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Feature Article
Mitochondrial Dysfunction and
New Therapeutic Targets in
Bipolar Affective Disorder
Iveta Fizikova, MD; and Jozef Dragasek, MD, PhD, MSc, MHA
Bipolar affective disorder (BAD) is a
complex illness encompassing varying
degrees of fluctuating disturbances of
emotions, behavior, thought, cognition,
and hedonic and motoric drive over the
course of a patient’s life. Mitochondrial
dysfunction may play an important role
in the pathophysiology of BAD. Mitochondrial dysfunction may explain the
repeatedly observed changes in the brain
of patients with BAD. In BAD, studies of
peripheral blood cells have shown changes in antioxidant enzymes, increased lipid
peroxidation, elevated levels of reactive
nitrogen species, and increased DNA and
RNA fragmentation. Early intervention is
important in slowing the progression of
BAD. Not all patients respond to treatment in the same way, but new treatments are expected to address these
clinical challenges. This article reviews the
hypothesis of mitochondrial dysfunction
and provides a new perspective on therapeutic targets in BAD. [Psychiatr Ann.
2017;47(2):100-104.]
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ABSTRACT
M
ood disorders such as bipolar affective disorder
(BAD) are severe, chronic,
and disabling psychiatric conditions
commonly associated with persistent
subsyndromal symptoms and frequent
episodic relapses. In addition, some
studies1,2 support the notion that mood
disorders are heterogeneous conditions
with a wide range of clinical features.
Iveta Fizikova, MD, is a Psychiatrist, Psychiatric Hospital of Professor Matulay. Jozef Dragasek,
MD, PhD, MSc, MHA, is an Assistant Professor of Psychiatry, 1st Department of Psychiatry, Pavol
Jozef Safarik University.
Address correspondence to Jozef Dragasek, MD, PhD, MSc, MHA, 1st Department of Psychiatry, Pavol Jozef Safarik University, Faculty of Medicine, Trieda SNP 1, 040 11, Kosice, Slovakia;
email: [email protected].
Disclosure: The authors have no relevant financial relationships to disclose.
doi: 10.3928/00485713-20170103-01
100
It has been increasingly recognized
that people with BAD are at a higher
risk for chronic general medical conditions, such as obesity, diabetes mellitus,
and cardiovascular diseases, which, in
turn, are directly associated with the
increased morbidity and mortality observed in BAD.1
MITOCHONDRIAL DYSFUNCTION
IN BIPOLAR AFFECTIVE DISORDER
Mitochondrial physiology is a
source of energy production. One of the
byproducts of oxidative phosphorylation is the production of reactive oxygen species (ROS), which are capable
of reacting with a wide variety of biological substrates, including proteins,
membrane lipids, and nucleic acids,
leading to cell damage and mutations.
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Kato et al.2 anticipated some of the
recent developments in the field when
they first proposed that mitochondrial
dysfunction might play an important
role in the pathophysiology of BAD.
Recently, there has been an increasing number of studies3,4 dealing
with the biochemical aspects of this
disorder. Results are based primarily
on studies5,6 in which magnetic resonance spectroscopy was used to show
some abnormalities of energy metabolism or improvement by treatment.
Table 1 shows the changes in brain
concentrations of certain molecules in
people with BAD.7,8
OXIDATIVE STRESS AND BIPOLAR
AFFECTIVE DISORDER
Oxidative damage results from
an overproduction of ROS that overwhelms cellular antioxidant capacity. Brain cells are more vulnerable
than other cells to oxidative damage.
This is because the brain, although it
constitutes less than 2% of total body
weight, consumes approximately 20%
of the body’s total oxygen.
Studies of peripheral blood cells
in BAD have shown changes in antioxidant enzymes, increased lipid peroxidation, elevated levels of reactive
nitrogen species, and increased DNA
and RNA fragmentation.3
ANTIOXIDANT ENZYMES AND
PROTEIN DAMAGE
In a study3 that focused on the
glutathione system (glutathione peroxidase [GPX], glutathione reductase
[GR], and glutathione-S-transferase
[GST]) and protein damage, activity of GR and GST was increased
and 3-nitrotyrosine levels were elevated in patients with late-stage
BAD (10-20 years of illness), compared with healthy participants.
In patients with early-stage BAD
(0-3 years), only an elevation of 3nitrotyrosine levels was found.
PSYCHIATRIC ANNALS • Vol. 47, No. 2, 2017
Protein oxidation, assessed as the
level of carbonylation and GPX activity, did not differ significantly between
patients in the early and late phases of
BAD and healthy controls.
LIPID PEROXIDATION
Increased lipid peroxidation and
decreased activity of the antioxidant
defense enzymes (superoxide dismutase and catalase) have been found
in the plasma of patients with BAD.3,9
Additionally, the expression of the
antioxidant enzyme GST A4 and M3
subtypes was found to be reduced in
postmortem brain samples from patients with BAD.9
DAMAGE TO DNA AND RNA
ROS react not only with lipids and
proteins but also with nucleic acids,
thereby inducing oxidative damage to
DNA and RNA. Guanine in DNA and
RNA is more sensitive to ROS attacks
than are the other bases. ROS oxidize guanine and generate 8-oxo-7,8dihydroguanosine (8-OHG) in RNA
and 8-oxo-7,8-dihydro-2-deoxyguanosine (8-OHdG) in DNA. These findings suggest that the process of oxidative damage may play an important
role in the pathology of BAD.9,10
BIPOLAR AFFECTIVE DISORDER
AND INFLAMMATION
Studies11,12 have shown that patients in the early and late phases of
BAD have elevated levels of proinflammatory cytokines (interleukin
[IL]-1, IL-2, IL-6, and tumor necrosis
factor-alpha) compared with healthy
controls. Increased anti-inflammatory
IL-10 was documented only in patients with early-stage disease.3 This
suggests that the long-term course
of BAD is associated with disturbed
anti-inflammatory defense.
Proinflammatory cytokines increase the activity of the hypothalamicpituitary-adrenal (HPA) axis, which
TABLE 1.
Changes in Brain
Concentrations of Certain
Molecules in Patients with
Bipolar Affective Disorder
Molecule
Change
N-acetylaspartate
Decrease7,8
Glutamate/glutamine
Increase7,8
Compounds containing choline
Increase7,8
Myo-inositol
Increase7,8
Lactate
Increase7,8
Creatine phosphate
Decrease8
Phosphate monoesters
Increase8
Intracellular pH
Decrease7,8
causes production of free radicals.
IL-1 plays a key role in the activation
of the HPA.
Induction of BAD by cytokines may
be due to their effect on serotonergic,
noradrenergic, glutamatergic, and HPA
systems. For example, proinflammatory cytokines activate indoleamine-2,3dioxygenase, which degrades serotonin and tryptophan.
Pterin released from macrophages
is an important factor that connects
the immune and nervous systems.
Production of neopterin is associated
with increased degradation of tryptophan (a precursor of serotonin). Tetrahydrobiopterin is an essential cofactor
of hydroxylase of tyrosine and tryptophan (the rate-limiting enzyme of biosynthesis of serotonin, noradrenaline,
and dopamine), as well as nitric oxide
synthase. Elevated plasma concentrations of neopterin and decreased concentration biopterin have been found
in patients in the depressive phase of
BAD.11,12
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THE ROLE OF DOPAMINE IN THE
OXIDATIVE STRESS ASSOCIATED
WITH BIPOLAR AFFECTIVE
DISORDER
Increased levels of dopamine is associated with symptoms of mania. Conversely, reducing dopamine transmission, or reducing dopamine synthesis
or blockade of dopamine D2 receptors,
is responsible for the antimanic effect.
Interestingly, the increased level of dopamine is an important initiator of oxidative stress in the brain because of its
oxidative metabolism.
6-Hydroxydopamine is toxic to the
nervous system. Mechanisms associated
with its toxicity include endoplasmic
reticulum stress, activation of glycogen
synthase kinase-3-beta phosphorylation
on tyrosine 216, and inhibition of protein kinase B phosphorylation on serine
473.3
THERAPEUTIC TARGETS FOR
MOOD DISORDERS
Delay in initiation of appropriate
forms of therapy in the early stages of
BAD can cause significant functional
impairment. Recently, a number of studies3,13 have shown that mood-stabilizing
drugs and antipsychotic drugs inhibit
oxidative damage and increase activity
of various antioxidant enzymes, suggesting that the process of oxidative
damage may be targeted by these drugs.1
MITOCHONDRIA AS NEW
THERAPEUTIC TARGETS FOR
MOOD DISORDERS
New treatments are expected to address clinical challenges and be more
effective, better tolerated, and act faster
than currently available treatments.
N-acetyl Cysteine
Altered levels of glutathione, the most
abundant antioxidant substrate in all tissues, have been described in patients
with BAD.14 Treatment with N-acetyl
cysteine (NAC), a precursor of gluta102
thione, increases glutathione levels.15 A
recent randomized, double-blind, multicenter, placebo-controlled study involving 75 patients with BAD evaluated the
effect of the treatment with NAC (1 g
twice a day) as an addition to usual treatment during a period of 24 months.13
New treatments are expected
to address clinical challenges
and be more effective, better
tolerated, and act faster.
This was followed by a 4-week washout phase. By the end of the study, NAC
showed superior antidepressant effects
compared to placebo, as assessed by
Montgomery Asberg Depression Rating
Scale scores and most secondary scale
scores. It is interesting to note that the
patients were not necessarily selected
for having a major depressive episode.
The authors hypothesized that the efficacy of NAC might be due to its ability to
reverse increased oxidative stress during
episodes of high or low moods.13
Creatine
Creatine plays a key role in brain
energy homeostasis, and its dysfunction has been shown to be implicated in
BAD.16 Brain creatine kinase has been
shown to be altered in the hippocampus
in animal models of mania as well as in
patients with BAD during a manic episode.13 Thus, creatine supplementation
may modify brain high-energy phosphate metabolism in people with BAD.
Recently, an open-label study16 involving 10 treatment-resistant patients with
depression (two of whom had BAD)
found that 3 to 5 mg/day of creatine
monohydrate added to the ongoing treatment led to a significant improvement in
depressive symptoms in the patients with
major depressive disorder; however, the
two patients with BAD experienced
transient hypomanic/manic symptoms.
Glycogen Synthase Kinase-3
Glycogen synthase kinase-3 (GSK-3)
is an important regulator of glycogen
synthesis, gene transcription, synaptic
plasticity, apoptosis, cellular structure,
and resilience. It has been suggested that
GSK-3 regulates behavior by affecting
beta-catenin, glutamate receptors, circadian rhythms, and serotonergic neurotransmission. All of these have been
found to be implicated in the pathophysiology of severe mood disorders.4
Lithium has been shown to target
GSK-3-beta in several paradigms.13
Lithium also induces neurotrophic and
neuroprotective effects in rodents, partly
due to GSK-3-beta inhibition. Valproate
was initially reported to inhibit GSK3-beta activity in SH-SY5Y cells;17
however, these effects have not been
confirmed in neuronal cells.
Carbamazepine was reported to be
involved in signal transduction of cyclic adenosine monophosphate secondmessenger systems;13 however, no effect
on Akt/GSK-3-beta has been reported to
date.
Inhibition of GSK-3-beta is associated with some limitations due to its
involvement with diverse pathways that
contain multiple substrates, which may
lead to side effects or toxicity. At the
time of this writing, no GSK-selective
inhibitors that can cross the bloodbrain barrier have been clinically tested.
Proof-of-principle studies focused on
selective and safe GSK-3-beta inhibitors
are needed to establish the potential reliability and therapeutic relevance of this
group of inhibitors in mood disorders.4
Protein Kinase C Signaling Cascade
Protein kinase C (PKC) plays an important role in regulating neuronal excitability, neurotransmitter release, and
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long-term alterations in gene expression and plasticity. Some of the studies18 show that PKC is regulated by the
mood stabilizers lithium and valproate.
Two recent clinical trials19,20 provide
further evidence for the involvement of
this system in bipolar mania. Although
well known for its anti-estrogenic properties, tamoxifen is also a potent PKC
inhibitor at high concentrations. In all
cases, the antimanic effects of tamoxifen were not shown to be related to its
sedative effects, and no increased risk of
depression was observed.13 However, it
is possible that some of tamoxifen’s antimanic effects may be due to its antiestrogen properties. It is also important to
note that other drugs tested in patients
with BAD, such as omega-3 fatty acids and verapamil, inhibit PKC activity,
which reinforces the role of this target
in developing medications for BAD. For
instance, verapamil showed significant
antimanic effects when combined with
lithium in a double-blind, randomized
study.21
Histone Deacetylases
Histone acetylation has been considered as promising therapeutic target
in mood disorders because of its ability to control epigenetic effects that
regulate cognitive and behavioral processes. Histone acetylation reduces histones’ affinity for DNA and is a major
epigenetic regulator of gene expression
for several key proteins. Thus, diverse
histone deacetylase (HDAC) inhibitors
that could serve as novel neuroprotective agents have been developed. Their
ability to affect neuronal function and
protection occurs largely through epigenetic mechanisms.
Furthermore, it has been suggested that central nervous systempenetrant HDAC inhibitors may eventually have potential therapeutic relevance in mood disorders, supposedly
due to their ability to reverse dysfunctional epigenetic effects associated with
PSYCHIATRIC ANNALS • Vol. 47, No. 2, 2017
early life events.22 In neuronal tissue,
HDAC inhibitors limit histone deacetylation mostly by inactivating class I or II
HDACs, thus increasing histone acetylation.
Notably, the mood stabilizer valproate is an HDAC inhibitor, suggesting
that its effects at this target may play
a therapeutic role in mood stabilization, although it may also be associated
with side effects such as teratogenicity
or polycystic ovarian syndrome.23 Also,
down-regulation of reelin and glutamic
acid decarboxylase expression in cortical interneurons in people with BAD
may be regulated by epigenetic hypermethylation.22 The same group noted
that valproate blocked methionineinduced reelin promoter hypermethylation and reelin mRNA downregulation,
thus improving social interaction in preclinical models.24
The Melatonergic System
Melatonin is expected to protect cells
by preventing mitochondrial injury and
thus preserve membrane potential and
the energy-producing function (adenosine triphosphate levels) of mitochondria.
Melatonin receptors MT1 and MT2 are
highly expressed in the brain and induce
biological effects mostly through G protein–coupled receptors. Supersensitivity
to melatonin suppression by light was
described in people with mood disorders
and their unaffected offspring.13
A recent, open-label, 6-week study25
in 21 people with bipolar depression
assessed the effects of agomelatine (25
mg/day), a nonselective MT1 and MT2
receptor agonist. Approximately 81% of
patients achieved significant improvement at endpoint, and 47% showed
response during the first week of treatment.
In preclinical models, agomelatine
had significant antidepressant-like effects in the forced swim test, the chronic
mild stress test, and the learned helplessness paradigm.26 It was also capable
of resynchronizing a disrupted circadian rhythm and had circadian phaseadvancement properties. Agomelatine
is also known to increase the amount
of both norepinephrine and dopamine,
and to increase cell proliferation and
neurogenesis in the ventral dentate gyrus. Thus, a growing body of evidence
supports a relevant role for melatonergic
modulators as therapeutics for major
depressive disorder, especially its neurovegetative symptoms.27
CONCLUSION
The hypothesis of mitochondrial dysfunction may explain the repeatedly observed changes in the brain of patients
with BAD. Early intervention is important in slowing the progression of BAD.
Not all patients react to treatment in
the same way. For instance, lower response rates are seen in patients with
rapid cycling, as well as in those presenting with a greater number of psychiatric comorbidities or suicidality. This
is why new treatments are expected to
address today’s clinical challenges. It is
critical to the health of patients that the
next generation of treatments for mood
disorders be more effective, better tolerated, and act faster than currently available treatments.1,11
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