of randomization in many studies,
and some difficulty extrapolating from mixed-aged geriatric/
adult bipolar dis clinical trials.

5 Concluding Remarks

There is a small yet increasing evidence base that lithium
is effective in all phases of OABD, which echoes the adult
bipolar literature [12]. Although there can be adverse effects
with lithium, it is generally well-tolerated. As seen in the
recent GERI-BD study, lithium had a similar tolerability
profile to another standard bipolar pharmacotherapy, i.e.
valproate [11]. There are special considerations to help mini-
mize the risks of physical health adverse events, which have
been mentioned in this review. Furthermore, there are also
data suggesting potential physical health benefits of lithium
OABD, which need more in-depth study. Additional research
would strengthen the evidence base and further guide lith-
ium therapy in OABD. In the meantime, given that there
are more geriatric data and clinical experience using lith-
ium compared with other bipolar medications, lithium still
remains the gold-standard treatment for OABD.

Compliance with Ethical Standards

Conflict of interest Jocelyn Fotso Soh, Sivan Klil-Drori, and Soham
Rej have no conflicts of interest to declare. Soham Rej has received an
investigator-initiated research grant from Satellite Healthcare for an
unrelated project.

Funding This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.

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