Author's Accepted Manuscript

The pharmacodynamic properties of lurasidone

and their role in its antidepressant efficacy in
bipolar disorder
Konstantinos N. Fountoulakis, Maria Gazouli,
John Kelsoe, Hagop Akiskal

www.elsevier.com/locate/euroneuro

PII: S0924-977X(14)00321-6
DOI: http://dx.doi.org/10.1016/j.euroneuro.2014.11.010
Reference: NEUPSY10931

To appear in: European Neuropsychopharmacology

Received date: 5 May 2014

Revised date: 18 October 2014
Accepted date: 20 November 2014

Cite this article as: Konstantinos N. Fountoulakis, Maria Gazouli, John Kelsoe,
Hagop Akiskal, The pharmacodynamic properties of lurasidone and their role in
its antidepressant efficacy in bipolar disorder, European Neuropsychopharmacol-
ogy, http://dx.doi.org/10.1016/j.euroneuro.2014.11.010

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The pharmacodynamic properties of lurasidone and their role in its antidepressant efficacy
in bipolar disorder

Konstantinos N. Fountoulakis
Associate Profesor, 3rd Department of Psychiatry, School of Medicine, Aristotle University of
Thessaloniki, Greece
kfount@med.auth.gr

Maria Gazouli
Department of Basic Biological Science, Laboratory of Biology, school of Medicine, University
of Athens, Greece
maria.gazouli@gmail.com

John Kelsoe
Profesor, Department of Psychiatry, Director, Laboratory of Psychiatric Genomics, University of
California, San Diego and VA San Diego Healthcare System, La JollaCA, USA
jkelsoe@ucsd.edu

Hagop Akiskal
Distinguished Profesor, International Mood Disorders Center, University of California at San
Diego, CA, USA
hakiskal@ucsd.edu

Address for Communication

Konstantinos N. Fountoulakis MD
6, Odysseos str (1st Parodos Ampelonon str.),
55535 Pylaia Thessaloniki, Greece
Tel: +30 2310 435702
fax: +30 2310 266570
e-mail: kfount@med.auth.gr

number of words in the abstract: 212

number of words in the text: 2904
number of tables: 1
number of figures: 2
number of supplementary material: 0

key words: lurasidone, bipolar depression, neurobiology, biologica models

Fountoulakis et al Lurasidone in bipolar depression

Abstract

The treatment of bipolar depression is one of the most challenging issues in contemporary

psychiatry. Currently only quetiapine, the olanzapine-fluoxetine combination and recently

lurasidone are officially FDA-approved against this condition. The neurobiology of bipolar

depression and the possible targets of bipolar antidepressant therapy remain elusive. The current

study investigated whether the pharmacodynamic properties of lurasidone fit to a previously

developed model which was the first to be derived on the basis of the strict combination of

clinical and preclinical data with no input from theory or opinion. The authors performed a

complete and systematic review of the literature to identify the pharmacodynamic properties of

lurasidone. The original model suggests that a constellation of effects on different receptors are

necessary but the serotonin reuptake inhibition does not seem to play a significant role for

bipolar depression. On the contrary norepinephrine activity seems to be very important. Probably

the early antidepressant effect can be achieved through an agonistic activity at 5HT-1A and

antagonism at alpha1 noradrenergic and 5-HT2A receptors, but the presence of a norepinephrine

reuptake inhibition is essential in order to sustain it. Overall the properties of lurasidone fit well

the model and add to its validity. A point that needs clarification is norepinephrine reuptake

inhibition which is not yet studied for lurasidone.

Key Words: lurasidone, aniconvulsants, antidepressants, antipsychotics, bipolar disorder,

evidence-based, lithium, mood stabilizers, treatment, depression, serotonin, serotonine reuptake,

norepinephrine reuptake

2
Fountoulakis et al Lurasidone in bipolar depression

Introduction

Bipolar Depression is the phase bipolar disorder (BD) which is the most refractory to treatment

and responsible for most of observed global disability in BD patients (Calabrese et al., 2004;

Judd and Akiskal, 2003; Judd et al., 1998; Judd et al., 2002; Post, 2005). However, in spite of

this fact, only recently its treatment has become a major focus of research, and still is far behind

the manic phase as a research priority. This is partially because until recently our knowledge

concerning BD was essentially limited and the efficacy of the so-called ‘mood stabilizing agents’

was overvalued. Unfortunately, in this frame, bipolar depression was erroneously believed either

to respond to the traditional ‘mood stabilizers’ or it was considered to be similar to unipolar

depression and thus it was treated accordingly. The above are reflected in most treatment

guidelines (Fountoulakis et al., 2007a; Fountoulakis and Vieta, 2008; Fountoulakis et al., 2005;

Fountoulakis et al., 2007b). Therefore, it is of prime importance that recently, lurasidone was the

third agent after quetiapine and the olanzapine-fluoxetine combination which received official

approval by the Food and Drug Administration (FDA) for the treatment of bipolar depression.

It is unfortunate that the neurobiology of bipolar depression still remains elusive, and this

deprives pharmacologic research from a driving theory to rely on and develop new treatment

options. While for unipolar depression there is a strong hypothesis which is based mainly on

treatment data (TCAs and SSRIs), and involves primarily the serotonergic system in the brain,

this hypothesis is problematic concering bipolar depression since antidepressants are generaly

proven ineffective against bipolar depression. A detailed discussion on the role of

3
Fountoulakis et al Lurasidone in bipolar depression

antidepressants in the treatment of bipolar depression can be found elsewhere (Pacchiarotti et al.,

2013).

The were have been some efforts till now to develop a neurobiological theory concerning bipolar

depression and its treatment. In the first, Yatham et al (Yatham et al., 2005) proposed the 5HT-

1A receptor as the most likely target. In another one Brugue et al suggested there is an

involvement of dopaminergic activity also (Brugue and Vieta, 2007). On the basis of quetiapine

data alone, Jesten et all proposed that norepinephrine reuptake and 5HT-1A receptors mediate

the antidepressant effect of quetiapine (Jensen et al., 2008). However at that time there was not

enough scientific knowledge to arrive at a reliable conclusion. The available data today do not

support such an assumption, since that the receptor is activated by a number of compounds

which were proven not to be efficacious in the treatment of bipolar depression. These include

aripiprazole, lamotrigine, ziprasidone and others.

The second theory is the only evidence-based model until today and was proposed by

Fountoulakis et al (Fountoulakis et al., 2012b). According to this model (which will be described

in detail in the discussion section) norepinephrine reuptake and 5HT-1A agonism are central and

closer to the core deficit in bipolar depression. This is in accord with both a norepinephrine and

serotonin hypoactivity. A second line of neurotransmitter regulation includes 5HT-2A blockade

(which further increases serotonin activity). The presence of anticholinergic activity might shift

the balance between norepinephrine and acetylcholine further in favour of norepinephrine

without the need for an excessive increase in norepinephrine function. If such an excessive

increase happens, the risk for switching to mania/hypomania increases. D2 and D3 blockade acts

possibly as an antidepressant mechanism. D3 blockade increases dopaminergic activity while D2

blocade has variable effects depending on whether the receptor is pre-or post-synaptic. At a third

4
Fountoulakis et al Lurasidone in bipolar depression

level, alpha-1 blockade further increases norepinephrine function when necessary, and D1

blockade decreases dopamine function and thus exerts an antimanic action. At the same level

regulation of histaminergic activity might play an antimanic role possibly via sedation. A graphic

representation of the model is shown in figure 1.

The complete pharmacodynamic properties of the various agents which contributed in the

development of the model are shown in table 1, as these were identified in the original paper

which concerned the development of the model (Fountoulakis et al., 2012b).

Chemically, lurasidone or (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-

1-ylmethyl] cyclohexylmethyl} hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride is

structurally related to perospirone and ziprasidone, risperidone, paliperidone, and iloperidone

(Caccia et al., 2012).

The aim of the current article was to systematically search and analyze whether the efficacy of

lurasidone against bipolar depression is compatible with the neurobiological model we had

proposed and whether it adds to our current neurobiological understanding of BD. This paper

will compare the pharmacodynamic profile of lurasidone in relationship to the pharmacodynamic

properties of agents with definitely positive and negative treatment data, as well as against the

neurobiological model previously proposed. The hypothesis is that lurasidone should act as 5HT-

1A agonist, norepinephrine reuptake blocker and antagonist at alpha1 noradrenergic, 5-HT2A,

and D1, D2 and D3 as well as muscarinic and H1 histamine receptors.

Experimental Procedures

5
Fountoulakis et al Lurasidone in bipolar depression

The current paper built further on the results of the previously published paper by the same

authors.

The data concerning lurasidone were searched with the use of the keywords ‘lurasidone’ and

‘SM-13496’ separately in MEDLINE. The search was last time performed in October 15th 2014.

The method was over-inclusive and aimed to identify all studies published concerning lurasidone

for any reason. The PRISMA method was followed in the selecton of relevant studies.

Also the data concerning the effect of olanzapine, quetiapine and fluoxetine on the 5HT-7

receptor with searched with the combination of the drug name plus the receptor name.

Results

The MEDLINE search returned 304 articles and after discarding dublicate records 152 articles

remained. The PRISMA flowchart concerning the process of selecting those papers which were

relevant is shown in figure 2. Eventually 17 of them had direct relevance to lurasidone’s

pharmacodynamics properties

According to the review of the literature, lurasidone acts as a high-affinity blocker concerning

D2 (Caccia et al., 2012; Cruz, 2011; Guay, 2011; Ishibashi et al., 2010; Meyer et al., 2009;

Nakazawa et al., 2013; Potkin et al., 2014; Tarazi and Riva, 2013; Wong et al., 2013), 5HT-2A

(Caccia et al., 2012; Cruz, 2011; Guay, 2011; Hopkins, 2011; Ichikawa et al., 2012; Ishibashi et

al., 2010; Meyer et al., 2009; Nakazawa et al., 2013; Tarazi and Riva, 2013), 5HT-7 (Caccia et

al., 2012; Cates et al., 2013; Guay, 2011; Hopkins, 2011; Horisawa et al., 2011; Horisawa et al.,

2013a; Horisawa et al., 2013b; Huang et al., 2012; Ichikawa et al., 2012; Ishibashi et al., 2010;

Ishiyama et al., 2007; Meyer et al., 2009; Nakazawa et al., 2013; Tarazi and Riva, 2013), and

6
Fountoulakis et al Lurasidone in bipolar depression

Į2c-adrenergic receptors (Caccia et al., 2012; Cruz, 2011; Guay, 2011; Hopkins, 2011; Ishibashi

et al., 2010; Ishiyama et al., 2007; Meyer et al., 2009; Tarazi and Riva, 2013). It is a high-affinity

partial agonist for 5HT-1A receptors (Caccia et al., 2012; Cruz, 2011; Guay, 2011; Hopkins,

2011; Horisawa et al., 2011; Huang et al., 2012; Ishibashi et al., 2010; Ishiyama et al., 2007;

Meyer et al., 2009; Nakazawa et al., 2013; Tarazi and Riva, 2013). It binds as an antagonist with

low affinity to D3 (Meyer et al., 2009; Nakazawa et al., 2013), Į2ǹ (Caccia et al., 2012; Cruz,

2011; Guay, 2011; Meyer et al., 2009; Tarazi and Riva, 2013), and Į1-adrenergic receptors

(Caccia et al., 2012; Guay, 2011; Ishibashi et al., 2010; Meyer et al., 2009; Tarazi and Riva,

2013). It is also a low affinity for 5-HT2C (Caccia et al., 2012; Ishibashi et al., 2010) , and acts

as antagonist on D1 receptors (Meyer et al., 2009). It manifests a weak blocking effect on

histamine H1 (Caccia et al., 2012; Ichikawa et al., 2012; Ishibashi et al., 2010; Meyer et al.,

2009) and negligible affinity for muscarinic receptors (Caccia et al., 2012; Ichikawa et al., 2012;

Ishibashi et al., 2010; Meyer et al., 2009).

Lurasidone manifests negligible binding affinity for 5-HT3, 5-HT4, noradrenaline ȕ, ȕ1, ȕ2,

adenosine A1, A2, benzodiazepine, cholecystokinin CCKA, CCKB, L-type Ca2+ channel, N-

type Ca2+ channel, GABAA, glutamate AMPA, kainate, NMDA, glycine, nicotine, opiate,

sigma, 5-HT uptake sites, and dopamine uptake sites (Caccia et al., 2012). It is interesting that

there seems to be no affinity of lurasidone for the D4 receptor (Murai et al., 2014).

Furthermore, the results from the acute models strongly suggest that the antidepressant effect of

lurasidone requires functional 5-HT7 receptors (Cates et al., 2013), but this is not relevant with

the model under testing.

No papers were found concerning the effect of olanzapine, quetiapine and fluoxetine on the

5HT-7 receptor

7
Fountoulakis et al Lurasidone in bipolar depression

The results tabulated by compound receptors are shown in table 1.

Discussion

The results of the current study confirm the hypothesis that lurasidone acts as parial agonist at

5HT-1A and antagonist at alpha1 noradrenergic, 5-HT2A, and D1, D2 and D3 and H1 but has

negligible affinity for muscarinic receptors. It is not known whether it has any effect on

norepinephrine reuptake. Its receptor affinity profile seems to be close to that of aripiprazole and

maybe to olanzapine, with the reservation concerning norepinephrine reuptake. A significant

problem in the interpretation of the data is that the positive lurasidone monotherapy trial in

bipolar depression had a duration of only 6 weeks (Loebel et al., 2013). This should be a matter

of caution since in the negative trials of aripiprazole (Thase et al., 2008) and ziprasidone

(NCT00141271), the results were positive at week 6, only to collapse afterwards. However the

magnitude of improvement and the absolute values of the change in the MADRS scores in the

lurasidone and placebo groups support the efficacy of lurasidone, since they are similar to the

results of the respective quetiapine trials.

In the frame of the above, the recent positive data concerning lurasidone, viewed in combination

with the data concerning also aripiprazole and ziprasidone, suggest that the early antidepressant

effect in bipolar depression (until week 6) (Cruz et al., 2010; Vieta, 2010a, b; Vieta et al., 2010)

can be achieved through an agonistic activity at 5HT-1A and antagonism at alpha1 noradrenergic

and 5-HT2A receptors. Unfortunately, the need for the presence of a norepinephrine reuptake

inhibition in order to sustain the antidepressant effect can neither be confirmed nor rejected by

the lurasidone data. On the contrary the lurasidone data reject the usefulness of a blocking effect

8
Fountoulakis et al Lurasidone in bipolar depression

on histamine receptors. Overall, the positive data of lurasidone add validity to the model

previously published by our group (Fountoulakis et al., 2012b). However we were not able to test

the possible role of 5HT-7 which is supposed to be responsible for the antidepressant efficacy of

lurasidone. There are no data in the literature concerning the possible effect of olanzapine,

quetiapine and fluoxetine on this receptor, therefore it can not be part of the proposed model.

It is very important to point out that the data so far and subsequently the model proposed by us,

drive the focus away from serotonin reuptake and the classic view of antidepressants. It is clear

that quetiapine and lurasidone have no effect on serotonin reuptake and antidepressants with the

exception of fluoxetine do not exert an antidepressant effect in BD patients either as

monotherapy or in combinations with other agents.

Overall the model for the antidepressant pathways in bipolar depression is not unidimentional

but instead it consists of multiple pathways of actions, maybe with connections and feedback

between them. Probably (as mentioned in the original publication) norepinephrine reuptake and

5HT-1A agonism are core elements in this pathway and this is suggestive of both a

norepinephrine and serotonin hypoactivity in bipolar depression. A second line of regulation

includes 5HT-2A blockade (which probably further increases serotonin activity). Anticholinergic

activity might restore the balance between norepinephrine and acetylcholine without the need for

an excessive increase in norepinephrine function, thus adding to the long term stability of the

antidepressant effect. If such an excessive increase happens, the risk for switching to

mania/hypomania increases, and then D2 and D3 blockade acts as a protective mechanism.

However this blockade might simply serve the restoration of the balance between

acetylcholine/dopamine after the reduction of muscarinic activity. At a third and final level,

alpha-1 blockade further increases norepinephrine function when necessary, and D1 blockade

9
Fountoulakis et al Lurasidone in bipolar depression

regulates dopamine function. Although initially histamine was believed to play an important role

at this last stage, the lurasidone data dispute it. An important feature of this model is that it points

to the need for the restoration and maintenance of the balance between

norepinephrine/acetylcholine and acetylcholine/dopamine as a prerequisite for the sustainability

of the antidepressant effect in a ‘tripolar’ treatment model for bipolar illness (Fountoulakis et al.,

2012b).

This model is also in accord with the temperament theory for bipolar spectrum disorders,

predicting a depressive (5-HT axis), a cyclothymic (norepinephrine- dopamine axis) and an

irritable (acetylcholine-norepinephrine) dimension within bipolar depression. Interestingly, after

the publication in 1962 of the first suggestion that an imbalance between norepinephrine and

acetylcholine could underlie psychotic disorders (Rubin, 1962) and its refinement during the ‘70s

(Davis and Berger, 1978; Davis et al., 1975; Siever et al., 1981; Yudofsky, 1976), the subsequent

failed trials with anticholinergic agents as add-on treatment led to the conclusion that cholinergic

supersensitivity represented probably a ‘personality factor’ in depressed patients (Bymaster and

Felder, 2002; Fritze, 1993).

Concerning the role of serotonin pathways, which are considered to play the major role in the

treatment of unipolar depression, what emerges as a core conclusion is that serotonin reuptake is

neither sufficient nor necessary as a condition for the antidepressant efficacy in bipolar

depression. It is clear that no class effect exists in the treatment of bipolar depression and this

concerns especially antidepressants (Fountoulakis et al., 2011a; Fountoulakis et al., 2012a; Rosa

et al., 2011). Only 5HT-1A activation and 2A blockade are necessary, and this is in accord with

the model proposed by Yatham et al (Yatham et al., 2005). However although these actions are

necessary they are not sufficient, but the role of dopamine does not seem to be as central as

10
Fountoulakis et al Lurasidone in bipolar depression

Brugue et al suggested (Brugue and Vieta, 2007). Another core conclusion is that norepinephrine

activity is also absolutely necessary probably in order to sustain the antidepressant effect, and

this is in accord with the suggestions by Jensen et al (Jensen et al., 2008).

The literature provides further although indirect support for this model, since it has been reported

that both serotonin and norepinephrine are lower in the locus ceruleous of bipolar patients who

died from suicide (Wiste et al., 2008) and that norepinephrine might play a more important role

than serotonin in the pathophysiology of bipolar disorder (Young et al., 1994). Additionally, it

has been proposed that the antidepressant activity of quetiapine is mediated, at least in part, by its

metabolite N-Desalkylquetiapine through norepinephrine reuptake inhibition and partial 5-

HT(1A) agonism (Jensen et al., 2008). Chronic administration of olanzapine alone significantly

increased the firing of locus cerouleous (LC) neurons, while, chronic administration of fluoxetine

alone significantly reduced the firing of LC neurons. It seems that in the combination condition

(OFC), olanzapine was able to block the fluoxetine-induced suppression of the LC, and thus a

significant increase in LC activity has been reported (Seager et al., 2005; Seager et al., 2004)

As already mentioned in the original paper (Fountoulakis et al., 2012b) the major advantage in

our effort to develop a model for the antidepressant pathways in bipolar depression was that the

authors followed a systematic review of the literature and derived conclusions after the analysis

of the results in an evidence-based approach. This effort constituted an attempt to combine RCTs

results and basic research data in a systematic and analytical way in order to develop a

comprehensive disease and treatment model in psychiatry.

The disadvantages include a number of methodological issues and literature publication bias and

gaps in knowledge. Efficacy data concerned only 8 medications and one combination with

adequate positive or negative data. The RCT trial of lurasidone lasted only 6 weeks and in view

11
Fountoulakis et al Lurasidone in bipolar depression

of the aripiprazole and ziprasidone negative trials one should be reserved towards any final

conclusions. Pharmacodynamic data were not available to the same extend for all 8 medications

and mostly concern animal and not human studies. Some of them (e.g. olanzapine and

fluoxetine) are extensively studied; others (e.g. aripiprazole) are studied to a lesser extend,

maybe because they appeared more recently. Data concerning lurasidone are limited and it is not

known whether it exerts any effect on norepinephrine reuptake. Also, negative studies

concerning pharmacodynamic properties might be less likely to be published and the literature is

somewhat fussy in many areas. The authors included only papers that clearly showed that a

compound binds to a specific receptor, or inhibits an enzyme or reuptake directly directly.

However there are many papers suggesting changes in the number or sensitivity of receptors or

in mRNA or other indirect evidence of modification of a specific receptor function. However this

evidence does not necessarily imply a direct effect; in many cases it is indirect and it is mediated

through other receptors (Tarazi et al., 2003). Another unsolved issue is the regional specificity; a

compound could have opposite effects on a specific neurotransmitter in different brain regions,

and this could be due to different patterns of receptors distribution in different regions of the

brain (Gessa et al., 2000). In the meantime data positive on olanzapine monotherapy have

emerged (Tohen et al., 2013; Tohen et al., 2012) however the effect size is around 0.17, which is

similar to that supposed for aripiprazole (Fountoulakis et al., 2011b), the data are overall

inconsistent and of questionable clinical utility. Further study on whether these results should

affect the model proposed for the mode of action of treatment against bipolar depression is

necessary.

Another issue is the effect lurasidone has on 5HT-7 receptors. Since there are no data from other

compounds on this class of receptors and it is not included in the current model, there is no way

12
Fountoulakis et al Lurasidone in bipolar depression

to test whether the 5HT-7 plays any role in the antidepressant action of lurasidone, which

however can not be ruled out.

However in spite of the above limitations, the authors consider that the model developed is the

most complete effort to indentify targets and pathways for the antidepressant treatment in bipolar

depression. It has been developed on the basis the clinical and pharmacodynamic data of 7 agents

and confirmed with the current paper by the respected data on lurasidone.

Conflict of interest

Dr Fountoulakis is/was member of the International Consultation Board of Wyeth for

desvenlafaxine, BMS for aripiprazole in bipolar disorder and Servier for agomelatine and has

received honoraria for lectures from AstraZeneca, Janssen-Cilag, Eli-Lilly and research grants

from AstraZeneca and Pfizer Foundation

Dr Gazouli has no conflict of interest relevant to the current study

Dr Kelsoe is a consultant for Psynomics, Astra-Zeneca and Merck. The terms of this

arrangement have been reviewed and approved by UCSD in accordance with its conflict of

interest policies.

Dr Akiskal has no conflict of interest relevant to the current study

The authors have no other relevant affiliations or financial involvement with any organization or

entity with a financial interest in or financial conflict with the subject matter or materials

discussed in the manuscript apart from those disclosed.

Awknowledgement

13
Fountoulakis et al Lurasidone in bipolar depression

None

Sources of funding

None

Conflict of interest: none concerning the current paper

14
Fountoulakis et al Lurasidone in bipolar depression

agent

Aripiprazole
Buproprion
Lamotrigine
Paroxetine
Ziprasidone
Olanzapine
Fluoxetine
Quetiapine
OFC
Lurasidone
% for positive agents *
% for negative agents *
Difference in % *

Antidepressant
Neg Neg Neg Neg Neg Neg Neg Pos Pos Pos
efficacy
Serotonin + - + + + - + - + - 50 71 21
Norepinephrine - + + + + - + + + ? 100 71 29
Reuptake
Dopamine - + + - - - - - - - 0 29 29
inhibition
Glutamate - - - - - - - - - - 0 0 0
GABA - - - - - - - - - - 0 0 0
1A Pa A A - A A - A A Pa 100 71 29
1B - - - - Pa B - - B - 50 14 36
Serotonin receptors 2A B - - - B B - B B B 100 43 57
2C B - - - B B B - B - 50 57 7
3 - - - - - B B - B - 50 29 21
Alpha1 B - A - - B - B B B 100 29 71
Norepinephrine Alpha2 B A A - - - A B A B -
receptors Beta1 - - - - - A - - A - 50 14 36
Beta2 - - - - - A - - A - 50 14 36
Cholinergic Muscarinic - - - B - B B B B B 100 43 57
receptors Nicotinic - B A B - - B - B - 50 43 7
D1 - - - - B B - B B B 100 29 71
Dopamine
D2 Pb - - - B B - B B B 100 43 57
receptors
D3 Pb - - - B B - B B B 100 43 57

15
Fountoulakis et al Lurasidone in bipolar depression

Histamine
H1 B - - - - B - B B - 100 29 71
receptors
GABA- A - - B - - B B - B - 50 43 7
GABA
GABA-B - - - - - - B - B - 50 14 36
MAO- A - - - - - - B - B - 50 14 36
MAO
MAO-B - - - - - - B - B - 50 14 36
Melatonin M1 - - - - - - - - - - 0 0 0
receptors M2 - - - - - - - - - - 0 0 0
AchE - - - B - - B - B - 50 29 21
AMPA - - B - - - - - - - 0 14 14
Glutamatergic
NMDA - - B B - - B - B - 50 43 7
Sigma-1 - A - A - - A - A - 50 43 7
Sodium Channels - - B B - - B - B - 50 43 7
Calcium Channels - - B - - - B - B - 50 29 21
Epileptic activity ? Pro Anti Pro ? Pro Anti Pro ? ? ?

Table 1: Pharmacodynamic properties of compounds studied for the treatment of bipolar depression and different in % between those
with positive vs. those with negative data concerning efficacy
A: agonist B: blocker Pa: partial agonist Pb: partial blocker -: lack of effect +: inhibition

* Lurasidone is not included in the % figures.

Pro: refers to the tendency of the agent to induce epileptic seizures

Anti: refers to antiepileptic activity

16
Fountoulakis et al Lurasidone in bipolar depression

Figure 1: Schematic representation of levels of targeting for the treatment of bipolar depression.
As shown in the figure, the antimanic effect is mainly mediated by antidopaminergic activity,
probably on D1 receptors. All the other neurotransmitter systems but also D2 and D3
dopaminergic receptors are probably involved in the antidepressant effect.
Concentric cycles denote suggested levels of activity while the ovals denote bridges between
receptor systems (e.g. the connection between dopamine and norepinephrine is probably
mediated by acetylcholine). These theoretical bridges allow the functional interconnection of all
receptors in a single proposed model.

Figure 2: The PRISMA flowchart concerning the process of selecting those papers which were
relevant

References

Brugue, E., Vieta, E., 2007. Atypical antipsychotics in bipolar depression: neurobiological basis
and clinical implications. Prog Neuropsychopharmacol Biol Psychiatry 31, 275-282.
Bymaster, F.P., Felder, C.C., 2002. Role of the cholinergic muscarinic system in bipolar disorder
and related mechanism of action of antipsychotic agents. Mol Psychiatry 7 Suppl 1, S57-63.
Caccia, S., Pasina, L., Nobili, A., 2012. Critical appraisal of lurasidone in the management of
schizophrenia. Neuropsychiatr Dis Treat 8, 155-168.
Calabrese, J., Hirschfeld, R.M., Frye, M.A., 2004. Impact of depressive symptoms compared
with manic symptoms in bipolar disorder: results of a US community-based sample. The Journal
of clinical psychiatry 65, 1499-1504.
Cates, L.N., Roberts, A.J., Huitron-Resendiz, S., Hedlund, P.B., 2013. Effects of lurasidone in
behavioral models of depression. Role of the 5-HT(7) receptor subtype. Neuropharmacology 70,
211-217.
Cruz, M.P., 2011. Lurasidone HCl (Latuda), an Oral, Once-Daily Atypical Antipsychotic Agent
for the Treatment of Patients with Schizophrenia. P T 36, 489-492.
Cruz, N., Sanchez-Moreno, J., Torres, F., Goikolea, J.M., Valenti, M., Vieta, E., 2010. Efficacy
of modern antipsychotics in placebo-controlled trials in bipolar depression: a meta-analysis. Int J
Neuropsychopharmacol 13, 5-14.
Davis, K.L., Berger, P.A., 1978. Pharmacological investigations of the cholinergic imbalance
hypotheses of movement disorders and psychosis. Biol Psychiatry 13, 23-49.
Davis, K.L., Hollister, L.E., Berger, P.A., Barchas, J.D., 1975. Cholinergic imbalance hypotheses
of psychoses and movement disorders: strategies for evaluation. Psychopharmacol Commun 1,
533-543.
Fountoulakis, K.N., Gonda, X., Vieta, E., Rihmer, Z., 2011a. Class effect of pharmacotherapy in
bipolar disorder: fact or misbelief? Annals of general psychiatry 10, 8.
Fountoulakis, K.N., Grunze, H., Panagiotidis, P., Kaprinis, G., 2007a. Treatment of bipolar
depression: An update. J Affect Disord.
Fountoulakis, K.N., Kasper, S., Andreassen, O., Blier, P., Okasha, A., Severus, E., Versiani, M.,
Tandon, R., Moller, H.J., Vieta, E., 2012a. Efficacy of pharmacotherapy in bipolar disorder: a

17
Fountoulakis et al Lurasidone in bipolar depression

report by the WPA section on pharmacopsychiatry. European archives of psychiatry and clinical
neuroscience 262 Suppl 1, 1-48.
Fountoulakis, K.N., Kelsoe, J.R., Akiskal, H., 2012b. Receptor targets for antidepressant therapy
in bipolar disorder: an overview. J Affect Disord 138, 222-238.
Fountoulakis, K.N., Vieta, E., 2008. Treatment of bipolar disorder: a systematic review of
available data and clinical perspectives. Int J Neuropsychopharmacol 11, 999-1029.
Fountoulakis, K.N., Vieta, E., Sanchez-Moreno, J., Kaprinis, S.G., Goikolea, J.M., Kaprinis,
G.S., 2005. Treatment guidelines for bipolar disorder: a critical review. J Affect Disord 86, 1-10.
Fountoulakis, K.N., Vieta, E., Schmidt, F., 2011b. Aripiprazole monotherapy in the treatment of
bipolar disorder: a meta-analysis. J Affect Disord 133, 361-370.
Fountoulakis, K.N., Vieta, E., Siamouli, M., Valenti, M., Magiria, S., Oral, T., Fresno, D.,
Giannakopoulos, P., Kaprinis, G.S., 2007b. Treatment of bipolar disorder: a complex treatment
for a multi-faceted disorder. Annals of general psychiatry 6, 27.
Fritze, J., 1993. The adrenergic-cholinergic imbalance hypothesis of depression: a review and a
perspective. Rev Neurosci 4, 63-93.
Gessa, G.L., Devoto, P., Diana, M., Flore, G., Melis, M., Pistis, M., 2000. Dissociation of
haloperidol, clozapine, and olanzapine effects on electrical activity of mesocortical dopamine
neurons and dopamine release in the prefrontal cortex. Neuropsychopharmacology 22, 642-649.
Guay, D.R., 2011. Comment on the potential utility of the new atypical antipsychotic lurasidone
in the geriatric population. Consult Pharm 26, 579-582.
Hopkins, C.R., 2011. ACS chemical neuroscience molecule spotlight on latuda (lurasidone; SM-
13,496). ACS Chem Neurosci 2, 58-59.
Horisawa, T., Ishibashi, T., Nishikawa, H., Enomoto, T., Toma, S., Ishiyama, T., Taiji, M., 2011.
The effects of selective antagonists of serotonin 5-HT7 and 5-HT1A receptors on MK-801-
induced impairment of learning and memory in the passive avoidance and Morris water maze
tests in rats: mechanistic implications for the beneficial effects of the novel atypical
antipsychotic lurasidone. Behav Brain Res 220, 83-90.
Horisawa, T., Ishiyama, T., Ono, M., Ishibashi, T., Taiji, M., 2013a. Binding of lurasidone, a
novel antipsychotic, to rat 5-HT7 receptor: analysis by [3H]SB-269970 autoradiography. Prog
Neuropsychopharmacol Biol Psychiatry 40, 132-137.
Horisawa, T., Nishikawa, H., Toma, S., Ikeda, A., Horiguchi, M., Ono, M., Ishiyama, T., Taiji,
M., 2013b. The role of 5-HT7 receptor antagonism in the amelioration of MK-801-induced
learning and memory deficits by the novel atypical antipsychotic drug lurasidone. Behav Brain
Res 244, 66-69.
Huang, M., Horiguchi, M., Felix, A.R., Meltzer, H.Y., 2012. 5-HT1A and 5-HT7 receptors
contribute to lurasidone-induced dopamine efflux. Neuroreport 23, 436-440.
Ichikawa, O., Okazaki, K., Nakahira, H., Maruyama, M., Nagata, R., Tokuda, K., Horisawa, T.,
Yamazaki, K., 2012. Structural insight into receptor-selectivity for lurasidone. Neurochem Int
61, 1133-1143.
Ishibashi, T., Horisawa, T., Tokuda, K., Ishiyama, T., Ogasa, M., Tagashira, R., Matsumoto, K.,
Nishikawa, H., Ueda, Y., Toma, S., Oki, H., Tanno, N., Saji, I., Ito, A., Ohno, Y., Nakamura, M.,
2010. Pharmacological profile of lurasidone, a novel antipsychotic agent with potent 5-
hydroxytryptamine 7 (5-HT7) and 5-HT1A receptor activity. J Pharmacol Exp Ther 334, 171-
181.

18
Fountoulakis et al Lurasidone in bipolar depression

Ishiyama, T., Tokuda, K., Ishibashi, T., Ito, A., Toma, S., Ohno, Y., 2007. Lurasidone (SM-
13496), a novel atypical antipsychotic drug, reverses MK-801-induced impairment of learning
and memory in the rat passive-avoidance test. Eur J Pharmacol 572, 160-170.
Jensen, N.H., Rodriguiz, R.M., Caron, M.G., Wetsel, W.C., Rothman, R.B., Roth, B.L., 2008. N-
desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT1A agonist, as a
putative mediator of quetiapine's antidepressant activity. Neuropsychopharmacology 33, 2303-
2312.
Judd, L.L., Akiskal, H.S., 2003. The prevalence and disability of bipolar spectrum disorders in
the US population: re-analysis of the ECA database taking into account subthreshold cases. J
Affect Disord 73, 123-131.
Judd, L.L., Akiskal, H.S., Maser, J.D., Zeller, P.J., Endicott, J., Coryell, W., Paulus, M.P.,
Kunovac, J.L., Leon, A.C., Mueller, T.I., Rice, J.A., Keller, M.B., 1998. A prospective 12-year
study of subsyndromal and syndromal depressive symptoms in unipolar major depressive
disorders. Arch Gen Psychiatry 55, 694-700.
Judd, L.L., Akiskal, H.S., Schettler, P.J., Endicott, J., Maser, J., Solomon, D.A., Leon, A.C.,
Rice, J.A., Keller, M.B., 2002. The long-term natural history of the weekly symptomatic status
of bipolar I disorder. Arch Gen Psychiatry 59, 530-537.
Loebel, A., Cucchiaro, J., Silva, R., Kroger, H., Hsu, J., Sarma, K., Sachs, G., 2013. Lurasidone
Monotherapy in the Treatment of Bipolar I Depression: A Randomized, Double-Blind, Placebo-
Controlled Study. Am J Psychiatry.
Meyer, J.M., Loebel, A.D., Schweizer, E., 2009. Lurasidone: a new drug in development for
schizophrenia. Expert Opin Investig Drugs 18, 1715-1726.
Murai, T., Nakako, T., Ikeda, K., Ikejiri, M., Ishiyama, T., Taiji, M., 2014. Lack of dopamine D4
receptor affinity contributes to the procognitive effect of lurasidone. Behav Brain Res 261, 26-
30.
Nakazawa, S., Yokoyama, C., Nishimura, N., Horisawa, T., Kawasaki, A., Mizuma, H., Doi, H.,
Onoe, H., 2013. Evaluation of dopamine D(2)/D(3) and serotonin 5-HT(2)A receptor occupancy
for a novel antipsychotic, lurasidone, in conscious common marmosets using small-animal
positron emission tomography. Psychopharmacology (Berl) 225, 329-339.
Pacchiarotti, I., Bond, D.J., Baldessarini, R.J., Nolen, W.A., Grunze, H., Licht, R.W., Post, R.M.,
Berk, M., Goodwin, G.M., Sachs, G.S., Tondo, L., Findling, R.L., Youngstrom, E.A., Tohen, M.,
Undurraga, J., Gonzalez-Pinto, A., Goldberg, J.F., Yildiz, A., Altshuler, L.L., Calabrese, J.R.,
Mitchell, P.B., Thase, M.E., Koukopoulos, A., Colom, F., Frye, M.A., Malhi, G.S., Fountoulakis,
K.N., Vazquez, G., Perlis, R.H., Ketter, T.A., Cassidy, F., Akiskal, H., Azorin, J.M., Valenti, M.,
Mazzei, D.H., Lafer, B., Kato, T., Mazzarini, L., Martinez-Aran, A., Parker, G., Souery, D.,
Ozerdem, A., McElroy, S.L., Girardi, P., Bauer, M., Yatham, L.N., Zarate, C.A., Nierenberg,
A.A., Birmaher, B., Kanba, S., El-Mallakh, R.S., Serretti, A., Rihmer, Z., Young, A.H.,
Kotzalidis, G.D., MacQueen, G.M., Bowden, C.L., Ghaemi, S.N., Lopez-Jaramillo, C.,
Rybakowski, J., Ha, K., Perugi, G., Kasper, S., Amsterdam, J.D., Hirschfeld, R.M., Kapczinski,
F., Vieta, E., 2013. The International Society for Bipolar Disorders (ISBD) task force report on
antidepressant use in bipolar disorders. Am J Psychiatry 170, 1249-1262.
Post, R.M., 2005. The impact of bipolar depression. The Journal of clinical psychiatry 66, 5-10.
Potkin, S.G., Keator, D.B., Kesler-West, M.L., Nguyen, D.D., van Erp, T.G., Mukherjee, J.,
Shah, N., Preda, A., 2014. D2 receptor occupancy following lurasidone treatment in patients with
schizophrenia or schizoaffective disorder. CNS spectrums 19, 176-181.

19
Fountoulakis et al Lurasidone in bipolar depression

Rosa, A.R., Fountoulakis, K., Siamouli, M., Gonda, X., Vieta, E., 2011. Is anticonvulsant
treatment of mania a class effect? Data from randomized clinical trials. CNS neuroscience &
therapeutics 17, 167-177.
Rubin, L.S., 1962. Patterns of adrenergic-cholinergic imbalance in the functional psychoses.
Psychol Rev 69, 501-519.
Seager, M.A., Barth, V.N., Phebus, L.A., Rasmussen, K., 2005. Chronic coadministration of
olanzapine and fluoxetine activates locus coeruleus neurons in rats: implications for bipolar
disorder. Psychopharmacology (Berl) 181, 126-133.
Seager, M.A., Huff, K.D., Barth, V.N., Phebus, L.A., Rasmussen, K., 2004. Fluoxetine
administration potentiates the effect of olanzapine on locus coeruleus neuronal activity. Biol
Psychiatry 55, 1103-1109.
Siever, L.J., Risch, S.C., Murphy, D.L., 1981. Central cholinergic-adrenergic imbalance in the
regulation of affective state. Psychiatry Res 5, 108-109.
Tarazi, F.I., Baldessarini, R.J., Kula, N.S., Zhang, K., 2003. Long-term effects of olanzapine,
risperidone, and quetiapine on ionotropic glutamate receptor types: implications for
antipsychotic drug treatment. J Pharmacol Exp Ther 306, 1145-1151.
Tarazi, F.I., Riva, M.A., 2013. The preclinical profile of lurasidone: clinical relevance for the
treatment of schizophrenia. Expert Opin Drug Discov 8, 1297-1307.
Thase, M.E., Jonas, A., Khan, A., Bowden, C.L., Wu, X., McQuade, R.D., Carson, W.H.,
Marcus, R.N., Owen, R., 2008. Aripiprazole monotherapy in nonpsychotic bipolar I depression:
results of 2 randomized, placebo-controlled studies. J Clin Psychopharmacol 28, 13-20.
Tohen, M., Katagiri, H., Fujikoshi, S., Kanba, S., 2013. Efficacy of olanzapine monotherapy in
acute bipolar depression: a pooled analysis of controlled studies. J Affect Disord 149, 196-201.
Tohen, M., McDonnell, D.P., Case, M., Kanba, S., Ha, K., Fang, Y.R., Katagiri, H., Gomez, J.C.,
2012. Randomised, double-blind, placebo-controlled study of olanzapine in patients with bipolar
I depression. The British journal of psychiatry : the journal of mental science 201, 376-382.
Vieta, E., 2010a. Long-term treatment of bipolar depression and other issues. J Clin Psychiatry
71, e07.
Vieta, E., 2010b. Role of antidepressants in bipolar depression. J Clin Psychiatry 71, e21.
Vieta, E., Locklear, J., Gunther, O., Ekman, M., Miltenburger, C., Chatterton, M.L., Astrom, M.,
Paulsson, B., 2010. Treatment options for bipolar depression: a systematic review of
randomized, controlled trials. J Clin Psychopharmacol 30, 579-590.
Wiste, A.K., Arango, V., Ellis, S.P., Mann, J.J., Underwood, M.D., 2008. Norepinephrine and
serotonin imbalance in the locus coeruleus in bipolar disorder. Bipolar Disord 10, 349-359.
Wong, D.F., Kuwabara, H., Brasic, J.R., Stock, T., Maini, A., Gean, E.G., Loebel, A., 2013.
Determination of dopamine D2 receptor occupancy by lurasidone using positron emission
tomography in healthy male subjects. Psychopharmacology (Berl) 229, 245-252.
Yatham, L.N., Goldstein, J.M., Vieta, E., Bowden, C.L., Grunze, H., Post, R.M., Suppes, T.,
Calabrese, J.R., 2005. Atypical antipsychotics in bipolar depression: potential mechanisms of
action. The Journal of clinical psychiatry 66 Suppl 5, 40-48.
Young, L.T., Warsh, J.J., Kish, S.J., Shannak, K., Hornykeiwicz, O., 1994. Reduced brain 5-HT
and elevated NE turnover and metabolites in bipolar affective disorder. Biol Psychiatry 35, 121-
127.
Yudofsky, S., 1976. Adrenergic-cholinergic imbalance in affective disorders. Lancet 2, 1342-
1343.

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Role of funding source

NONE

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Fountoulakis et al Lurasidone in bipolar depression

Konstantinos N. Fountoulakis
Associate Profesor, 3rd Department of Psychiatry, School of Medicine, Aristotle University of
Thessaloniki, Greece
kfount@med.auth.gr

Maria Gazouli
Department of Basic Biological Science, Laboratory of Biology, school of Medicine, University
of Athens, Greece
maria.gazouli@gmail.com

John Kelsoe
Profesor, Department of Psychiatry, Director, Laboratory of Psychiatric Genomics, University of
California, San Diego and VA San Diego Healthcare System, La JollaCA, USA
jkelsoe@ucsd.edu

Hagop Akiskal
Distinguished Profesor, International Mood Disorders Center, University of California at San
Diego, CA, USA
hakiskal@ucsd.edu

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Fountoulakis et al Lurasidone in bipolar depression

AWKNOWLEDGMENT

NONE

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Fountoulakis et al Lurasidone in bipolar depression

CONFLICT OF INTEREST

Dr Fountoulakis is/was member of the International Consultation Board of Wyeth for

desvenlafaxine, BMS for aripiprazole in bipolar disorder and Servier for agomelatine and has

received honoraria for lectures from AstraZeneca, Janssen-Cilag, Eli-Lilly and research grants

from AstraZeneca and Pfizer Foundation

Dr Gazouli has no conflict of interest relevant to the current study

Dr Kelsoe is a consultant for Psynomics, Astra-Zeneca and Merck. The terms of this

arrangement have been reviewed and approved by UCSD in accordance with its conflict of

interest policies.

Dr Akiskal has no conflict of interest relevant to the current study

The authors have no other relevant affiliations or financial involvement with any organization or

entity with a financial interest in or financial conflict with the subject matter or materials

discussed in the manuscript apart from those disclosed.

24
Figure(s)
Figure(s)