TAB 2 (EMa)

Accepted Article
DR GERARD ANMELLA (Orcid ID : 0000-0002-6798-4054)
DR LLUC COLOMER (Orcid ID : 0000-0001-9964-0822)
PROFESSOR EDUARD VIETA (Orcid ID : 0000-0002-0548-0053)
Article type : From Research to Clinical Practice
How to treat mania
Authors: Isabella Pacchiarotti*1 & Gerard Anmella*1, Lluc Colomer1, Eduard Vieta1.
1Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of
Barcelona, IDIBAPS, CIBERSAM, 170 Villarroel st, 12-0, 08036, Barcelona, Catalonia, Spain.
* The first two authors contributed equally to this work
Corresponding author: Eduard Vieta, MD, PhD, Hospital Clinic, University of Barcelona, IDIBAPS,
CIBERSAM, 170 Villarroel st, 08036 Barcelona, Catalonia, Spain.
Email: [email protected]
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/ACPS.13209
This article is protected by copyright. All rights reserved
Abstract:
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Objective: In this paper we aimed at reviewing evidence-based treatment options for bipolar
mania and proposed tentative evidence-based clinical suggestions regarding the management of
a manic episode, especially regarding the choice of the proper mood stabilizer and antipsychotic
medication.
Method: A narrative review was undertaken addressing “treatment of bipolar mania”. Findings
have been synthesized and incorporated with clinical experience into a model to support
different treatment choices.
Results: To date, there is solid evidence supporting the use of several medications, such as
lithium, divalproex and carbamazepine, and the antipsychotics chlorpromazine, haloperidol,
risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, inhaled loxapine, asenapine and
cariprazine in acute mania, and some evidence supporting the use of clozapine or
electroconvulsive therapy in treatment-refractory cases. However, in clinical practice, when
taking decisions about treatment, a personalized treatment is needed, according to the different
clinical presentations and more complex clinical situations within the manic episode and
considering a long-term view and with the objective of not only a symptomatic but also
functional recovery. After remission from acute mania, psychoeducation strategies are useful to
ensure adherence.
Discussion: Despite the evidence for efficacy of many currently available treatments for mania,
the majority of RCTs provide little direction for the clinician as to what steps might be optimal in
different presentations of mania as well as in the presence of specific patient characteristics.
Manic episodes should be managed on a personalized basis considering clinical, course and
patient criteria and with the expectation of maintaining that treatment in the long-term.
Key words: bipolar, mania, treatment, mood stabilizer, antipsychotic.

Conflicts of interest: Dr. Pacchiarotti has received CME-related honoraria, or consulting fees
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from ADAMED, Janssen-Cilag and Lundbeck and reports no financial or other relationship
relevant to the subject of this article. Dr. Anmella has received CME-related honoraria, or
consulting fees from Janssen-Cilag, Lundbeck and Angelini and reports no financial or other
relationship relevant to the subject of this article. Prof. Vieta has received research support from
or served as consultant, adviser or speaker for AB-Biotics, Abbott, Allergan, Angelini, Dainippon
Sumitomo Pharma, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka, Sage pharmaceuticals,
Sanofi-Aventis, Takeda. All other authors declare no conflict of interests.

Clinical recommendations
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- Randomized placebo controlled clinical trials (RCTs) in mania offer little direction for the
clinician in providing specific suggestions and the clinical experience has influenced the
treatment recommendations in the face of varied and complex situations.
- Manic episodes should be managed on a personalized basis considering clinical criteria to
assist treatment choice and with a long-term view.
- Manic episodes will most commonly require hospitalization and combination treatment
of antipsychotic (AP) plus mood-stabilizer (MS)
- Regarding the choice of a MS, lithium should be preferred in cases of euphoric/grandiose
mania and a manic-depressive-euthymic clinical course.
- Divalproex could be a better treatment choice in cases of psychotic/mixed mania and in
patients with a rapid cycling course.
- With respect to AP choice in mania, a D2 antagonist such as paliperidone or risperidone
should be used in the presence of non-congruent psychotic symptoms.
- D2/D3 partial agonist AP, such as aripiprazole or cariprazine, should be preferred in
mood congruent psychotic symptoms.
- Transitorily use of sedative second generation AP (SGAs), such as olanzapine, quetiapine,
asenapine or even benzodiazepines could be needed in cases of mania with mixed
features or anxious distress.
- After remission of the acute manic episode, and depending on short- and long-term
illness severity, illness awareness, and tolerability, the gradual discontinuation of the AP
may be considered and most patients may stay on MS monotherapy unless proven
otherwise.
Additional comments
- Lithium is preferred over divalproex when suicidal ideation is present due to its anti-
suicidal long-term effects.
- Clozapine and electroconvulsive therapy (ECT) should be used in treatment-resistant
manic episodes.

-
Accepted Article Long acting injectable formulations of antipsychotics (LAIs) can be started during
admission and are indicated as maintenance treatment for poorly-adherent patients with
a manic predominant polarity (PP) course.
- Divalproex and carbamazepine are contraindicated during pregnancy and should be
avoided in childbearing women.
Limitations
- The non-systematic nature of this review does not allow for a comprehensive analysis of
the existing evidence, but the real aim of this piece was to put forward a document that
would match evidence and experience.
- The lack of clinical trial evidence for many medications makes it difficult to make specific
suggestions other than those based on clinical practice. However, the absence of
evidence does not constitute evidence of lack of efficacy.
- The clinical experience ingredient is largely subjective, and may vary according to the
cultural environment and personal involuntary biases.

Introduction
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Bipolar disorders (BD) are chronic and recurrent disorders that affect >1% of the global
population 1. Mania is the most characteristic phase of BD, and a major cause of disability,
stigma, and cognitive impairment 2. Manic episodes lead to rapid and major changes in the
individual’s usual behavior impairing social or occupational functioning or even lead to hospital
admission 3. DSM-5 4 has changed to “criterion A” for mania which now requires a distinct period
of abnormally and persistently elevated, expansive, or irritable mood and abnormally and
persistently increased activity or energy present most of the day, nearly every day for at least 1
week (or less time if hospitalization is necessary). In addition, a diagnosis of a “manic episode”
requires at least three (or four if the mood is only irritable) of the following symptoms: inflated
self-esteem or grandiosity, decreased need for sleep, more talkative than usual or pressure of
speech, flight of ideas or subjective experience that thoughts are racing, distractibility, increased
goal-directed activity or psychomotor agitation, or excessive involvement in activities with a high
potential for painful consequences. The mood disturbance must lead to marked impairment in
functioning, require hospitalization, or be accompanied by psychotic features. In contrast to
DSM-IV, according to DSM-5, a diagnosis of BD-I can be made in patients with major depression
whose mania emerges during treatment (i.e., during medication or ECT) when a fully syndromic
level of mania persists beyond the physiological effect of the treatment. In DSM-5 the term
“mixed episode” specifier has been eliminated, replacing it with the more dimensional “mixed
features” 5.
Several pharmacological strategies have been investigated in mania. First consideration, the
treatment of acute mania deserves a long-term view that includes not only the short-term
efficacy and tolerability, but its efficacy in preventing mania or depression, its long-term
safety/tolerability profile and the risk of treatment-emergent switch. Other considerations that
should be taken into account in order to choose the best possible treatment are the
characteristics of manic patients, the clinical presentation of the manic episode, the course of the
illness, and treatment adherence. Lithium still remains the traditional treatment option, but the
majority of patients do not respond to lithium monotherapy, and other drugs have been

introduced in the past decades, such as the anticonvulsants divalproex and carbamazepine,
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which have also their own limitations. AP are established as the main treatment for
schizophrenia, but they have been traditionally used in mania, and to date a growing number of
trials have turned them into a broader therapeutic option for BD, as both alternative and adjunct
to traditional MS. APs have been extensively studied in mania, but there is also increasing
evidence of the efficacy of at least some of them in the treatment of bipolar depression and
maintenance treatment of BD. Moreover, some APs may be helpful in the treatment of mixed
states and rapid cycling 2,5–9. Another important issue is to decide monotherapy vs polytherapy in
the treatment choice during a manic episode. Data from RCTs in mania are considered the gold
standard for making clinical judgments. However, there are too many biases for generalizing this
assumption. For example, patients are highly selected for homogeneity for the RCTs and typically
do not represent the range and complexity and severity of patients in the treatment-seeking
population 9,10. In clinical reality, the majority of patients with acute mania are treated with
combinations of the drugs mentioned above, and even benzodiazepines as adjuvant treatment.
As an alternative option to lithium, anticonvulsants, APs, or their combination, ECT is supported
in cases of refractory mania 2,5. Lastly, the frequent presence of poor adherence in some manic
patients implies considering the use of LAIs. The treatment of milder forms of mania and
hypomania has clearly been insufficiently studied, although it is generally assumed that what
works for mania should work for hypomania as well. However, clinical decisions are generally
made on a benefit:risk ratio framework, and therefore more head to-head studies and specific
trials in this subpopulation are needed.
Aims of the study
The aim of this paper is to consider factors that might assist medication choice for the treatment
of a manic episode based on the available evidence and authors’ experience. We will also provide
specific evidence-based clinical recommendations for the treatment of bipolar mania,
considering clinical factors that might influence AP and MS medication choice.

Material and methods
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A narrative review of scientific literature and clinical guidelines until December 2019 was
undertaken addressing “treatment of bipolar mania” considering a range of parameters –
broadly divided into patient factors, manic episode characteristics and treatment factors – either
weighted by patients and clinicians or suggested in the scientific literature. This body of evidence
was synthesized and incorporated with clinical experience into a model of evidence-based clinical
recommendations to assist treatment choice. The Barcelona Bipolar Disorders Program has a
long-standing tradition of combining expert clinical care. Education and research in the field of
bipolar illness and beyond (now including as well depressive disorders) (Vieta, 2011a, 2011b;
Kirby, 2015) 11–13. Moreover, this expert center is part of the Center for Network Biomedical
Research on Mental Health in Spain 14. The combination of a thorough review of the evidence
base plus the extensive experience in treating manic patients has yielded the present
manuscript.

Results
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The management of a manic episode
Ideally, the ultimate goals of the treatment of an acute manic episode should be to reduce
symptoms and allow a return to the premorbid levels of functioning. Achieving a rapid control of
agitation, aggression, and impulsivity is particularly important to ensure the safety of patients
and those around them, and to allow the establishment of a therapeutic alliance. Sometimes, an
involuntary hospitalization is needed to start effective treatment 2 in order to ensure a calming
environment and reduced stimulation, and to avoid further social disruption. Manic patients
should be advised not to make important decisions until they have recovered and encouraged to
maintain their relationships with their carers 15.
Some basic principles should be identified for the management of mania: in patients not taking
long-term treatment for BD, once a successful treatment has been initiated for mania,
maintenance treatment should be considered. Poor adherence is the commonest reason for
relapse, and poor illness awareness the main reason for poor adherence; this is why
psychoeducation is so important. For patients who develop mania while adherent to long-term
treatment, the effectiveness of the current treatment should be reassessed, including the dose. If
the manic episode is due to poor adherence, consider if it is associated with adverse effects, then
consider dose reduction, switch to a more tolerable drug regimen or the use of LAI 2,5,6,9.
The management of manic episodes should be handled in three differential steps according to
the symptomatic severity and stage of the manic episode: (1) the management of agitation, (2)
the treatment during an acute manic phase, (3) the maintenance therapy after an acute manic
episode.
The split between acute treatment and long-term treatment makes sense from an operational
perspective. However, the integrative approach for the management of BD has proven the most

efficacious, dealing with the acute intervention while keeping perspective on the long-term ones
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and the functional outcome, keeping in mind the principles exposed in Table S1 2.
---------------------------------------Insert TAB S1 about here------------------------------------------
(1) Management of manic agitation
Agitation is common in mania, especially when mixed features are present 16. It is defined as
“excessive motor activity associated with a feeling of inner tension”4 and can lead to aggressive
behaviors and require prompt attention 17. Its rapid onset claims for preventive considerations,
especially in mixed and psychotic mania. Therefore, rapid acting antimanic treatments have
proven the most effective and should be considered first. If agitation persists after antimanic
treatments, additional rapid onset agents are often needed. Table 1 summarizes the evidence of
different agents in the treatment of manic agitation. The lines of recommendation are based on
the the clinical experience of authors and the combination of the efficacy and safety/tolerability
of the different treatments defined according to the international guidelines on BD 5,6,18–20
exposed in Tables 1-2.
---------------------------------------Insert TAB 1 about here------------------------------------------
Non-primary psychiatric etiologies for agitation should always be considered (ie, intoxication,
medical conditions, treatment side effects, etc.) in order to determine a safe treatment and the
adequate dose 21.
In the treatment choice for manic agitation, several considerations should be made: the severity
of manic symptoms, the risk of auto- and hetero-aggressiveness, the insight of the patient and
the willingness to take medication and non-psychiatric causes 21. Despite the evidence exposed in
Table 1, if possible, clinical experience suggests that oral or inhaled formulations of an
antipsychotic are preferred. Rapidly-melt, oral liquid or inhaled forms should be considered if
suspicion that the patient might not take the medication properly. Inhaled loxapine has the
benefit of a lung absorption with a rapid transition to the systemic circulation, providing an
intravenous-like pharmacokinetic, presenting as a valid first-line option 22–24. If oral or inhaled

preparations are ineffective, the agitation is severe and/or the patient is refusing oral
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administration, intramuscular (IM) formulations, such as aripiprazol or olanzapine should be
considered 21. Intravenous treatments should be avoided except in cases where there is no
alternative 21.
(2) Management of the acute manic phase
The treatment recommendations for acute mania, according to efficacy, safety and tolerability
criteria, are summarized in Table 2. Nevertheless, in the new era of personalized medicine 25,
treatment choice should be made according to a personalized basis considering the integrated
characteristics of each patient as well as the patient’s preferences 5.
Monotherapy versus Polytherapy
Monotherapy is recommended as a first-line treatment for acute mania in most guidelines 5,6,18–
20, but this is mainly driven by the fact that the best design clinical trials are those aimed at
seeking regulatory approval, and in that case, monotherapy is a requirement (while adjunctive
designs are just recommended). Hence, the best evidence comes from placebo-controlled trials
in which patients provide written consent to participate and their condition is obviously milder
than in real-world clinical practice. Moreover, the trials that used and adjunctive design (MS
combined with AP) showed greater improvements in the mania scales than monotherapy
studies. For these reasons, several considerations should be made for this clinical decision, such
as the rapidity of response needed (polytherapy tends to work faster), the patient’s previous
history of response to monotherapy, the severity of mania (better response rates with
polytherapy), tolerability history (usually worse with polytherapy), the long-term adherence
(worse with polytherapy) and the patient’s preferences. Another point is to evaluate the efficacy
and tolerability of the treatment after 1-2 weeks and modify the treatment accordingly, aiming at
long-term treatment strategies 26. For inpatients, who are generally more severe that
outpatients, our recommendation is to start with the combination of AP and MS.

Secondary causes for manic symptoms, including drug abuse, medications or general
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medical/neurological conditions, should be ruled out before initiating pharmacological
treatment. If present, antimanic treatment should be applied on a short-term basis.
Antidepressant-induced mania should be considered with a rapid discontinuation of the
antidepressant drug 27. Moreover, the use of stimulants should be discontinued, including
caffeine and alcohol. Previously diagnosed BD patients should commence antimanic agents
without delay. However, in patients with a first-manic episode, a comprehensive study should be
performed to confirm the diagnosis of BD and the need for antimanic treatment. In patients with
histories of substance abuse, attention should be paid to managing withdrawal symptoms. First-
line recommendations (monotherapy or polytherapy) should be considered for all patients, for
initiation or optimization treatments. Also, adherence should be checked and addressed.
First-line treatments
Monotherapy
Around 50% of manic patients will respond to monotherapy within 3-4 weeks according to
clinical trials 28. Lithium, divalproex, aripiprazole, paliperidone, risperidone, asenapine,
olanzapine, quetiapine, and cariprazine are all recommended as first-line treatment options with
level 1 efficacy-evidence and comparable efficacy (Cohen’s d 0.32-0.66; small to medium effect
size) as presented in Table 2 9,29. Even though their comparable efficacy for treating acute mania,
several aspects must be considered.
Lithium is preferred over divalproex as MS for the treatment for acute mania and posterior
maintenance treatment unless there are specific contraindications (previous non-response, renal
failure, severe dermatological disease, severe gastrointestinal intolerance, cardiovascular
insufficiency, Addison’s disease or/and untreated hypothyroidism). Lithium is specially indicated
in patients presenting with factors of favorable-response to lithium: those who present classical
euphoric grandiose mania (elated mood in the absence of depressive symptoms), a course of
mania-depression-euthymia, few prior episodes of illness, and/or family history of BD, especially
with a family history of lithium response 26,30. Divalproex has been classically recommended for

patients with predominant irritable or dysphoric mood, comorbid substance abuse, multiple
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prior episodes, or those with a history of head trauma 31–35. However, the long-term beneficial
effects of lithium, especially its anti-suicidal properties, have been consistently reported over the
past 40 years 36–38 in addition to better mortality results over divalproex 39. Considering this fact
along with the teratogenic potential of divalproex, lithium appears as the preferred MS, which
use may still be underrepresented in clinical practice and should be incorporated more
assertively into current guidelines. The serum concentrations target range must be checked and
higher serum concentrations (0.8-1.0 mmol/l) may be more effective during the acute phase 6,38,
but levels can be lower when used in combination or over the longer term 40.
Olanzapine in mono or polytherapy, despite level 1 for efficacy in acute mania, has been
relegated to a second-line treatment for acute mania in some of the latest guidelines due to its
long-term tolerability and metabolic issues 5,19,41 whereas other guidelines have considered it a
first-line treatment 6,15,18. It is key to consider that in the acute phase of mania, especially with
severe symptoms, the anxiolytic properties of olanzapine can be very useful to reduce the
anxious distress during the first weeks of an acute episode. Therefore, we recommend it as first-
line treatment keeping in mind that it’s use should be transitory and goal directed, avoiding long-
term treatment.
Polytherapy
First-line polytherapies include lithium or divalproex combined with SGAs such as aripiprazole,
risperidone, asenapine, olanzapine or quetiapine. Combination therapy has shown greater
efficacy than MS monotherapy, with 20% more patients responding, especially in patients with
greater severity 42–44. Also, combination therapy has been suggested more efficacious than SGA
monotherapy 45,46. Paliperidone and ziprasidone lack evidence for additional efficacy in
polytherapy 29,47.
Add-on/Switch strategies
When symptoms persist using first-line options (mono- or polytherapy), dosing should be
optimized, non-adherence identified and other causes assessed (substance abuse,

antidepressant use, etc.). Even if an abrupt switch is justified in acutely ill patients, cross-taper
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switch (within 1 week) is preferred in acute mania 48,49. In hypomanic patients with low severity a
plateau cross-taper switch may be preferred 48,49. Response should be expected within 1-2
weeks according to comparative studies 29. Therefore, after 2-week unresponsiveness with
therapeutic doses of antimanic agents without other causes contributing for non-response, add-
on/switch strategies ought to be considered. Moreover, if the patient does not tolerate a first-
line agent at optimal dosage, it should be switched or another agent added-on. Second- and
third-line agents are only recommended after unsuccessful trials of multiple first-line strategies,
since there are many efficacious alternatives with adequate tolerability/safety profile.
Second-line treatments (add-on/switch)
Haloperidol, ziprasidone and carbamazepine have level 1 evidence for efficacy, but are
considered second-line options due to safety/tolerability risks 29. Haloperidol is a potent
antimanic drug but it clearly increases the risk of depression switch 50. The combination of
lithium-divalproex is also recommended as second-line choice with evidence limited to
uncontrolled trials 51,52. ECT is recommended as a second-line option 53 with evidence suggesting
that up to 80% of patients will show marked improvement 54.
Third-line treatments (add-on/switch)
Clozapine (in mono- or polytherapy) lacks specific RCTs in acute mania 55–57. Moreover, it has not
been approved for use other than schizophrenia and its adverse effects (especially
agranulocytosis) and the mandatory monitoring have relegated it as a third-line treatment option
in acute mania according to all clinical guidelines 5,6,18–20. However, in a recent review of
literature, clozapine was shown as an effective and safe treatment in resistant-BD, with lower
severe adverse effects reported than those reported in the published schizophrenia literature,
with just 0.3% of agranulocytosis 58. Therefore, and considering its unique properties (including
its anti-suicidal effects and by extrapolation from its likely superiority in treating psychosis 59), it
is becoming more used and seen by many as a useful treatment in resistant BD 60,61.
Refractory BD

In case of refractory BD, it is important to consider that the required treatment and dosage
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durations have been fulfilled, thus ensuring treatment adherence and adequate dosing as a first
step. Moreover, factors responsible for treatment refractoriness, such as medical comorbidities,
drug abuse or treatment interactions, should be comprehensively assessed. When no secondary
causes are found and the patient has fulfilled the timing and dosage of treatments, a
pharmacogenetic study on cytochrome P450 enzymes (particularly 2D6 and 3A4, which
metabolize most psychotropic drugs) is recommended, especially if the patient has shown
tolerance to high doses of different drugs with scarce adverse effects. This assessment will
exclude the possibility of rapid/ultra-rapid metabolic status contributing to poor response.
Clozapine 58 and ECT 62 as primary or adjunctive therapy should be considered in treatment-
resistant mania and/or refractory BD.
(3) Maintenance therapy after acute manic episode
As abovementioned, the treatment choice for a manic episode should be integrative and keep
perspective on the long-term outcome and the main principles exposed in Table 1. Generally,
medications that have been found to be effective in the acute phase should be continued during
the maintenance phase. However, some of these drugs are not adequate for the maintenance
long-term treatment and should be used only in the acute phase of mania. For instance,
benzodiazepines should be used at the lowest possible effective dose for the shortest possible
period of time due to their risk of generating tolerance and physical dependence 63, divalproex
should be carefully used in childbearing woman 64,65 and olanzapine and quetiapine are related
to long-term use adverse effects, mainly metabolic syndrome 66. For these reasons, if possible,
their use should be limited to the acute manic phase and their adverse effects monitored in case
of used as maintenance treatment. Hence, to avoid switching treatments from the acute to the
maintenance phase, those patients who may benefit from drugs with a better long-term
tolerability profile (for example, amongst the AP, aripiprazole or asenapine) should be given the
opportunity to be managed acutely with those drugs.
The choice of agent or agents used in maintenance treatment should be discussed with the
patient and their caregivers (as appropriate) and personalized on the patient’s characteristics

that may influence prognosis. As a rule, for inpatients with mania, the choice of the combination
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of AP+MS gives the opportunity to slowly discontinue the AP over the long term and check
whether MS monotherapy is feasible. Patients and caregivers appreciate very much the chance
of having a perspective of reducing the burden of treatment over time. However, some patients
may need AP and MS combination as long-term maintenance treatment, especially those who
relapse after AP discontinuation.
After an acute manic episode, if a patient has responded to a non-first-line maintenance

treatment regime, it is recommended to be continued as maintenance treatment with
progressive dose adjustment. In case of switch, in stable BD patients, the plateau cross-taper
strategy is preferred 49 with slow tapering (over 4 weeks or more recommended) for relapse
prevention 6. Likewise, slow tapering is recommended in case of discontinuation 67.
The optimization of the maintenance treatment is key to ensure adherence and stabilization.
Therefore, it should be simplified to the necessary drugs at the effective dose. If it is possible,
monotherapy with MS has proven as the most efficacious treatment for relapse-prevention in
stable BD, especially lithium 68.
The use of SGA is effective in preventing relapse of manic episodes but not as much depressive
episodes 5. When combining a SGA with lithium/divalproex to treat acute mania, continuing the
SGA for the first 6 months following response offers clear benefit in reducing risk of recurrence,
but the benefits beyond 6 months remain uncertain 69. Therefore, clinicians are advised to
reevaluate risks and benefits after 6 months of sustained response to determine whether
maintenance combination therapy with a SGA is required.
In contrast with first-line treatments for acute mania, for maintenance treatment, oral
aripiprazole, due to its safety/tolerability profile 70,71, is preferred over oral risperidone and
paliperidone, even that all of them have proven efficacious in preventing manic episodes, but
less effective in preventing depression 69,72. The lack of data regarding cariprazine as
maintenance treatment in BD claims for new studies, but its efficacy in the treatment of acute
mania and its favorable metabolic profile suggests its potential as a maintenance treatment for

BD 73. Lurasidone, despite the inconclusive results of the maintenance trial, could be considered
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an option specially in patients with a depressive PP 74.
When the symptoms of mania have remitted, preventive strategies, such as behavioral and
psychoeducation approaches should be applied to reduce relapse rates 1. These strategies
include promoting ongoing medication adherence, reduce residual symptoms, help identify early
signs of relapse, and support functional recovery 75–78.
In this line, LAIs ought to be considered and offered as maintenance treatment in patients with
poor adherence 79. Aripiprazole monohydrate once-monthly LAI monotherapy has shown to
delay time to recurrence of manic episodes without inducing depressive episodes 80. Risperidone
LAI monotherapy 81 or adjunctive therapy 82 was found to be effective in protecting from manic,
but not depressive recurrences 79. The studies regarding the use of paliperidone palmitate LAI in
the treatment of BD are limited to case-reports 83,84. The clinical experience suggests a similar
effect to risperidone LAI with less adverse extrapiramidal effects in paliperidone palmitate LAI. In
sum, it should be noted that LAIs have shown to prevent manic, but not depressive recurrences
and may worsen depressive symptoms, therefore it should be indicated as first-line treatments
for BD patients with a manic PP 79. LAIs can be started during admission for an acute manic
episode, thus ensuring adherence during the sensitive period of convalescence. Tentative clinical
indications for maintenance treatment with LAIs are shown in Table S2.
Ongoing clinical monitoring, including medication blood levels as appropriate, is crucial a part of
maintenance treatment that should be used to support enhanced medication adherence,
detection of early symptoms of recurrence, and monitoring of side effects.

Special populations
Accepted Article Children and adolescents
Around 50-70% of patients experience their first manic episode during childhood or adolescence,
peaking at 15-19 years 85. This population has high suicidal risk 86 and higher comorbidities 87. The
delay of treatment is a poor prognostic factor later in life. Therefore, an early-diagnosis and
intervention is mandatory 88. Manic episodes in this population present usually with atypical
symptoms, including erratic and non-persistent mood changes, irritability, recklessness,
aggressiveness and deterioration in behavioral and functional domains 5. Preserving social
cognition and cognitive reserve is of utmost importance in this population 89,90.
Older-age BD
10% of BD cases begin after the age of 50, with a lifetime prevalence from 0.5-1% over 65 91.
They exhibit longer and more frequent affective episodes 92 with more severe manic episodes
than depressions, usually present with cognitive dysfunction 93. These patients have an average
of 3-to-4 medical comorbidities (especially neurological and CVD diseases), which account for a
reduced life expectancy 94. Regarding treatment choice, additional considerations regarding
medical comorbidities, medication tolerability and age-related changes in pharmacokinetics and
pharmacodynamics must be considered 5.
The recommendations of different agents in the treatment of pediatric and older-age mania is
summarized in Table S3.
Childbearing women
The perinatal period is associated with up to 2/3 relapses in untreated BD, especially during the
first trimester of pregnancy 95. In BD childbearing women with a manic episode, pregnancy
should always be considered and ruled out before initiating pharmacotherapy 5. A state of
pregnancy or pregnancy plannification accounts for specific treatments selection and dosing

adjustment. An overview of medications commonly used to treat mania and the pregnancy
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exposure risk categories can be seen in Table S4.
Clinical guidelines advise the use of monotherapy at the lowest effective dose whenever possible
to minimize fetal drug exposure, sparing polytherapy for more complex cases 15,52. A special
warning should be placed on the use of divalproex: it has been associated with the highest risk of
serious neurodevelopmental disorders in children exposed in utero 96. This has brought to
tightened restrictions to its use by regulatory agencies 97–99 and clinical guidelines 5,6,18–20.
Evidence-based clinical recommendations concur that it is mandatory to stop divalproex during

pregnancy 64,65. Lithium, lamotrigine, quetiapine, olanzapine or aripiprazole are considered as
valid alternatives 64,65.
Lithium has proven as the most efficacious treatment for relapse-prevention during pregnancy
100. Lithium’s teratogenic risk (cardiotoxicity and Ebstein's anomaly) has been overestimated in
the past 38,101,102. Therefore, it has been recommended as first-line treatment during pregnancy
in severe BD women by some clinical guidelines 18,103 with close monitoring during the whole
pregnancy 5,6,18. Nevertheless, notable differences in clinical recommendations exist across
guidelines, including avoidance or continuation of lithium and the degree to which SGA
treatment is prioritized 104.
Among FGA, haloperidol has proven the most efficacious drug for acute mania. Its long-known
reproductive safety profile makes it appealing for the treatment of pregnant BD manic patients
105. However, FGA may be associated with increased risk for extrapyramidal side effects in
neonates 106. SGA are considered relatively safe during pregnancy and can be used as an
alternative to MS 107. Aripiprazole, olanzapine, and quetiapine appear to be safe, whereas
risperidone and paliperidone may be associated with a very minor increased risk of congenital
malformations 108. Safety data on clozapine and ziprasidone remain scarce and insufficient for a
quantitative safety evaluation. No or minimal safety data are available for amisulpride,
asenapine, lurasidone, and sertindole 109,110, and other alternatives are recommended.

Moreover, the risk of excess weight gain and/or gestational diabetes, must be considered
Accepted Article 111.
Finally, ECT is recommended for severe or refractory symptoms 62.
Breastfeeding considerations
In manic BD breastfeeding women several considerations should guide treatment choice. First,
most psychotropic drugs are excreted in breast milk and the risk of toxicity for breast-fed infants
is significant 112. Second, medications with short half-life taken after breastfeeding are
recommended to minimize the exposure of the infant 41. However, the beneficial effects of
breastfeeding for both infant and mother, including the establishment of emotional bond,
reduction of the incidence and severity of many infectious, respiratory, endocrine and
hematological diseases, cannot be underscored. Therefore, breastfeeding is recommended for all
newborns, being drug use a relative contraindication 113. The lactation risks categories during
lactation of commonly used medications to treat mania can be seen in Table S3 5.
In case of severe manic symptoms, which pose the patient or infant at risk, or/and the need of a
contraindicated medication for breastfeeding is needed, replacement or supplementation of
breast milk with formula should be outweighed 114.

Clinical criteria to assist treatment choice
Accepted Article
Clinical specifiers are used to provide additional detail about the nature of the symptoms of an
episode or throughout the course of the disorder. Their utility is key in selecting treatment
options for manic episodes. The main clinical criteria used to assist treatment choice in manic
episodes are summarized in Table 3.
---------------------------------------Insert FIG 1 about here------------------------------------------

Tentative treatment algorithms during a manic episode according to
Accepted Article
different clinical presentations
The previous evidence along with clinical experience has been summarized into schematic flow-
chart resolution processes to assist the choice of a MS and an AP (Figure 2). It should be
considered that normally the severity of an acute manic episode claims for the combination of
both a MS and an AP treatment, whereas for the maintenance therapy, the treatment regime
should be simplified whenever possible.
---------------------------------------Insert FIG 2 about here------------------------------------------

Discussion
Accepted Article
The treatment of mania still poses very important challenges, particularly as far as the long term
is concerned. In fact, despite a great number of drugs have proved to be effective and have
increased our treatment armamentarium for this condition, the gap between evidence base and
clinical practice is still huge, and the majority of patients have to be treated with combinations of
several drugs and psychosocial interventions in order to achieve a reasonable outcome from the
clinical as well as functional point of view. Manic episodes should be managed on a personalized
basis considering several clinical criteria to assist treatment choice (Table 3). Clinical criteria
include manic episode presentations (Figure 1) (psychotic, mixed and anxious features), course
specifiers (PP and rapid cycling) and patient factors (disease severity, comorbidities, treatment
adherence, present and past treatment and the stage of disease). Also, the choice of treatment
for acute mania must consider the efficacy, safety and tolerability of antimanic drugs along with
the patient’s characteristics and preferences and should keep perspective on the long-term
treatment strategies 5. Based on existing evidence-based data, we provided a tentative
treatment algorithm for MS and AP choice during a manic episode taking into account the above
mentioned clinical, course and patient variables with the aim of giving practical
recommendations in daily practice (Figure 2). Another important matter is that for ethical
reasons most of the evidence base comes from studies where participants agreed to participate
had milder forms of mania compared to the patients generally seen in clinical practice. For this
reason, guidelines tend to recommend lower doses than those used in practice and are more
supportive of monotherapy, while combination is the rule in the real world.
The limitations of this article are closely connected with its strengths. Hence, the non-systematic
nature of this review does not allow for a comprehensive analysis of the existing evidence, but
the real aim of this piece was to put forward a document that would match evidence and
experience. Second, the lack of clinical trial evidence for many medications, make it difficult to
make specific suggestions for the management of mania, other than those based on clinical
practice. However, the absence of evidence does not constitute evidence of lack of efficacy.
Finally, the clinical experience ingredient is largely subjective, and may vary according to the

cultural environment and personal involuntary biases. As mentioned, our group has extensive
Accepted Article
experience over 3 decades of treating large numbers of manic patients and we follow a large
cohort of bipolar patients, which has been the source of extremely valuable knowledge.
Assuming that the choice of treatment is based on clinical observations of superior efficacy
according to different clinical variables, our suggestions may be useful to inform future clinical
studies in the treatment of mania.

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2007;277(1):1-13. doi:10.1007/s00404-007-0433-2

Accepted Article
Table 1. Levels of recommendation for pharmacological management of agitation
Levels of Dose range Level of evidenceb

a
Agent Formulation
recommendation Single dose Maximum daily
Aripiprazole IM 9.75 mg 15 mg 1,2
Olanzapine IM 2.5 mg 10 mg 3–7

First-line
Loxapine Inhaled 5 mg 10 mg ◆ 8,9
Haloperidol IM 5 mg 15 mg 5,10,11
Asenapine Sublingual 10 mg 12
Second-line
Lorazepam IM 2 mg 1,3
Risperidone ODT 2 mg 4 mg 10
Haloperidol PO 5 mg 15 mg 13,14
Third-line
Quetiapine PO ≈300 mg 13,14
IM: intramuscular; ODT: orally disintegrating tablet; PO: per os.

a. Clinical experience suggests that oral antimanic formulations are preferred and intravenous treatments should be avoided except in cases where there is
15
no alternative .
b. The absence of evidence does not constitute lack of efficacy. The grading based on efficacy has been defined according to the international guidelines on
BD
16–20
in the following levels of evidence: ◆ level 1: good research-based evidence, supported by meta-analysis with narrow confidence interval or good

Accepted Article
quality replicated randomized controlled trials (RCT); level 2: fair research-based evidence, supported by meta-analysis with wide confidence interval or
one good quality RCT; level 3: some evidence from at least one poor quality RCT or health system administrative data ; level 4: poor evidence from
uncontrolled trials, anecdotal reports, or expert opinion; ◆ level 5: negative evidence; - : no data.
1. Zimbroff DL, Marcus RN, Manos G, et al. Management of acute agitation in patients with bipolar disorder: Efficacy and safety of
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Pharmacotherapy. 2013;33(6):603-614. doi:10.1002/phar.1260
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5. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a
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239. doi:10.1016/j.eurpsy.2010.04.005
7. Kishi T, Matsunaga S, Iwata N. Intramuscular olanzapine for agitated patients: A systematic review and meta-analysis of randomized

Accepted Article
controlled trials. J Psychiatr Res. 2015;68:198-209. doi:10.1016/j.jpsychires.2015.07.005
8. Kwentus J, Riesenberg RA, Marandi M, et al. Rapid acute treatment of agitation in patients with bipolar I disorder: A multicenter,
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5618.2011.00975.x
9. Citrome L. Inhaled loxapine for agitation revisited: Focus on effect sizes from 2 Phase III randomised controlled trials in persons with
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10. Lim HK, Kim JJ, Pae CU, Lee CU, Lee C, Paik IH. Comparison of risperidone orodispersible tablet and intramuscular haloperidol in the
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doi:10.1159/000315437
11. Lenox RH, Newhouse PA, Creelman WL, Whitaker TM. Adjunctive treatment of manic agitation with lorazepam versus haloperidol: a
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12. Pratts M, Citrome L, Grant W, Leso L, Opler LA. A single-dose, randomized, double-blind, placebo-controlled trial of sublingual asenapine
for acute agitation. Acta Psychiatr Scand. 2014;130(1):61-68. doi:10.1111/acps.12262
13. Currier GW, Chou JC-Y, Feifel D, et al. Acute treatment of psychotic agitation: a randomized comparison of oral treatment with
risperidone and lorazepam versus intramuscular treatment with haloperidol and lorazepam. J Clin Psychiatry. 2004;65(3):386-394.
http://www.ncbi.nlm.nih.gov/pubmed/15096079. Accessed December 6, 2019.
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15. Garriga M, Pacchiarotti I, Kasper S, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol
Psychiatry. 2016;17(2):86-128. doi:10.3109/15622975.2015.1132007

Accepted Article
16. Yatham LN, Kennedy SH, Parikh S V, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for
Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170.
doi:10.1111/bdi.12609
17. Malhi GS, Bassett D, Boyce P, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood
disorders. Aust New Zeal J Psychiatry. 2015;49(12):1087-1206. doi:10.1177/0004867415617657
18. Goodwin G, Haddad P, Ferrier I, et al. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations
from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30(6):495-553. doi:10.1177/0269881116636545
19. Grunze H, Vieta E, Goodwin GM, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological
treatment of bipolar disorders: update 2012 on the long-term treatment of bipolar disorder. World J Biol Psychiatry. 2013;14(3):154-
219. doi:10.3109/15622975.2013.770551
20. Fountoulakis KN, Grunze H, Vieta E, et al. The International College of Neuro-Psychopharmacology (CINP) treatment guidelines for
Bipolar disorder in adults (CINP-BD-2017), part 3: The clinical guidelines. Int J Neuropsychopharmacol. 2016;20(2):pyw109.

Accepted Article
Table 2. Pharmacological treatments recommended for the management of acute mania
Safety and tolerability considerations

Maintenance after maniaa
Acute Recommended dosage for treatment selectionb
Levels of recommendation
maniaa (mg/day) Prevention Prevention of
Acute Maintenance
of mania depression
First-linec
600-1200 (serum level
Lithium ◆ ◆ ◆ △ ▲
0.6-1.0 mmol/l or mEq/l)
1200-3000
DVPd ◆ △ ▲
(serum level 75-150 mg/l)
Aripiprazole ◆ 15-30 - △ △
Paliperidone ◆ 6-12 - △ ▲
Risperidone ◆ 2-6 - △ ▲
Asenapine ◆ 10-20 △ △
Olanzapine ◆ 10-20 ◆ ◆ ▲ ▲

Accepted Article
Quetiapine ◆ 400-800 ◆ ◆ ▲ ▲
Cariprazine ◆ 3-12 - - △ △
†
Aripiprazole + Li/DVPd - ▲ ▲
†
Risperidone + Li/DVPd ◆ - ▲ ▲
†
Asenapine + Li/DVPd - ▲ ▲
†
Olanzapine + Li/DVPd ◆ ▲ ▲
Quetiapine + Li/DVPd ◆ † ◆ ◆ ▲ ▲
Second-lineb
ECT ▲ ▲
600-1200
Carbamazepined ◆ ▲ ▲
(serum level 4-15 mg/l)
Haloperidol ◆ 5-20 ◆ ▲ ▲
Ziprasidone ◆ 80-120 - ▲ ▲

Accepted Article
Lithium + DVPd † - ▲ ▲
Abbreviations: DVP: divalproex; ECT: electroconvulsive therapy; Li: lithium.

1–5
a. The absence of evidence does not constitute lack of efficacy. The grading based on efficacy has been defined according to the international guidelines on BD in the
following levels of evidence: ◆ level 1: good research-based evidence, supported by meta-analysis with narrow confidence interval or good quality replicated randomized
controlled trials (RCT); level 2: fair research-based evidence, supported by meta-analysis with wide confidence interval or one good quality RCT; level 3: some
evidence from at least one poor quality RCT or health system administrative data ; level 4: poor evidence from uncontrolled trials, anecdotal reports, or expert opinion;
◆ level 5: negative evidence; - : no data.
in the following levels: △ level 1: very good tolerability

1–5
b. The grading based on safety and tolerability has been defined according to the international guidelines on BD
and few side effects which are not enduring, they do not cause significant distress and are not life-threatening and they do not compromise the overall somatic health of the
patient; ▲ level 2: moderate tolerability and/or side effects which could be enduring, and cause significant distress but they are not life- threatening although they could
compromise the overall somatic health of the patient; ▲ level 3: poor tolerability and/or many side effects which are enduring, cause significant distress, compromise the
overall somatic health of the patient or are life-threatening (even rare).

c. Treatments have been presented in the following order: mood stabilizers, antipsychotics and combination treatments. In these subsections, the recommendations follow a
hierarchical order (i.e. lithium before divalproex, aripiprazole before paliperidone, etc). Although monotherapies are listed above combination therapies in the hierarchy,
combination therapies may be indicated as the preferred choice in patients with previous history of partial response to monotherapy or severe manic episodes.
d. Divalproex and carbamazepine should be used with caution in women of childbearing age.
† same recommended doses as monotherapy for each individual treatment.

Accepted Article
1. Yatham LN, Kennedy SH, Parikh S V, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for
Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170.
doi:10.1111/bdi.12609
2. Malhi GS, Bassett D, Boyce P, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood
disorders. Aust New Zeal J Psychiatry. 2015;49(12):1087-1206. doi:10.1177/0004867415617657
3. Goodwin G, Haddad P, Ferrier I, et al. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations
from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30(6):495-553. doi:10.1177/0269881116636545
4. Grunze H, Vieta E, Goodwin GM, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological
treatment of bipolar disorders: update 2012 on the long-term treatment of bipolar disorder. World J Biol Psychiatry. 2013;14(3):154-
219. doi:10.3109/15622975.2013.770551
5. Fountoulakis KN, Grunze H, Vieta E, et al. The International College of Neuro-Psychopharmacology (CINP) treatment guidelines for
Bipolar disorder in adults (CINP-BD-2017), part 3: The clinical guidelines. Int J Neuropsychopharmacol. 2016;20(2):pyw109.

Table 3. Clinical criteria to assist treatment choice in manic episodes
Clinical criteria Considerations and Implications

The detailed characterization about the nature of the symptoms of a
Clinical specifiers on manic episode characterization
manic episode (Figure 1A), is key in selecting an adequate treatment.
 No evidence of superiority of any first-line monotherapy or
Present in about 75% of manic episodes (1,2) combination treatment in treating mania with psychotic features
 Mood congruent (grandiosity, megalomania, or (3–7).
Psychotic features messianic ideation).  Use a combination of mood stabilizer and SGA in:
 Mood incongruent (persecutory delusions) in up to o manic episodes with mood-incongruent psychotic
30% of manic episodes (1). features.
o If schizoaffective disorder is considered.
Traditional division of mania:
 Euphoric mania (with expansivity and elation)
 Irritable/dysphoric mania (with anger or
aggressiveness) (8).
 Aripiprazole, asenapine, carbamazepine, olanzapine, and
ziprasidone show the strongest evidence of efficacy in acute-
DSM-V dimensional “mixed features” specifier (≥3
phase treatment of mixed mania (16,17).
depressive symptoms during a manic episode) (9)
 Combination therapies are frequently required, particularly in
Mixed features  The DSM-V classification still remains a matter of
severe cases (18,19).
controversy and debate (10).
 Olanzapine and quetiapine (as monotherapy and in combination
 30% prevalence of mixed manic episodes (11) with
with lithium/divalproex) show the strongest evidence of efficacy
variations according to the criteria applied (12,13).
as maintenance treatments (12,20).
 More severe and disabling course (higher suicidality,
substance abuse, etc.) (14).
 The mixed presentation of mania is important for
diagnosis and has key treatment implications (15).
Anxiety symptoms are highly prevalent during mania and are
Use treatments with specific anxiolytic benefits:
predictors of worse outcome (21):
 Mood stabilizers: divalproex and carbamazepine (GABAergic
 More severe manic symptoms
Anxious distress properties) (23).
 Longer time to remission
 Antipsychotics: olanzapine and quetiapine (histaminergic
 More reported side effects of medication (22).
affinity) (23–25).
 Commonly associated with mixed states.
The course of BD is chronic and widely variable. The inter-individual
Course specifiers variablity and precise characterization have led to the establishment of
the following course specifiers:
The PP of episodes in BD appears to have important clinical
and therapeutic implications (26).
Operative definition: ≥2/3 lifetime episodes of one polarity
(27).
The polarity index (PI) (Figure 1B) is a metric used to classify
Around 50% of BD patients present a predominant polarity.
maintenance therapies (31,32):
In BD-I (28):
 predominant antimanic prophylactic profile
Predominant polarity  manic PP ~ 30%
 antidepressant prophylactic profile.
(PP)  depressive PP ~ 40%
Different prevalences in BD-II (26).
The PP is considered in most international guidelines for the choice of
Most individuals with BD, over the long term, will spend at
long-term treatment on BD (33–37)
least half their lives with some degree of depressive
symptomatology (29). In 20 years of follow-up, depressive
symptoms predominated over (hypo)manic symptoms with
a ratio of 3 to 1 in BD-I (30).
≥ 4 mood episodes per year (9)
 with partial or full remissions in between  No evidence for the superiority of any first-line treatment in
 or switch to the opposite polarity addressing acute manic episodes in rapid-cycling BD patients
≥ 1/3 of BD-I patients (38) (41).
Rapid cycling More severe BD subtype (38)
 medical comorbidities  Combinations of mood-stabilizing drugs may be necessary as
 suicidal risk (39) maintenance treatment (42).
 poorer outcomes (39)
 worse response to pharmacological treatment (40)
It has not proven useful in guiding pharmacological choice in mania
Seasonal pattern Present in more than 20% of BD (43)
(34,43).
Patient factors
Current episode severity  These are key factors to target the pharmacological treatment
Longitudinal course of illness and the dose required (34).
Disease severity  number of episodes  Severely ill manic patients will mostly need the combination of
 severity of relapses AP and MS.
 durations of euthymia
Somatic comorbidities
 Associated current treatments
 2-to-3-increased mortality rate (44)
 Potential pharmacokinetic issues
Comorbidities  7-to-24 years shortened life expectancy (45)
 Drug-drug interactions
 Mostly cardiovascular diseases (CVD) (46) and
 Side effects
metabolic syndrome (47).
Psychiatric comorbidities (48)  Need for ongoing monitoring
 Including:
o anxiety disorders
o substance use disorders
o attention‐deficit/hyperactivity disorder
o personality disorders
 Poorer outcomes
 More difficult diagnosis and management
Current treatment
 periods of stability reached
 Personalized and precise recommendations
 tolerability
 Consider reinstatement of treatment versus add-on or switch
Treatment Treatment history
strategies (balancing the need for polytherapy)
 level of response to different drugs in the past
 Consider long-acting injectables if poor adherence
 history of relapses on different drugs
 tolerability of different drugs
The staging model in BD (59) considers the need of different approaches
Progressive and deteriorating course of BD (regarding according to the evolutive stage of BD, with a special focus on the initial
clinical, neuroimaging and neurocognition) (49): phases and the number of episodes (49). This model can help to refine
 Increased duration and symptomatic severity after diagnosis, adjust prognosis and choose the best treatment according to
the first episode (50) illness stage (60):
 More comorbidities and suicidal risk (51)
 Weaker response to pharmacological and  Prodromal stages: reducing stressors and increasing coping skills.
psychological treatments (52,53), even response to  Early stages: psychoeducation and simpler pharmacological
lithium (54) regimens (61).
 Brain atrophy after multiple manic episodes (55)  Mid-stages: more intensive psychotherapies and more complex
The stage of disease  Reduction of cognitive performance leading to pharmacotherapies (62).
functional disability (56).  Chronic stages: clozapine or functional remediation therapies
All these alterations seem to be a consequence of (63,64).
progressive changes in the central nervous system due to  Refractory illness: “palliative” approaches (reduction of side-
subsequent mood episodes in BD. This phenomenon has effects and unnecessary polypharmacy, limited symptom control,
been called neuroprogression (57) and several possible targeting psychological and social problems, and setting realistic
pathways have been suggested as a neurobiological goals to aim for the best quality of life for people and their
explanation, including inflammation, oxidative stress, families within the envelope of their disability (65).
neurotrophins imbalance, mitochondrial dysfunction and
epigenetics (58). However, even if the staging model proposes stage-targeted treatments
that might provide a better clinical outcome with less side effects, there
are still differences among the patients of a particular stage. Therefore,
the “treatment based on stages” may not be useful for every patient at
a particular stage, and should be combined with “treatment based on
patients’ characteristics” in order to increase the level of precision and
achieve an even more personalized approach (66).
Abbreviations: SGA: second generation antipsychotic.
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acps_13209_f1.pdf
Antidepressant
Accepted Article
A Schizoaffective
psychosis
B
Mood stabilizers
predominance
0.1
Antipsychotics
Lurasidone
Mood-
is
Ps
incongruent
os Lamotrigine
yc
h
yc
h
os
Ps Quetiapine
is
Severity of episode
Mood-congruent
Similar relative efficacy Asenapine
in prevention of 1
mania and depression Olanzapine
Mania
1
Mixed Depression 1
Lithium Ziprasidone
Aripiprazole
Risperidone
15 Paliperidone
Antimanic
Euthymia predominance
Figure 1. Clinical specifiers on manic episode characterization. A. The detailed characterization about the nature of the
symptoms of a manic episode is key in selecting an adequate treatment. The presence of mood-incongruent psychotic
features (represented in Y-axis) and mixed features (represented in X-axis) are associated with more severe episodes and
therefore require specific treatment, usually the combination of antipsychotics and mood stabilizers. B. Polarity index.
The polarity index of drugs is a metric used to guide the maintenance treatment of patients with BD. It classifies therapies
as those with an antimanic prophylactic effect and those with an antidepressant prophylactic effect. It is the ratio of the
number of patients needed to treat for prevention of depression to the number of patients needed to treat for prevention
of mania on the basis of results of randomized placebo-controlled trials 1,2. A polarity index of 1 reflects an equal efficacy
in preventing manic and depressive episodes.
1. Popovic D, Reinares M, Goikolea JM, Bonnin CM, Gonzalez-Pinto A, Vieta E. Polarity index of pharmacological
agents used for maintenance treatment of bipolar disorder. Eur Neuropsychopharmacol. 2012;22(5):339-346.
doi:10.1016/j.euroneuro.2011.09.008
2. Vieta E, Berk M, Schulze TG, et al. Bipolar disorders. Nat Rev Dis Prim. 2018;4:18008. doi:10.1038/nrdp.2018.8

acps_13209_f2.docx
Accepted Article
Figure 2. Tentative treatment algorithms during a manic episode according to different clinical
presentations. A. Mood stabilizer choice for acute manic episodes. B. Antipsychotic choice for acute
manic episodes.
CBZ: carbamazepine; DVP: divalproex; ECT: electroconvulsive therapy; LAI: Long-acting injectables; MS:
mood stabilizer; SGA: second-generation antipsychotic.
† Contraindications for lithium: previous non-response, renal failure, severe dermatological disease,
severe gastrointestinal intolerance, cardiovascular insufficiency, Addison’s disease or/and untreated
hypothyroidism.
‡ In case of refractory mania, it is mandatory to: firstly, ensure adherence and adequate dosing; second,
to assess comorbidities, drug abuse or treatment interactions; third, consider performing a
pharmacogenetic study on cytochrome P450 enzymes.
§ Lamotrigine has not proven efficacious in the treatment of acute mania, so that it should be used as
add-on treatment with antipsychotics aiming at maintenance prevention of depressive episodes
specially in case of childbearing women or in case of non-severe hypomania.

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DR GERARD ANMELLA (Orcid ID : 0000-0002-6798-4054)

DR LLUC COLOMER (Orcid ID : 0000-0001-9964-0822)

PROFESSOR EDUARD VIETA (Orcid ID : 0000-0002-0548-0053)

Article type : From Research to Clinical Practice

How to treat mania

Key words: bipolar, mania, treatment, mood stabilizer, antipsychotic.

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Aims of the study

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(1) Management of manic agitation

exposed in Tables 1-2.

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(2) Management of the acute manic phase

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Monotherapy versus Polytherapy

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Second-line treatments (add-on/switch)

Third-line treatments (add-on/switch)

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(3) Maintenance therapy after acute manic episode

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After an acute manic episode, if a patient has responded to a non-first-line maintenance

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Evidence-based clinical recommendations concur that it is mandatory to stop divalproex during

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Finally, ECT is recommended for severe or refractory symptoms 62.

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