Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 730–743
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological
Psychiatry
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p n p
Beyond the serotonin hypothesis: Mitochondria, inflammation and
neurodegeneration in major depression and affective spectrum disorders
Ann Gardner a,⁎, Richard G. Boles b,1
a
Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden
Division of Medical Genetics, Saban Research Institute, Childrens Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern Californa, Los Angeles,
CA 90027, USA
b
a r t i c l e
i n f o
Article history:
Received 31 January 2010
Received in revised form 2 July 2010
Accepted 28 July 2010
Available online 5 August 2010
Keywords:
ATP
Inflammation
Major depression
Mitochondrial
mtDNA
Unipolar depression
a b s t r a c t
For many years, a deficiency of monoamines including serotonin has been the prevailing hypothesis on
depression, yet research has failed to confirm consistent relations between brain serotonin and depression.
High degrees of overlapping comorbidities and common drug efficacies suggest that depression is one of a
family of related conditions sometimes referred to as the “affective spectrum disorders”, and variably
including migraine, irritable bowel syndrome, chronic fatigue syndrome, fibromyalgia and generalized
anxiety disorder, among many others. Herein, we present data from many different experimental modalities
that strongly suggest components of mitochondrial dysfunction and inflammation in the pathogenesis of
depression and other affective spectrum disorders. The three concepts of monoamines, energy metabolism
and inflammatory pathways are inter-related in many complex manners. For example, the major categories
of drugs used to treat depression have been demonstrated to exert effects on mitochondria and
inflammation, as well as on monoamines. Furthermore, commonly-used mitochondrial-targeted treatments
exert effects on mitochondria and inflammation, and are increasingly being shown to demonstrate efficacy in
the affective spectrum disorders. We propose that interactions among monoamines, mitochondrial
dysfunction and inflammation can inspire explanatory, rather than mere descriptive, models of these
disorders.
© 2010 Elsevier Inc. All rights reserved.
1. Introduction
1.1. Depression and affective spectrum disorders
For many years, the prevailing hypothesis on depression has been
that depression is caused by an absolute or relative deficiency of
Abbreviations: ADHD, attention deficit hyperactivity disorder; ADP, adenosine
diphosphate; ATP, adenosine triphosphate; bp, base pair; complex I, NADH dehydrogenase; complex II, succinate dehydrogenase (SDH); complex III, ubiquinol: cytochrome c oxidoreductase; complex IV, cytochrome c oxidase (COX); complex V, ATP
synthase; CoQ10, Co-enzyme Q10; kb, kilobyte; IBS, irritable bowel syndrome; LHON,
Leber's hereditary optic neuropathy; ME/CFS, Myalgic encephalomyelitis/chronic
fatigue syndrome; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis
and stroke-like episodes; MPT, mitochondrial permeability transition; mRNA, messenger RNA; MS, multiple sclerosis; mtDNA, mitochondrial DNA; NADH, nicotinamide
adenine dinucleotide; nDNA, nuclear DNA; NSRI, norepinephrine serotonin reuptake
inhibitors; ROS, reactive oxygen species; RRF, ragged red fibers; rRNA, ribosomal RNA;
sJIA, systemic juvenile idiopathic arthritis; SSRI, (selective) serotonin reuptake
inhibitor.
⁎ Corresponding author. Kista psykiatriska mottagning, Knarrarnäsgatan 15, SE-164
40 Kista, Sweden. Fax: + 46 8 752 70 61.
E-mail addresses: agtorndal@odenhall.se (A. Gardner), rboles@chla.usc.edu
(R.G. Boles).
1
Fax: + 1 323 665 5937.
0278-5846/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.pnpbp.2010.07.030
monoamines. The serotonin hypothesis of depression arouse due to
the observation that reserpine, an antihypertensive drug that depletes
the brain of monoamine neurotransmitters including serotonin,
inadvertently caused depression. Studies on the mode of action of
tricyclic antidepressants also suggested that serotonin is primarily
involved in the control of mood. A causal relationship was suggested
between disturbances in monoamine metabolism and depression
(Coppen, 1967; Schildkraut, 1965). In a review of serotonin and
psychiatric disorders, it was pointed out that the relation between
genetic variants in the genes regulating levels of serotonin in the brain
and various psychiatric traits has not always been consistent, has
displayed interactions with environmental factors, and in some cases
even opposite directions between the genders (Nordquist and
Oreland, 2010).
We believe that the literature does not support the hypothesis that
the pathogenesis of depression is predominately a function of
monoamines alone. After a lifetime investigating mood disorders,
Winokur proposed that unipolar depression is clinically homogeneous but etiologically heterogeneous (Judd et al., 1998; Winokur,
1997). In this review we will present the “mitochondrial psychiatry”
model of depression in Sections 2 and 3, and the “inflammatory
hypothesis” model of depression in Section 4. Since depression is one
of a family of inter-related disorders, and consideration of that family
A. Gardner, R.G. Boles / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 730–743
can shed some light on pathogenesis, we begin the review by the
presentation of major depression in the context of the family of
affective spectrum disorders.
1.2. The concept of major depression
Depression is a relatively recent word in the history of the English
language, and was first coined by Samuel Johnson who used it in the
1750s to describe low spirits (Rousseau, 2000). The historical origins
of the present-day concept of major depression are presented in a
recent essay. Fatigue and loss of energy were recognized as common
symptoms in depression in the 1950–70s (Kendler et al., 2010) and
are included as the A.6 criterion in DSM-IV for Major Depressive
Episode. Pain (e.g., headaches or joint, abdominal, or other pains) is
mentioned as a frequent associated feature in the introductory
chapter (American Psychiatric Association, 1994) and multiple
somatic symptoms have been suggested to be a core component of
depression (Simon et al., 1999).
Chronic pain, leaden paralysis (a heavy, leaden feeling in the limbs)
and hypersomnia are common features in atypical depression, a
depression subtype which has been a subject of nosological debate
since its conception in the late 1950s. Atypical depression has been
reported in 31–62% of those with major depressive episodes. Clinical
studies have showed that 64–72% of those with atypical depression have
bipolar II or subthreshold bipolar II. Atypical depression may occupy an
intermediate nosological position in the unipolar–bipolar spectrum of
mood disorders (Lee et al., 2009). Bipolar II patients were recently
reported to experience more depressive episodes and more leaden
paralysis than bipolar I patients suggesting that these groups may not
represent a continuum. Clinical variables other than the intensity of
hypomanic/manic symptoms may differentiate these groups
(Janowsky, 2009). It is difficult to clinically differentiate recurrent
major depression from bipolar II, which was reported in 21% of
depressive outpatients in a study (Mak, 2009), since patients may not
consider hypomanic episodes as ego-dystonic (Cassano et al., 1999).
For the above-mentioned reasons, studies of major depression
may contain variable proportions of patients with atypical depression
and bipolar II. Other confounding factors are comorbidity with ADHD,
as ADHD may be common in individuals with major depression
(Goodman and Thase, 2009), that atypical depression may be
common in ADHD (Asherson, 2005), and that lifetime ADHD is a
frequent comorbid condition in adults with bipolar disorder (Nierenberg
et al., 2005). Among patients with ADHD plus bipolar disorder in one
study, 88% had bipolar II (Wilens et al., 2003).
Episodes of major depression may be the most severe state of
illness representing only the tip of the iceberg of a common, chronic
and disabling disease with alternating symptom severity. A conceptual shift has occurred in the understanding of depression and it is
now seen as a chronic medical disease (Angst, 1999; Judd et al., 1998).
Cognitive impairment affecting the domains of executive functioning,
attention, memory, visuo-spatial processing and psychomotor function, is a feature of major depression. Lasting cognitive impairment in
immediate memory and attention has been reported in subjects with
previous depression (Baune et al., 2010).
1.3. Common physical/medical comorbidities in major depression
In a study of depressed inpatients, 92% reported pain, headache and/
or myalgia at admission (Corruble and Guelfi, 2000). Major depression
has been reported to increase the risk for migraine, and migraine to
increase the risk for major depression (Breslau et al., 2003). Tinnitus has
been reported in 49% of unmedicated depressed patients, while it was
only present in 12% of the controls (Mathew et al., 1981). Irritable bowel
syndrome (IBS) has been demonstrated to co-associate with depression
in numerous studies (Garakani et al., 2003; Gros et al., 2009). The
presence of a functional state of insulin resistance during major
731
depression, with serum glucose concentrations remaining elevated for
a longer time than in controls, suggests impaired glucose utilization and
thus that major depression represents a more generalized biological
disturbance in some patients. The results from those patients were
similar to type 2 diabetes in which the most important site of insulin
resistance is in the muscle tissue (Winokur et al., 1988). A meta-analysis
revealed that depression is associated with a 60% increased risk of type 2
diabetes, while type 2 diabetes is associated with only a modest
increased risk of depression (Mezuk et al., 2008).
1.4. The concept of affective spectrum disorders
The term “affective spectrum disorders” has been proposed for a
group of psychiatric and medical disorders suggested to share specific
but unknown pathogenic factors — because each disorder has been
shown to respond to three or more chemically unrelated classes of
antidepressant medications (Hudson et al., 2004). As such, it has been
proposed that the affective spectrum disorders include the conditions
of major depression, ADHD, bulimia nervosa, dysthymic disorder,
generalized anxiety disorder (GAD), obsessive–compulsive disorder
(OCD), panic disorder, posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder, social phobia, fibromyalgia, IBS, migraine,
and cataplexy (attacks of muscular weakness triggered by strong
emotions) (Hudson et al., 2004). Chronic fatigue syndrome (CFS, or
ME/CFS) is common in patients with fibromyalgia (Hudson et al.,
2004), was included in the “affective–sensory model” of functional
somatic syndromes in a twin study (Kato et al., 2009), and has a high
co-occurrence with major depression (Ciccone and Natelson, 2003).
For these reasons we include ME/CFS in this review although the
inclusion of ME/CFS into the affective spectrum disorder group is
controversial.
1.5. The nosology of the major depression diagnosis
Sullivan and Kendler have suggested that the scale of the cooccurrence between major depression and other conditions is not
consistent with an orthodox conceptualization of major depression as
a discrete nosological entity. Psychiatric nosology, as in the DSM-IV,
does not adequately capture the “natural” tendency to health-related
as well as psychiatric comorbidity (Sullivan and Kendler, 1998). Klein
has suggested that the shift from conceptualizing mood disorders as
episodic or remitting conditions ought to be replaced by a twodimensional system assessing severity and chronicity in the classification of depressive disorders in the upcoming DSM-V (Klein, 2008).
Zimmerman et al. have reported that at omission of the four somatic
criteria of major depression in the DSM-IV (weight loss, weight gain,
sleep disturbance, and fatigue, which may be sequelae of medical
illnesses) and only assessing three of five mood and cognitive
symptoms (low mood, loss of interest, guilt or worthlessness,
impaired concentration or indecisiveness, and death wishes or
suicidal thoughts), a high level of concordance with the original
DSM-IV classification was found between this simpler definition of
major depression in three patient samples. The authors comment that
an unintended consequence of the elimination of the somatic items
from the criteria may be the reduced appreciation of the somatic
expression of psychiatric illness, and that the elimination might
interfere with clinicians recognizing depression in patients who
present with somatic complaints, thus overlooking symptoms that are
important to assess in depressed patients (Zimmerman et al., 2010).
2. Mitochondrial disorders
2.1. The pathophysiology of mitochondrial disorders
Mitochondria are cytoplasmic-located cellular organelles whose most
fundamental function is the production of adenosine triphosphate (ATP)
732
A. Gardner, R.G. Boles / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 730–743
in the respiratory chain. Tissues and organs that are heavily dependent
upon ATP production, predominantly nerve and muscle, are affected first
and foremost in mitochondrial disorders. However, variability in terms of
clinical manifestations and severity is extremely broad. Mitochondrial
disorders, because of the widespread cellular distribution of mitochondria, in fact may lead to all kinds of clinical signs and symptoms ranging
from mild myopathic complaints to neonatal death and virtually
everything in between (Smeitink, 2003).
Mitochondrial disorders may arise due to mutations in two distinct
genetic systems: the nuclear DNA (nDNA) within the chromosomes and
the mitochondrial DNA (mtDNA). Some patients appear to be sporadic
cases, whereas others are clearly familial. The first pathogenic mtDNA
mutations that could be linked to specific disorders were reported in
1988 (Holt et al., 1988; Lestienne and Ponsot, 1988; Wallace et al., 1988;
Zeviani et al., 1988). mtDNA is inherited only from the ova, and hence is
transmitted in the maternal line. A maternal inheritance pattern has
been established for some mtDNA mutations, including most point
mutations and duplications. Paternal inheritance of mtDNA in a human
has been reported only once (Schwartz and Vissing, 2003). The concept
“Mitochondrial Medicine” was coined in 1994 by Rolf Luft who in 1962
reported the first case of a mitochondrial disorder in a female patient
investigated at Karolinska Hospital in Stockholm (Luft, 1994; Luft et al.,
1962). This patient later committed suicide (personal communication
2005, A.G. and Rolf Luft).
Most people have a single dominant mtDNA sequence throughout
their tissues, although individual tissues harbour sequence variations, a
condition known as “homoplasmy”. By contrast, patients harbouring
pathogenic mtDNA defects often have a mixture of two different mtDNA
sequences throughout their tissues, which is known as “heteroplasmy”.
The percentage of the mutated mtDNA sequence can vary widely among
different members of the same maternal line, as well as from tissue to
tissue within the same individual, and even between individual cells in a
tissue. Various nuclear genes have also been identified that are
fundamentally important for mtDNA homeostasis, and when these
genes are disrupted, they cause autosomally-inherited (dominant or
recessive) mitochondrial disease. Some such disorders cause secondary
mtDNA abnormalities (deletions and/or copy number depletion), and are
considered as defects in intergenomic communication (Spinazzola and
Zeviani, 2009). In recent years, disease-causing mechanisms affecting the
import of proteins into mitochondria, and mitochondrial dynamics
(fission, fusion, and intracellular transport) have been described
(DiMauro and Schon, 2008).
H+
While most human cells contain two copies of nDNA, they contain
many more copies of mtDNA (from 100 to 100,000, depending on the
cell type). The expression of over 90% of the whole mtDNA consisting
of a ~16,569 base pair (bp) circle of double stranded DNA is essential
for mitochondrial bioenergetic function, whereas only ~ 7% of the
nuclear genome of ~109 bp has been proposed to be expressed at any
particular differentiated stage (Ozawa, 1997).
The proportions of mutated mtDNA in individual tissues may
change during development and throughout adult life, potentially
influencing the phenotype within an individual. Two mechanisms
contribute to this process: relaxed replication and mitotic segregation.
mtDNA replication is independent of the cell cycle, i.e., it is relaxed.
Unlike nDNA which replicates only once during each cell cycle,
mtDNA is continuously recycled, even in nondividing tissues such as
skeletal muscle and brain. In a heteroplasmic cell, mutated and wildtype mtDNA can replicate at subtly different rates — either by chance
or because of a subtle selective effect in favour of one particular type.
This mechanism can lead to changes in the proportions of mutated
mtDNA in patients with mtDNA disease, providing an explanation for
the late onset and progression of some mtDNA disorders. When a
heteroplasmic cell divides, subtle differences in the proportion of
mutated mtDNA may be passed on to the daughter cells, leading to
changes in the level of mutated mtDNA within a dividing tissue.
Presumed shifts due to functional selection against the mutant
mtDNA explain why the level of some pathogenic mtDNA mutations
decreases in some rapidly-dividing tissues, such as blood, during life.
Clinical expression of mitochondrial disorders is influenced by the
heteroplasmic proportions, mtDNA background, nuclear background,
and their interaction with the environment (Chinnery and Schon,
2003).
The overall process in which ATP is produced is schematically
presented in Fig. 1. Nuclear genes code for the majority of
mitochondrial respiratory chain polypeptides which make up the
five mitochondrial respiratory chain enzyme complexes, see the
bottom line in the figure.
These polypeptides are synthesised in the cytoplasm with a
mitochondrial targeting sequence that directs them through the
translocation machinery spanning the outer and inner membranes of
mitochondria which are depicted in Fig. 2. ATP is the high energy
source used for most active metabolic processes within the cell, and it
must be released from the mitochondrion in exchange for cytosolic
ADP. Thus the respiratory chain is an elaborate system that must
H+
H+
Intermembrane
space
H+
Cyt c
CoQ
Complex I
Complex
IV
Complex
III
2H ++ 1/2 O2+
NAD+ + H +
NADH
matrix
H+
Complex
II
Complex
V
ATP
ADP+Pi
H+
H+
FAD + H +
FADH2
H2O
H+
Complex subunits:
mtDNA-encoded 7
nDNA-encoded
38
0
4
1
10
3
10
2
12
Fig. 1. The picture (modified and used with permission by Ben-Shachar (2002)) shows the respiratory chain complexes, with their rough spatial configurations, embedded in the
mitochondrial inner membrane (see Fig. 2). Reduced cofactors (NADH and FADH2) generated from the intermediary metabolism of carbohydrates, proteins, and fats, donate
electrons to complexes I and II. These electrons flow between the complexes down an electrochemical gradient, shuttled by complexes III and IV and by two mobile electron carriers,
ubiquinone (co-enzyme Q10) and cytochrome c (Cyt c). The liberated energy is used by complexes I, III, and IV to pump protons (H+) out of the matrix, the mitochondrial center, into
the intermembrane space, the space between the outer and inner membranes. This proton gradient, which generates the bulk of the mitochondrial membrane potential, is harnessed
by complex V to synthesise ATP from adenosine diphosphate (ADP) and inorganic phosphate (Pi).
A. Gardner, R.G. Boles / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 730–743
Fig. 2. A schematic image of a mitochondrion with outer and inner membranes. The
most fundamental function for mitochondria may be their role in cellular energy
metabolism. This includes the production of adenosine triphosphate (ATP) in the
respiratory chain and fatty acid β-oxidation.
respond to the energy requirements of the cell. While these
requirements may be constant (e.g., in hepatocytes), they may also
change dramatically over short periods of time (e.g., in muscle cells
and neurons) (Chinnery and Schon, 2003) in response to increased
demands.
Mitochondrial dysfunction can arise due to deficiencies of cofactors
necessary for the function of the mitochondrial respiratory chain. Coenzyme Q10 (CoQ10) transfers electrons from complexes I and II to
complex III in the respiratory chain. Mutations in two CoQ10
biosynthetic enzymes causing mitochondrial dysfunction have been
identified in cases of encephalomyopathy and nephrotic syndrome.
From its scientific importance, knowledge of CoQ10 deficiency
syndromes is important for physicians because most patients improve
with CoQ10 supplementation (DiMauro and Schon, 2008). Among other
deficiencies that may contribute to disease-related mitochondrial
dysfunction are deficiencies of selenium (Jeffree et al., 2007), B-vitamins
(Depeint et al., 2006), and carnitine, the latter of which is involved in the
lipid transport across the mitochondrial membranes (Parikh et al., 2008;
Scholte et al., 1987).
2.2. Common physical comorbidities, depression and other affective spectrum
disorders in mitochondrial disorders
733
2008). The authors of the book provided the chapter on mitochondrial
psychiatry because it deserves, in their stated view, more attention
both for clinical and therapeutic reasons and because it offers a
window on the pathogenic mechanisms of affective and behavioral
disorders (Rosenberg, 2006). Depression is not infrequent, and
sometimes the sole clinical manifestation, in mitochondrial patients
(DiMauro and Schon, 2008).
Lifetime diagnoses of 54% for major depression, 17% for bipolar
disorder, and 11% for panic disorder, were reported in a study of
various symptoms in 36 patients with mitochondrial disorders, while
the affective spectrum-related conditions of headaches and chronic
fatigue were reported by 81%, and 75%, respectively. The authors
suggested that labeling the patients with psychiatric disorders as
“psychosomatic” may have delayed the search for other etiologies
since this may have biased physicians to ignore physical signs and
symptoms that were eventually found to be part of their mitochondrial disease, believing the symptoms were simply reflections of the
psychiatric presentation. They concluded that psychiatrists should
consider the possibility of mitochondrial disease in patients presenting with multiple physical signs and symptoms that fit into the
spectrum of mitochondrial disorders (Fattal et al., 2007).
In another study, major depression was found in 5 out of 35
children and adolescents (14%) with various mitochondrial disorders.
It was suggested that abnormal central nervous system energy
metabolism may be an important contributing factor in the development of depression in the patients with mitochondrial disorders
(Koene et al., 2009). Paediatric depression in general varies between 3
and 4% in children and adolescents (Merikangas et al., 2010).
Two studies revealed that a several-fold increased likelihood of
developing depression can be maternally inherited along with the
mtDNA, which strongly argues that mtDNA sequence variants may
induce mitochondrial dysfunction that can predispose individuals
towards the development of depression (Boles et al., 2005; Burnett
et al., 2005).
3. Mitochondrial dysfunction in depression and other affective
spectrum disorders
3.1. Mitochondrial dysfunction in depression
Many symptoms in mitochondrial disorders are non-specific. The
symptoms may also show an episodic course, with periodic exacerbations. The episodic condition of migraine, as well as myalgia, gastrointestinal symptoms, tinnitus, depression, chronic fatigue, and diabetes,
are mentioned among the various manifestations of mitochondrial
disorders in review papers on mitochondrial medicine (Chinnery and
Turnbull, 1997; Finsterer, 2004). Cognitive features of mitochondrial
disorders in patients without general cognitive decline are impairments
of memory, executive functioning, attention, visuo-spatial processing
and psychomotor function (Bosbach et al., 2003; Turconi et al., 1999). In
patients with mitochondrial disorders, clinical symptomatology typically occur at times of higher energy demand associated with
physiological stressors such as illness, fasting, over-exercise, and
environmental temperature extremes. Furthermore, psychological
stressors also frequently trigger symptomatology, presumably due to
higher brain energy demands for which the patient is unable to match
with sufficient ATP production. In a patient with mitochondrial
dysfunction, episodes of severe depression occurred after long-term
work-related stress (Gardner et al., 2003a). It is unknown if such
deterioration at increased cellular work load is linked to a further
increase of the oxidative stress contributing to the pathology associated
with the mitochondrial defect (McKenzie et al., 2004).
The concept “Mitochondrial Psychiatry” has been used in the title
of a review about psychiatric symptoms in mitochondrial disorder and
of mitochondrial alterations in psychiatric disorders (Gardner and
Boles, 2005), and as chapter titles in a book and a review about
mitochondrial medicine (DiMauro et al., 2006; DiMauro and Schon,
The relationship between mitochondrial dysfunction and unipolar
depression has been explored in several studies. In studies of
postmortem brain from subjects with probable or diagnosed major
depression, of whom most subjects were (probably) medicated, no
increase of the common 5 kb mtDNA deletion could be detected (Kato
et al., 1997; Sabunciyan et al., 2007; Shao et al., 2008¸ Stine et al., 1993).
Alterations of translational products linked to mitochondrial function
were found in the frontal, prefrontal and tertiary visual cortices (Karry
et al., 2004; Whatley et al., 1996). Alterations of four mitochondriallocated proteins in the anterior cingulate cortex have been reported
(Beasley et al., 2006). Decreased gene expression for 6 of 13 mtDNAencoded transcripts in frontal cortex tissue (Brodmann areas (BA) 9 and
46) (Shao et al., 2008), and of nDNA-encoded mitochondrial mRNA and
proteins in the cerebellum, have also been reported in major depression
(Ben-Shachar and Karry, 2008). Levels of an electron transport chain
complex I subunit (NDUFS7), and complex I activity, in postmortem
prefrontal cortex were found to be below or at the lowest range of the
normal controls in half of the cases of major depressive disorder in a
recent study (Andreazza et al., 2010). In the two latter studies, the
authors were unable to detect any effect of medication on the results.
Decreases of respiratory chain enzyme ratios and ATP production
rates, and an increased prevalence of small mtDNA deletions (but not of
the common 5 kb mtDNA deletion), were found in muscle from patients
with a lifetime diagnosis of major unipolar depression with concomitant
physical symptoms. Medication did not seem to influence the results
(Gardner et al., 2003b). The finding that essentially every depressed
734
A. Gardner, R.G. Boles / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 730–743
subject with very high degrees of somatic complaints demonstrated low
ATP production rates in biopsied muscle suggested clinical relevance
(Gardner and Boles, 2008a). Six specific questions related to dysautonomia, muscle symptoms, and mental fatigue resulted in near-perfect
separation between depressed subjects with high degrees of such
somatic complaints and low muscle ATP production rates, and
depressed subjects with normal degrees of somatic complaints and
normal muscle ATP production rates (Gardner and Boles, 2008b).
3.2. Mitochondrial dysfunction in other affective spectrum disorders
Mitochondrial abnormalities in muscle with ragged red fibers (RRF,
collections of abnormal mitochondria oftentimes considered to be an
informative light microscopic alteration of mitochondrial disorders) and
reduction of the number and shape of mitochondria have been reported
in fibromyalgia (reviewed in Le Goff, 2006). In migraine, RRFs and
cytochrome c-oxidase (COX) negative fibers (considered “the histochemical signature” of most mitochondrial encephalomyopathies) have
been found in muscle in some patients, as well as biochemical
alterations indicating mitochondrial dysfunction (reviewed in Sparaco
et al., 2006). In ME/CFS, several differentially expressed genes affect
mitochondrial functions, including fatty acid metabolism (Vernon et al.,
2006). Anticardiolipin antibodies in the sera of ME/CFS patients indicate
alterations of mitochondrial inner membranes (Hokama et al., 2009). In
a study of the degree of dysfunction of ATP production in neutrophils in
ME/CFS patients and healthy controls, dysfunction was strongly
correlated with the severity of illness. The authors concluded that
mitochondrial dysfunction is the immediate cause of ME/CFS symptoms
(Myhill et al., 2009).
involving the local vascular system, the immune system, and various
cells within the injured tissue. A possible explanation for the parallel and
overlap between the pathways activated during immunity and those
controlling apoptosis (programmed cell death, death of a cell in any
form mediated by an intracellular program that may be stimulated due
to injury or disease) and cell survival indicate co-evolution of these
pathways/effectors under pressure imposed by infections. Bacteria, and
mitochondria (that are reminiscent of bacteria), sit on top of the
signaling pathway. Low-level caspase-1 activation does not only result
in inflammation, which alarms the system without killing the cell, but
also favours cell survival through regulation of lipid biogenesis and
membrane repair. Bcl-2 proteins that control mitochondrial cell death
appear to additionally regulate caspase-1 activation (Yeretssian et al.,
2008).
Caspases are a family of cysteine proteases, which play essential
roles in inflammation, apoptosis, and necrosis and have been termed
“executioner” proteins for their roles in the cell. Caspase-1 is required
in the immune system for the maturation of inflammatory cytokines.
Cytokines are produced by macrophages, T cells, platelets and
vascular wall cells and exert their biological effect by binding to
specific receptors on the surface of target cells. Cytokines also interact
with mitochondria to increase the production of reactive oxygen
species (ROS). Mitochondria also generate ROS as byproducts during
ATP production. ROS at low concentrations may function as signaling
molecules and participate in the regulation of cell activities such as
cell growth. In contrast, ROS at high concentrations may cause cellular
injury and death. ROS in turn increase cytokine expression, which
closes vicious circle of inflammation (Sprague and Khalil, 2009).
4.2. The concept of neurodegeneration
3.3. Mitochondrial dysfunction in bipolar disorder
The association between mitochondrial function and bipolar
disorder has been explored in many studies and will not be reviewed
here. The authors of a perspective paper on the topic concluded that
“accumulating evidence from microarray studies, biochemical studies,
neuroimaging, and postmortem brain studies all support the role of
mitochondrial dysfunction in the pathophysiology of bipolar disorder.
We propose that although bipolar disorder is not a classic mitochondrial disease, subtle deficits in mitochondrial function likely play an
important role in various facets of bipolar disorder” (Quiroz et al.,
2008). Impairment of complex I was seen in prefrontal cortex in all
patients with bipolar disorder (Andreazza et al., 2010), and
abnormalities of mitochondrial structure in the prefrontal cortex,
fibroblasts and lymphocytes in another recent study (Cataldo et al.,
2010). A mouse model with multiple mtDNA deletions in brain
demonstrates mood disorder-like phenotypes which resemble bipolar
disorder (Kasahara et al., 2006, 2008). Altered levels and/or turnover
of (several) monoamines compared to control littermates including
substantially decreased serotonin levels in the hippocampus and
amygdala were demonstrated in one of these studies (Kasahara et al.,
2006). This model is intriguing, linking mitochondrial dysfunction and
secondary monoamine depletion with the phenotype of a mood
disorder.
4. Inflammation and neurodegeneration in depression, other affective
spectrum disorders, and mitochondrial disorders
4.1. The concept of inflammation
Inflammation is the term for the complex biological response of
tissues to harmful stimuli, such as pathogens, damaged cells, or irritants.
Inflammation is a protective attempt by the organism to remove the
injurious stimuli as well as initiate the healing process for the tissue.
Inflammation is normally closely regulated by the body. A cascade of
biochemical events propagates and matures the inflammatory response,
Neurodegeneration is the umbrella term for the progressive death
and loss of neurons. Neurodegeneration can be found in many
different levels of neuronal circuitry ranging from molecular to
systemic (Bredesen et al., 2006; Rubinsztein, 2006; Thompson, 2008).
The most common form of cell death in neurodegeneration is through
the intrinsic mitochondrial apoptotic pathway. This pathway controls
the activation of caspase-9 by regulating the release of cytochrome c
from the mitochondrial intermembrane space. The concentration of
ROS, normal byproducts of mitochondrial respiratory chain activity, is
mediated in part by mitochondrial antioxidants. Over production of
ROS (oxidative stress) is a central feature of all neurodegenerative
disorders. In addition to the generation of ROS, mitochondria are also
involved with life-sustaining functions including calcium homeostasis, mitochondrial fission and fusion, the lipid concentration of the
mitochondrial membranes, and the mitochondrial permeability
transition (MPT). Mitochondrial disease leading to neurodegeneration is likely, at least on some level, to involve all of these functions
(DiMauro and Schon, 2008).
Palace has pointed out that in multiple sclerosis (MS), the
conventional hypothesis is that an autoimmune process and subsequent inflammation lead to neurodegeneration. However, data have
shown that neurodegeneration occurs early in the disease. Neurodegeneration can itself lead to inflammation, and laboratory and clinical
observations suggest that inflammation can be neuroprotective
(Hohlfeld et al., 2006). Thus, powerful immunomodulation at
onset may not only be ineffective but harmful. Alternative antiinflammatory treatments need to be developed if there is a low-grade
inflammation in MS, as suggested (Palace, 2007).
4.3. Inflammation and neurodegeneration in depression
Signs indicative of immune activation in major depression have
been reported since 1990–1991 (Maes et al., 1990–1991). The
presence of an inflammatory response in major depression has since
then been reported several times and is evidenced by, amongst other
A. Gardner, R.G. Boles / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 730–743
things, increased plasma levels of pro-inflammatory cytokines and
acute phase reactants, oxidative damage to red blood cell membranes
and serum phospholipids, and lowered serum zinc (Maes et al., 1995;
Maes et al., 2009a). In a recent review of the immunity hypothesis of
depression, Miller remarks that “it has been heartening for me to see
the tremendous progress that has been made in terms of understanding [—] how the immune system interacts with pathophysiologic
pathways relevant to depression” (Miller, 2010). In a recent metaanalysis of 24 studies involving unstimulated measurements of
cytokines in patients with major depression, the result was interpreted to strengthen the evidence that depression is accompanied by
activation of the inflammatory response system (Dowlati et al., 2010).
A support for the role of pro-inflammatory cytokines in depression
is the observation that they can induce depression in up to 70% of
patients treated with such agents (Maes et al., 2009a). While there is
considerable overlap in symptom expression between cytokineinduced depression and idiopathic depression, including general
somatic symptoms (muscle aches and fatigue) being increased to a
comparable degree in both groups, differences suggest that cytokines
may preferentially target neurocircuits relevant to psychomotor
activity (e.g. basal ganglia) while having a limited effect on cognitive
distortions regarding self-appraisal (Capuron et al., 2009a).
Depression is also associated with neurodegeneration and reduced
neurogenesis. Decreases of synaptic “products” indicative of spine
loss, and of prefrontal inhibitory local circuit neurons, alterations in
the packing density and size of cortical neurons in frontolimbic brain
regions, and reduced cortical glial cell numbers, have been described
in depression (reviewed in Gardner and Pagani, 2003). Decreased
volumes of various brain regions in major depression have been
reported using magnetic-resonance morphometry (Campbell et al.,
2004; Campbell and MacQueen, 2006; Parashos et al., 1998; Steingard
et al., 2002; Vasic et al., 2008; Zou et al., 2010). A significant reduction
in neuropil detected by decreased pyramidal neuron soma size may
account for the decreased hippocampal volume seen by neuroimaging
in major depression (Stockmeier et al., 2004).
4.4. Inflammation and neurodegeneration in the other affective spectrum
disorders
Elevations of cytokines have been reported in fibromyalgia (Gür
et al., 2002; Wallace et al., 2001; Zhang et al., 2008a). In a search for a
candidate gene affecting inflammatory pathways in fibromyalgia, rare
missense variants of the MEFV gene were found in 15% of the patients
which, on average, had higher levels of IL-1β (a pro-inflammatory
cytokine) compared to controls (Feng et al., 2009). Various mutations in
MEFV lead to Familial Mediterranean Fever (FMF), the most common
inherited autoinflammatory disease in the world. Mitochondrial
abnormalities in kidney (Kiliçaslan et al., 2007) and increased
depression scores (Makay et al., 2010) have been reported in FMF.
Other manifestations of MEFV mutations other than FMF have recently
been described (Ben-Chetrit et al., 2009).
Furthermore, decreased volumes of various brain regions in
fibromyalgia have been reported using magnetic-resonance morphometry (Burgmer et al., 2009; Kuchinad et al., 2007; Lutz et al.,
2008; Schmidt-Wilcke et al., 2007). However, when another group of
fibromyalgia patients was investigated, volume decreases were only
observed in those patients with concurrent major depression, bipolar
disorder, dysthymia, or general anxiety disorder (Hsu et al., 2009).
Elevations of cytokines have also been reported in migraine (Bø et al.,
2009; Koçer et al., 2009; Perini et al., 2005; Sarchielli et al., 2006) and IBS
(Dinan et al., 2006; Langhorst et al., 2009; Liebregts et al., 2007; Öhman
et al., 2009). Decreased volumes of various brain regions in migraine
have been reported using magnetic-resonance morphometry (Kim
et al., 2008). Morphological alterations indicating enteric neuropathy
have been reported in the gut in IBS (Lindberg et al., 2009; Törnblom
et al., 2002; Veress et al., 2009).
735
Numerous studies have shown that ME/CFS is characterized by
aberrations in inflammatory pathways including cytokine abnormalities
(Fletcher et al., 2009; Gupta et al., 1997; Patarca, 2001). Larger cerebral
ventricles and decreased volumes of various brain regions in ME/CFS
have been reported using magnetic-resonance morphometry (de Lange
et al., 2005; Lange et al., 2001).
4.5. Cellular degeneration and inflammation in mitochondrial disorders
It has been suggested that, as a general rule, muscle cells in
mitochondrial myopathies are disabled, but often do not die. Inflammatory reaction, connective tissue infiltration, and muscle necrosis, are
usually absent (Schon et al., 1997). However, remarkable atrophy with
variation in size and form of muscle fibers with unclear margins and
prominent nuclei may be observed (Mizukami et al., 1992).
Neuropathological examinations of the brain in patients who died
due to severe mitochondrial disorders have revealed prominent
neuronal degeneration, gliosis in both the grey and white matter, total
loss of regional nerve cells, and demyelination (Filosto et al., 2007;
Mizukami et al., 1992; Oldfors et al., 1990; Sparaco et al., 1993;
Tanahashi et al., 2000). Macrophage infiltration has been observed in
a few cases (Piao et al., 2006; Sparaco et al., 2003).
Recent findings in MS, generally considered to be an inflammatory
disease (Palace, 2007), suggest mitochondrial dysfunction in the
pathogenesis of disease progression (Mao and Reddy, 2010; Regenold
et al., 2008; Su et al., 2009). The inflammatory infiltrates in MS consist of
macrophages/microglial cells, T cells, plasma cells and B cells with
macrophages/microglia as the dominant cell population in newly
formed lesions. So-called chronic active lesions show a rim of
inflammatory cells (microglial cells and T cells) at the border to the
normal-appearing white matter (Kuhlmann et al., 2009). Remyelination
and inflammatory infiltrates apart from occasional macrophage
infiltration were not observed in brain of patients with primary
mitochondrial disorders (Filosto et al., 2007; Mizukami et al., 1992;
Oldfors et al., 1990; Sparaco et al., 1993; Tanahashi et al., 2000) except in
cases of Leber's Hereditary Optic Neuropathy (LHON), an mtDNA
disorder that presents clinically overwhelmingly in males, but can be
associated with an MS-like illness mainly in females (Palace, 2009; Perez
et al., 2009). Neuropathological lesions in LHON with demyelinating
plaques in white matter, presence of macrophages and lymphocytes
within lesions, and T cells in the frontal lobe, were described in a case. It
was suggested that mtDNA mutations may affect the nervous system on
a common metabolic basis and occasionally may aggravate or initiate
autoimmune pathology (Kovács et al., 2005).
It has been proposed that the over-expression of the Class I major
histocompatibility complex (MHC I) detected in fibroblasts from
patients with the mtDNA-mutation disorder Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like episoders (MELAS) provides
a mechanism by which the immune system can recognize and eliminate
cells containing mtDNA mutations (Gu et al., 2003). The MCH in humans
is oftentimes referred to as the human leukocyte antigen system (HLA),
and these molecules are found on every nucleated cell of the body with
the function to display fragments of proteins from within the cell to T
cells; thus healthy cells are ignored while cells containing foreign
proteins such as those infected by a bacterium or virus will be attacked
by the immune system. HLA types are inherited and people with certain
HLA antigens are more likely to develop some autoimmune diseases
such as type 1 diabetes. HLA typing in autoimmunity is being
increasingly used as a tool in diagnosis.
Diabetes mellitus is common in the mitochondrial disorder MELAS.
HLA typing in a MELAS patient with diabetes revealed DR3 and DR4
types that are linked to diabetes, and positive anti-GAD antibody. The
findings were interpreted to suggest that autoimmunity may have
contributed to diabetes in this patient (Huang et al., 1998). Islet cell
antibodies were found in three members of a family with MELAS and
diabetes indicating that mitochondrial diabetes may involve beta cell
736
A. Gardner, R.G. Boles / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 730–743
damage (Oexle et al., 1996). In a patient with Kearns–Sayre syndrome
(KSS) with a large-scale mtDNA deletion, and diabetes and hypoparathyroidism, HLA typing showed the presence of HLA-A24 and CW3
antigen. A genetic linkage, as well as mitochondrial dysfunction, was
considered as responsible for the co-occurrence of the disease states
(Isotani et al., 1996). Patients with mitochondrial gene mutations and
diabetes are usually autoantibody-negative (Zhang et al., 2004). One of
four LHON patients in a study also had an HLA haplotype associated with
MS. The disease progression was not more severe in this patients
compared to the other LHON patients (Morrissey et al., 1995). Some
mitochondrial disease patients are noted to have decreased CSF folate
levels, and treatment with folinic acid (which delivers folate to brain
independent of that receptor) appears efficacious in some. In one such
patient, folate receptor-blocking antibodies were found (Hasselmann
et al., 2010), demonstrating another mechanism in which immune
activation may result in clinical disease in these patients.
Systemic juvenile idiopathic arthritis (sJIA) is a rheumatic disease
in childhood characterized by systemic symptoms and a relatively
poor prognosis. An increase of foremost depressive disorder and
somatoform disorder has been reported (Mullick et al., 2005).
Peripheral leukocytes are thought to play a pathological role, and
overproduction of pro-inflammatory cytokines is reportedly involved
in the disease. These soluble factors may affect the peripheral
leukocytes and alter the gene expression profiles in the cells. In a
study of the gene expression profile in peripheral leukocytes, genes
involved in mitochondrial ATP production were downregulated,
suggesting mitochondrial dysfunction. Expression of mtDNA-encoded
genes were suppressed in patients with sJIA, while the investigated
nDNA-encoded mitochondrial genes were intact. Molecules constituting tumor necrosis factor (TNF) network cascades were upregulated. TNFα is a pro-inflammatory cytokine. The findings were
interpreted to suggest that sJIA is not only an immunological disease
but also a metabolic disease involving mitochondrial dysfunction. The
mitochondrial dysfunction may be secondary to overproduction of
TNF since TNF induces mitochondrial damage (Ishikawa et al., 2009).
Cytokines play a role in the regulation of chondrocyte function,
and pro-inflammatory cytokines are considered to be important in
cartilage destruction. In addition, multiple studies have implicated a
decrease in mitochondrial bioenergetic reserve as a pathogenic factor.
In a study of pro-inflammatory cytokine exposure, breaks in the
mtDNA and decreased ATP levels were found at increasing exposure
in osteoarthritic, but also in normal, human cartilage cells. Treatment
with a vector-delivered DNA-repair enzyme protected the chondrocytes from accumulation of mtDNA breaks and preserved ATP levels.
The authors conclude that the mitochondrion is an important target
for chondrocyte damage induced by pro-inflammatory cytokines.
Protection from this damage ameliorates mitochondrial dysfunction
and diminishes cell death induced by cytokines (Kim et al., 2010).
At reinterpretation of the previously mentioned study of mitochondrial biochemistry and small mtDNA deletions in muscle from patients
with a lifetime diagnosis of major depression (Gardner et al., 2003b)
with “inflammatory vision”, it cannot be excluded that the origin of the
small mtDNA deletions was the result of an inflammatory process. No
deletions were found in the investigated mtDNA regions in four of 25
investigated patients, one of whom was shown to have a primary mtDNA
disorder. An mtDNA duplication producing several mtDNA deletions in
this patient was described by another laboratory (Houshmand et al.,
2004). In the 22 controls, deletions were found in all elderly subjects.
Chronic low-grade inflammation is a characteristic of ageing (Capuron
et al., 2009b), and breaks in the mtDNA with pro-inflammatory cytokine
exposure were found in the above-mentioned study (Kim et al., 2010).
5. Diagnostic problems and promises in mitochondrial disorders
This section is included in order to give the reader a perspective of
the kinds of analyses that can be applied to searching for mitochondrial
disease, and mitochondrial dysfunction, on a clinical basis in individuals
with depression thought to possibly have a mitochondrial disorder, as
well as in studies of depression and other psychiatric disorders.
There is no one single test that will prove or disprove whether a
patient has a mitochondrial disorder (Chinnery and Schon, 2003; Haas
et al., 2008; Mancuso et al., 2009). The diagnosis is generally suspected
based upon the clinical presentation, including the presence of multiple
idiopathic, and generally intermittent, manifestations of nerve and
muscle disease. However, the range of known clinical manifestations is
so broad such that a large proportion of all patients in general have
consistent presentations. A family history of a high prevalence of
disorders among the matrilineal relatives can be helpful when present,
but such a history is often absent (autosomal recessive disease and new
mtDNA mutations), and when present the clinical manifestations are
generally radically different in each affected relative. Thus, biomarkers
for laboratory screening of at risk patients are needed, as well as
definitive testing at the protein or gene levels.
The first line of laboratory screening in most expert centres consists
of analyses of body fluid metabolites (blood and urine, sometimes CSF)
for markers of disturbed energy metabolism. Usually this consists of
screening for elevated intermediates of lipid and carbohydrate
metabolism, including assays of lactate, pyruvate, ketones, dicarboxylic
acids, and/or acylcarnitines, as well as for amino acid-derived
intermediates of the Krebs cycle. However, such testing is often normal
in the stable/fed state in all but the most severely-affected patients.
Serum markers of cell death, including transaminases and creatine
kinase, may be increased, but are often normal.
More sophisticated investigations are generally performed at
specialist centres, often including measurements of the individual
respiratory chain complexes in a sample obtained on muscle biopsy.
However, the muscle may be both morphologically and histochemically
normal, and not surprisingly especially in individuals whereas clinical
manifestations are more encephalopathic, and less myopathic. Respiratory chain enzymes in patients with mtDNA mutations may be within
the normal range as a mitochondrial disorder may result in a functional
defect that is not detectable in the laboratory (Chinnery and Turnbull,
1997; Chinnery and Schon, 2003; Sciacco et al., 2001). Furthermore,
interference of such highly transient cellular events as mitochondrial
calcium-handling affecting the membrane potential may be one of the
main effects of some mtDNA mutations (Brini et al., 1999).
Identifying the causative primary gene mutation is becoming
feasible in a rapidly growing subset of mitochondrial disease patients,
yet this is still a minority. Sequencing of the entire mtDNA genome
and many nuclear-encoded mitochondrial genes is now commercially
available. Also commercially available is sequencing of the POLG gene
whose protein, gamma polymerase, both replicates and proof reads
mtDNA, in which mutations can result in a wide variety of disease
manifestations, including migraine and depression (DiMauro and
Schon, 2008; Hudson and Chinnery, 2006; Komulainen et al., 2010).
Chip technology allows for the evaluation of the entire nuclear
genome at high density for single nucleotide polymorphisms that
indicate the presence of copy number variations (deletion and
duplications) and areas that are identical by descent, which can lead
to investigations of the mitochondrial-targeted genes within the
affected coding. However, powerful in research for identifying new
mitochondrial disorders, the above approaches are expensive, and
generally produce several sequence variants of unknown relationship
to the patients’ disease for every frank mutation identified.
6. Treatment of mitochondrial disorders
Treatment of mitochondrial disorders focuses on symptom-based
management, mitigating worsening during physiologic or psychologic
stress, and avoidance of drugs impairing mitochondrial functions
(Finsterer and Segall, 2010). Nutraceuticals acting on the pathogenic
cascade, “mitochondrial cocktail”, are often employed.
A. Gardner, R.G. Boles / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 730–743
737
6.1. The mitochondrial cocktail
7.3. Lithium
The mitochondrial cocktail targets the final common pathways of
mitochondrial dysfunction. There may be synergistic apart from
additive effects of the components (Parikh et al., 2009; Tarnopolsky,
2008). The components most frequently employed by experts in
mitochondrial medicine are CoQ10, riboflavin, and at least one
additional antioxidant (vitamin C, E, and/or α–lipoic acid). L-carnitine
is generally given when blood carnitine levels are low or low-normal.
Some evidence supports using antioxidants since ROS are produced in
increased amounts in mitochondrial disorders. A randomized doubleblind trial in which CoQ10, creatine monohydrate, and α-lipoic acid
were used showed reduced lactate and markers of oxidative stress in
patients with mitochondrial cytopathies (Rodriguez et al., 2007).
Commonly-used components are presented in Table 1 along with
effects in depression and other affective spectrum disorders, and in
inflammation.
According to the experiences of both authors, we believe that the
cocktail often demonstrates effects with the somatic symptoms in
depression and possibly in depression itself. Efficacy usually does not
occur for several months before there is an obvious improvement.
Gold and Cohen suggest that “providing [mitochondrial cocktail] as
part of an individual trial in which the patient serves as their own
control seems to be a reasonable approach” (Gold and Cohen, 2001).
Lithium has several uses in medicine apart from its classical role,
the treatment of bipolar disorder. Some cases of treatment-resistant
presumably unipolar depression may respond remarkably well to
lithium (A.G., personal observation). However, it cannot be excluded
that such cases in fact have bipolar II for which lithium is the only
preventive treatment for both depression and hypomania that is
supported by several controlled studies (Benazzi, 2007). Lithium is
also in use in the treatment of cluster headache (Steiner et al., 1997;
Van Alboom et al., 2009).
The activities of the mitochondrial respiratory chain complexes I + III,
complexes II + III and complex IV were measured in postmortem human
brain cortex homogenates following exposure to lithium. An increase in
complex I and complex II activities was shown to be induced by lithium,
thus suggesting a potential of lithium to enhance ATP production. The
authors write that the results raise the intriguing possibility that the use
of lithium may be considered in the prevention or treatment of disorders
associated with defects of the mitochondrial respiratory chain (Maurer
et al., 2009). Using multiple measures, a robust enhancement of
mitochondrial function by long-term treatment with lithium at
therapeutically-relevant concentrations was found in a study using
a cell line of human origin, neuronal phenotype, and rats with
methamphetamine-induced mitochondrially mediated toxicity in the
brain. The authors write that, taken together, the evidence suggests that
lithium has an effect on the regulation of mitochondrial functions in vitro
and in the CNS and that lithium may have potential clinical utility in the
treatment of other diseases associated with impaired mitochondrial
function (Bachmann et al., 2009).
7. Effects of psychopharmacological agents and ECT on mitochondria
and inflammation
7.1. Tricyclic antidepressants
The tricyclic drugs imipramine and chlorimipramine exhibit some
characteristics of classical mitochondrial uncouplers, i.e. they release
respiratory control, hinder ATP synthesis, and enhance ATPase activity
of isolated rat liver mitochondria. Unlike classical uncouplers, however,
both drugs only weakly stimulate proton uptake in intact mitochondria
(Weinbach et al., 1986). The effects of long-term intraperitoneal
administration of the tricyclic imipramine on energy metabolism of
rat brain mitochondria were examined in a study. Stimulation of the
state 3 respiration rates was seen with various substrates. The effect was
evident within a week of imipramine administration and was sustained
through the second week of the drug treatment. State 4 respiration rates
were also found to be increased in general. Respiration decreased with
substrates that are electron donors for complex IV. The intramitochondrial content of some respiratory chain subunits increased in the first
two weeks of the drug treatment (Katyare and Rajan, 1995). In a more
recent study of the tricyclic nortriptyline, which has been identified as a
strong inhibitor of MPT (which leads to mitochondrial dysfunction and
is implicated in acute neuronal death), the effects of nortriptyline were
studied in primary cerebrocortical neurons and in a mouse model.
Nortriptyline was found to inhibit oxygen/glucose deprivation-induced
cell death, loss of mitochondrial membrane potential, and downstream
release of mitochondrial factors. The authors concluded that the results
indicate that nortriptyline is neuroprotective (Zhang et al., 2008b).
7.2. SSRI antidepressants
The exact nature (agonist or antagonist) of the action of SSRI agents
is not known, and the effects of them on mitochondria are largely
untested. Fluoxetine has been found to exert multiple effects on the
energy metabolism of rat liver mitochondria, being potentially toxic in
high doses (Souza et al., 1994), and to affect electron transport and
ATPase activity inhibiting ATP production in isolated rat brain
mitochondria (Curti et al., 1999). In a study, fluoxetine was demonstrated to inhibit MPT and to interact with a MPT pore component, thus
protecting against induced apoptotic cell death (Nahon et al., 2005).
7.4. ECT
Little progress has been made in understanding the mechanism of
action of electroconvulsive therapy (ECT), a treatment for depression. The
activities of mitochondrial respiratory chain complexes II and IV were
increased for up to 30 days after one single shock in the hippocampus,
striatum and cortex in rats. Several shocks presented lesser effects
when compared to a single shock, but complex II activity in cortex was
increased in the rats that received several shocks (Búrigo et al., 2006).
7.5. Effects of antidepressants and lithium on inflammation
Antidepressant medications including tricyclics, SSRIs, the atypical
antidepressant tianeptine, and lithium, have been found to have antiinflammatory effects. Studies in animal models demonstrate that
antidepressants attenuate inflammation-induced brain cytokine production and prevent the development of depression induced by highdose IFNα (reviewed in Kenis and Maes, 2002; Maes et al., 2009a).
In a study in which whole blood from healthy volunteers was diluted
with various antidepressants and examined for ability to promote an
anti-inflammatory cytokine phenotype in human blood, all of the
antidepressants suppressed production of a pro-inflammatory cytokine
irrespective of their preference for serotonin or noradrenaline transporters. The results provide evidence questioning the relationship
between the monoaminergic reuptake properties of antidepressants
and their immunomodulatory effects (Diamond et al., 2006).
However, in another study, the impact of antidepressive medications
of several classes for at least six months on the expression of proinflammatory cytokines was investigated in patients with heart failure
with and without major depression. No differences were observed for
the pro-inflammatory cytokines between patients with depression
under treatment and those without depression. However, the level of
one pro-inflammatory cytokine and CRP levels were significantly lower
in patients receiving tricyclics or serotonin/norepinephrine reuptake
inhibitors (SNRI) compared to patients receiving SSRIs or those without
depression. The results showed that the type of antidepressive
738
A. Gardner, R.G. Boles / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 730–743
Table 1
Components of the mitochondrial cocktail, findings in depression, other affective spectrum disorders, and inflammation.
Components of the
Suggested dosages Effects on
Findings in
mitochondrial cocktail for adults
mitochondrial metabolism depression
Findings in other affective
spectrum disorders
Findings in inflammation
(Parikh et al., 2009)
CoQ10 as ubiquinol
(preferred)
or ubiquinone
Ubiquinol: 50–
600 mg daily;
ubiquinone: 300–
2400 mg daily
Transports electrons
across complexes within
the respiratory chain and
has antioxidant effects
Riboflavin
(vitamin B2)
50–400 mg daily
A key component in
respiratory chain
complexes I–II–III and in
several other key
enzymatic reactions in
energy metabolism
L-carnitine
100–1000 mg 2–3
times daily
A crucial role in
mitochondrial β-oxidation
by transferring long-chain
fatty acids across the
mitochondrial inner
membrane
Acetyl-carnitine
is an alternative
Decreased mean
plasma level in
treatment-resistant
depression. 51% of
patients below the
lowest values detected
in controls (Maes et al.,
2009b).
Fibromyalgia: increased plasma
and decreased mononuclear cell
level (Cordero et al., 2009).
Clinical improvement with
treatment (+ Ginkko biloba)
(Lister, 2002).
Migraine: Improvement with
treatment vs. placebo (Sándor
et al., 2005). 33% of 1550
patients below reference range.
Clinical improvement in a subset
(Hershey et al., 2007).
ME/CFS: decreased mean plasma
level in patients. 45% of patients
below the lowest values detected
in controls. Inverse relationships
with symptomatology ratings
(Maes et al., 2009c).
Deficiency in functional Migraine: efficacy in prophylaxis
red blood cell enzyme
in both open and randomized,
assay in a subset (Bell
placebo-controlled trials (Boehnke
et al., 1991;1992).
et al., 2004; Condò et al., 2009;
Schoenen et al., 1998). No effect
in another trial (MacLennan et al.,
2008). Efficacy greater in subjects
with non-H mtDNA haplotypes
(Di Lorenzo et al., 2009).
Antidepressant effect in
geriatric depression
after about four or
more weeks of
treatment which was
longer than in younger
patients according to a
review of nine studies.
Effect equals results
obtained with
antidepressants
(Pettegrew et al.,
2000).
Combines with phosphate Improved treatmentto form phosphocreatine
resistant depression in
which serves as a source of a small open-label
high energy phosphate
study. Possible
and acts as an intracellular precipitation of a manic
buffer for ATP
switch observed in the
two bipolar patients
(Roitman et al., 2007).
An antioxidant and
potentiates creatine
uptake in skeletal muscle
ME/CFS: effect by acetyl-L-carnitine
on mental fatigue, and by proprionylL-carnitine on general fatigue.
Worsening of fatigue after cessation
of either or combined L-carnitines
(Vermeulen and Scholte, 2004).
Fibromyalgia: plasma levels significantly
lower than in sex-matched controls
(Akkus et al., 2009).
Migraine: efficacy in menstrual migraine
in a placebo-controlled double-blinded
trial with reduction of pain severity and
functional disability. Superior effect
regarding photophobia, phonophobia, and
nausea (Ziaei et al., 2009).
ME/CFS: significantly lower serum
concentrations than in age- and sexmatched controls (Miwa and Fujita, 2009).
Creatine
monohydrate
5 g in one dose or
2 dosages daily
α-lipoic acid
(thioctic acid)
50–200 mg daily
Vitamin E
(tocopherol)
100–200 IU daily
An antioxidant
Significantly lower
serum or plasma
concentrations (Maes
et al., 2000; Owen et al.,
2005). Dietary intake
not related to plasma
level (Owen et al.,
2005). Significantly
increased plasma level
in another study
(Sarandol et al., 2007).
Vitamin C
(ascorbic acid)
50–200 mg daily
An antioxidant and cofactor in the synthesis of
carnitine
Decrease in plasma
levels (Khanzode et al.,
2003).
Lowers the production
of pro-inflammatory
cytokines (Schmelzer
et al., 2007a;2007b;2008).
Suppressive effect on
production of tissue
inflammatory mediators
in endotoxin-induced
shock in mice (Kodama
et al., 2005). Prevented
cytokine upregulation
and cytokine-induced
alterations in islet betacells (Cobianchi et al.,
2008).
Increase of plasma levels
and heart expression of
cytokines in hypertensive
rats reversed (MiguelCarrasco et al., 2008).
Increase of plasma proinflammatory cytokines
in athletes after
competition reduced in
the treated group in a
double-blind trial
(Bassit et al., 2008).
Migraine: beneficial in a randomized
double-blind placebo-controlled trial
(Magis et al., 2007).
Reduces various signs
of inflammation in
inflammation-induced
mice (Jesudason et al.,
2008).
Lower levels in elderly
subjects with increased
levels of pro-inflammatory
cytokines, poor physical
health and poor mental
health scores (Capuron
et al., 2009b). Individual
response at supplementation
on cytokine production
partly mediated by genetic
factors (Belisle et al., 2009).
Shown to inhibit cytokine
production in a dosedependent manner
(Härtel et al., 2004).
A. Gardner, R.G. Boles / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 730–743
treatment may have a significant effect on the underlying inflammatory
process (Tousoulis et al., 2009).
8. Main conclusions and future perspectives
In this review, we have presented findings “beyond the serotonin
hypothesis” of depression regarding the alternative mitochondrial and
inflammatory models of depression. There is, however, a role for
serotonin within the new models. A substantial decrease of serotonin
levels was observed in hippocampus and amygdala in a mouse model of
bipolar disorder with multiple mtDNA deletions in brain (Kasahara et al.,
2006), testifying to the necessity of cellular energy in the production of
serotonin. Serotonin depletion has also been shown to be related to
neuroinflammation since inflammation depletes the availability of
tryptophan resulting in reduced serotonin in brain (Maes et al., 2009a).
Brain tissue requires a high level of energy for its metabolism,
including the maintenance of the transmembrane potential, signal
transduction and synaptic remodeling. An increase of psychiatric
symptoms and disorders, in particular depression, is likely present in
patients with mitochondrial disorders. The above-mentioned similarities in cognitive impairments in major depression and mitochondrial
disorders suggest that the same neurobiological substrates for the
involved cognitive domains may be preferentially affected in both
conditions.
Mitochondrial structure and function, measured by a variety of
different techniques, have been shown to be abnormal in patients with
mood disorders including major depression as well as in the other
affective spectrum disorders. No definite conclusion can yet be drawn as
to whether mitochondrial dysfunction plays an important etiological
role in these conditions. However, many studies suggest this possibility.
The studies performed to date essentially rule out the presence of
“common” mtDNA mutations in most individuals with major depression. However, there may be large number of polymorphisms on both
mtDNA and nDNA genes involved in energy metabolism, either alone or
in combination with each other, that result in a moderately-lowered
energy metabolism and that can result in major depression and/or other
affective spectrum disorders in the presence of other factors. The other
factors likely include polymorphic variation in genes involved with
neurotransmitter and/or inflammatory pathways, as well as environmental risk factors. In recurrent early–onset depression, a modest
maternal bias in the susceptibility suggest that predisposing genetic
factors likely reside on the mtDNA (Bergemann and Boles, 2010).
Mitochondrial dysfunction leads to apoptosis, which primes the
immune system with intracellular antigens causing inflammation, and
which in susceptible individuals even may lead to autoimmune disease.
Although inflammatory processes have been reported to occur in some
patients with confirmed primary mitochondrial disorders as reviewed
herein, very few studies have investigated inflammatory markers in
such patients. Myelin pathology is common in mitochondrial diseases
(Lerman-Sagie et al., 2005), and has been described in unipolar
depression (Regenold et al., 2007). There is good evidence that a
metabolic injury to oligodendrocytes and myelin turnover may depend
on mitochondrial dysfunction (Carelli and Bellan, 2008). Signs of
accelerated apoptosis in classes of lymphocytes and neutrophils have
been demonstrated in major depression, and low mitochondrial
membrane potential in a higher percent of such cells in comparison
with controls (Szuster-Ciesielska et al., 2008). In a study of lymphocytes
from patients with the mitochondrial mtDNA-mutation disorder LHON,
a higher rate of apoptosis and alterations of the mitochondrial
membrane potential were found in comparison with controls (Battisti
et al., 2004).
The components of the mitochondrial cocktail used in the treatment
of mitochondrial disorder not only have direct effects on mitochondria,
they also as reviewed herein have beneficial effects on inflammation.
The major classes of agents used in the treatment of depression have
effects on mitochondrial metabolism as well as on inflammation. Since a
739
bidirectional relationship exists between mitochondria and inflammation, it is impossible to deduct if the established relationship between
depression and inflammation is due to a primary disturbance of
inflammatory pathways, or secondary inflammation due to a primary
disturbance of mitochondrial function. It may, therefore, be appropriate
that, in the search for factors etiologically related to the actions of these
agents, the center of interest shifts from neurotransmitter systems to
investigations of mitochondrial functions and inflammation.
In an essay on the development of the DSM-IV, of which that first
author was the chairperson of the task force that produced DSM-IV,
the authors write that “as we continue to understand the pathophysiology of brain disorders, as well as the biological effects of psychiatric
interventions, we will be able to move from a descriptive model
[DSM-IV] to an integrative, explanatory model of psychiatric illness”.
They list “the current alchemy of neurotransmitters” along with other
explanatory models such as the four humours and demonic
possession, and write that such models may be useful bridges to
future explanations “but tend to age quickly because they are based
on limited knowledge, which is easily superseded by new discoveries.” They conclude in their essay that “we are at the epicycle stage of
psychiatry where astronomy was before Copernicus and biology
before Darwin. [—]. Disparate observations will crystallise into
simpler, more elegant models that will enable us not only to
understand psychiatric illness more fully but also to alleviate the
suffering of our patients more effectively.” (Frances and Egger, 1999).
Perhaps as many as half of patients with major depression are
unresponsive to prescription drugs including SSRIs (Fournier et al.,
2010; Insel and Wang, 2009). This, along with the frequent side effects
of medications, should compel researchers to study the complex
nutritional therapies that are gaining both empirical and theoretical
support (Gardner et al., 2010). The increasing knowledge about the
pathophysiologies of depression reviewed herein will hopefully
assist in moving us towards a “post-Copernican” understanding of
depression, and treatment options that will enable depressed patients
to be more optimistic about what we can offer them. With our
current incomplete understanding, for many patients with treatmentresistant depression what we can offer them today is not much more
than what could be offered literally before the time of Copernicus, as
exemplified by a patient lamenting in an old Egyptian papyrus (when
the heart was believed to be the center of physical and emotional life;
Okasha and Okasha, 2000):
Disease has sneaked into me
I feel my limbs heavy
I no longer know my own body
Should the master physician come to me
My heart is not revived by his medicines.
Conflict of interests
The authors declare that they have no competing interests.
References
Akkus S, Naziroglu M, Eris S, Yalman K, Yilmaz N, Yener M. Levels of lipid peroxidation,
nitric oxide, and antioxidant vitamins in plasma of patients with fibromyalgia. Cell
Biochem Funct 2009;27(4):181–5.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders
(DSM-IV), 4th ed. Washington, DC: American Psychiatric Association; 1994.
Andreazza AC, Shao L, Wang JF, Young LT. Mitochondrial complex I activity and
oxidative damage to mitochondrial proteins in the prefrontal cortex of patients
with bipolar disorder. Arch Gen Psychiatry 2010;67(4):360–8.
Angst J. Major depression in 1998: are we providing optimal therapy? J Clin Psychiatry
1999;60(Suppl 6):5–9.
Asherson P. Clinical assessment and treatment of attention deficit hyperactivity
disorder in adults. Expert Rev Neurother 2005;5(4):525–39.
740
A. Gardner, R.G. Boles / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 730–743
Bachmann RF, Wang Y, Yuan P, Zhou R, Li X, Alesci S, et al. Common effects of lithium
and valproate on mitochondrial functions: protection against methamphetamineinduced mitochondrial damage. Int J Neuropsychopharmacol 2009;12(6):805–22.
Bassit RA, Curi R, Costa Rosa LF. Creatine supplementation reduces plasma levels of proinflammatory cytokines and PGE2 after a half-ironman competition. Amino Acids
2008;35(2):425–31.
Battisti C, Formichi P, Cardaioli E, Bianchi S, Mangiavacchi P, Tripodi SA, et al. Cell
response to oxidative stress induced apoptosis in patients with Leber's hereditary
optic neuropathy. J Neurol Neurosurg Psychiatry 2004;75(12):1731–6.
Baune BT, Miller R, McAfoose J, Johnson M, Quirk F, Mitchell D. The role of cognitive
impairment in general functioning in major depression. Psychiatry Res 2010;176(2–3):
183–9.
Beasley CL, Pennington K, Behan A, Wait R, Dunn MJ, Cotter D. Proteomic analysis of the
anterior cingulate cortex in the major psychiatric disorders: evidence for diseaseassociated changes. Proteomics 2006;6(11):3414–25.
Belisle SE, Leka LS, Delgado-Lista J, Jacques PF, Ordovas JM, Meydani SN. Polymorphisms
at cytokine genes may determine the effect of vitamin E on cytokine production in
the elderly. J Nutr 2009;139(10):1855–60.
Bell IR, Edman JS, Morrow FD, Marby DW, Mirages S, Perrone G, et al. B complex vitamin
patterns in geriatric and young adult inpatients with major depression. J Am Geriatr
Soc 1991;39(3):252–7.
Bell IR, Morrow FD, Read M, Berkes S, Perrone G. Low thyroxine levels in female
psychiatric inpatients with riboflavin deficiency: implications for folate-dependent
methylation. Acta Psychiatr Scand 1992;85(5):360–3.
Benazzi F. Bipolar II disorder: epidemiology, diagnosis and management. CNS Drugs
2007;21(9):727–40.
Ben-Chetrit E, Peleg H, Aamar S, Heyman SN. The spectrum of MEFV clinical
presentations—is it familial Mediterranean fever only? Rheumatology (Oxf)
2009;48(11):1455–9.
Ben-Shachar D. Mitochondrial dysfunction in schizophrenia: a possible linkage to
dopamine. J Neurochem 2002;83(6):1241–51.
Ben-Shachar D, Karry R. Neuroanatomical pattern of mitochondrial complex I
pathology varies between schizophrenia, bipolar disorder and major depression.
PLoS ONE 2008;3(11):e3676.
Bergemann ER, Boles RG. Maternal inheritance in recurrent early–onset depression.
Psychiatr Genet 2010;20(1):31–4.
Bø SH, Davidsen EM, Gulbrandsen P, Dietrichs E, Bovim G, Stovner LJ, et al.
Cerebrospinal fluid cytokine levels in migraine, tension-type headache and
cervicogenic headache. Cephalalgia 2009;29(3):365–72.
Boehnke C, Reuter U, Flach U, Schuh-Hofer S, Einhäupl KM, Arnold G. High-dose
riboflavin treatment is efficacious in migraine prophylaxis: an open study in a
tertiary care centre. Eur J Neurol 2004;11(7):475–7.
Boles RG, Burnett BB, Gleditsch K, Wong S, Guedalia A, Kaariainen A, et al. A high
predisposition to depression and anxiety in mothers and other matrilineal relatives
of children with presumed maternally inherited mitochondrial disorders. Am J Med
Genet B Neuropsychiatr Genet 2005;137B(1):20–4.
Bosbach S, Kornblum C, Schröder R, Wagner M. Executive and visuospatial deficits in
patients with chronic progressive external ophthalmoplegia and Kearns–Sayre
syndrome. Brain 2003;126(Pt 5):1231–40.
Bredesen DE, Rao RV, Mehlen P. Cell death in the nervous system. Nature 2006;443(7113):
796–802.
Breslau N, Lipton RB, Stewart WF, Schultz LR, Welch KM. Comorbidity of migraine and
depression: investigating potential etiology and prognosis. Neurology 2003;60(8):
1308–12.
Brini M, Pinton P, King MP, Davidson M, Schon EA, Rizzuto R. A calcium signaling defect
in the pathogenesis of a mitochondrial DNA inherited oxidative phosphorylation
deficiency. Nat Med 1999;5(8):951–4.
Burgmer M, Gaubitz M, Konrad C, Wrenger M, Hilgart S, Heuft G, et al. Decreased gray
matter volumes in the cingulo-frontal cortex and the amygdala in patients with
fibromyalgia. Psychosom Med 2009;71(5):566–73.
Búrigo M, Roza CA, Bassani C, Fagundes DA, Rezin GT, Feier G, et al. Effect of
electroconvulsive shock on mitochondrial respiratory chain in rat brain. Neurochem Res 2006;31(11):1375–9.
Burnett BB, Gardner A, Boles RG. Mitochondrial inheritance in depression, dysmotility
and migraine? J Affect Disord 2005;88(1):109–16.
Campbell S, MacQueen G. An update on regional brain volume differences associated
with mood disorders. Curr Opin Psychiatry 2006;19(1):25–33.
Campbell S, Marriott M, Nahmias C, MacQueen GM. Lower hippocampal volume in
patients suffering from depression: a meta-analysis. Am J Psychiatry 2004;161(4):
598–607.
Capuron L, Fornwalt FB, Knight BT, Harvey PD, Ninan PT, Miller AH. Does cytokineinduced depression differ from idiopathic major depression in medically healthy
individuals? J Affect Disord 2009a;119(1–3):181–5.
Capuron L, Moranis A, Combe N, Cousson-Gélie F, Fuchs D, De Smedt-Peyrusse V, et al.
Vitamin E status and quality of life in the elderly: influence of inflammatory
processes. Br J Nutr 2009b;102(10):1390–4.
Carelli V, Bellan M. Myelin, mitochondria, and autoimmunity: what's the connection?
Neurology 2008;70(13 Pt 2):1075–6.
Cassano GB, Dell'Osso L, Frank E, Miniati M, Fagiolini A, Shear K, et al. The bipolar
spectrum: a clinical reality in search of diagnostic criteria and an assessment
methodology. J Affect Disord 1999;54(3):319–28.
Cataldo AM, McPhie DL, Lange NT, Punzell S, Elmiligy S, Ye NZ, et al. Abnormalities in
mitochondrial structure in cells from patients with bipolar disorder. Am J Pathol
2010;177(2):575–85.
Chinnery PF, Schon EA. Mitochondria. J Neurol Neurosurg Psychiatry 2003;74(9):
1188–99.
Chinnery PF, Turnbull DM. Mitochondrial medicine. QJM 1997;90(11):657–67.
Ciccone DS, Natelson BH. Comorbid illness in women with chronic fatigue syndrome: a
test of the single syndrome hypothesis. Psychosom Med 2003;65(2):268–75.
Cobianchi L, Fornoni A, Pileggi A, Molano RD, Sanabria NY, Gonzalez-Quintana J, et al.
Riboflavin inhibits IL-6 expression and p38 activation in islet cells. Cell Transplant
2008;17(5):559–66.
Condò M, Posar A, Arbizzani A, Parmeggiani A. Riboflavin prophylaxis in pediatric and
adolescent migraine. J Headache Pain 2009;10(5):361–5.
Coppen A. The biochemistry of affective disorders. Br J Psychiatry 1967;113(504):
1237–64.
Cordero MD, Moreno-Fernández AM, deMiguel M, Bonal P, Campa F, Jiménez-Jiménez
LM, et al. Coenzyme Q10 distribution in blood is altered in patients with
fibromyalgia. Clin Biochem 2009;42(7–8):732–5.
Corruble E, Guelfi JD. Pain complaints in depressed inpatients. Psychopathology
2000;33(6):307–9.
Curti C, Mingatto FE, Polizello AC, Galastri LO, Uyemura SA, Santos AC. Fluoxetine
interacts with the lipid bilayer of the inner membrane in isolated rat brain
mitochondria, inhibiting electron transport and F1F0-ATPase activity. Mol Cell
Biochem 1999;199(1–2):103–9.
de Lange FP, Kalkman JS, Bleijenberg G, Hagoort P, van der Meer JW, Toni I. Gray matter
volume reduction in the chronic fatigue syndrome. Neuroimage 2005;26(3):
777–81.
Depeint F, Bruce WR, Shangari N, Mehta R, O'Brien PJ. Mitochondrial function and
toxicity: role of the B vitamin family on mitochondrial energy metabolism. Chem
Biol Interact 2006;163(1–2):94-112.
Di Lorenzo C, Pierelli F, Coppola G, Grieco GS, Rengo C, Ciccolella M, et al. Mitochondrial
DNA haplogroups influence the therapeutic response to riboflavin in migraineurs.
Neurology 2009;72(18):1588–94.
Diamond M, Kelly JP, Connor TJ. Antidepressants suppress production of the Th1
cytokine interferon-gamma, independent of monoamine transporter blockade. Eur
Neuropsychopharmacol 2006;16(7):481–90.
DiMauro S, Schon EA. Mitochondrial disorders in the nervous system. Annu Rev
Neurosci 2008;31:91-123.
DiMauro S, Hirano M, Kaufmann P, Mann JJ. Mitochondrial psychiatry. In: DiMauro S,
Hirano M, Schon EA, editors. Mitochondrial medicine. London: Informa Healthcare;
2006. p. 261–77.
Dinan TG, Quigley EM, Ahmed SM, Scully P, O'Brien S, O'Mahony L, et al. Hypothalamic–
pituitary–gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a
potential biomarker? Gastroenterology 2006;130(2):304–11.
Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. A meta-analysis of
cytokines in major depression. Biol Psychiatry 2010;67(5):446–57.
Fattal O, Link J, Quinn K, Cohen BH, Franco K. Psychiatric comorbidity in 36 adults with
mitochondrial cytopathies. CNS Spectr 2007;12(6):429–38.
Feng J, Zhang Z, Li W, Shen X, Song W, Yang C, et al. Missense mutations in the MEFV
gene are associated with fibromyalgia syndrome and correlate with elevated IL1beta plasma levels. PLoS ONE 2009;4(12):e8480.
Filosto M, Tomelleri G, Tonin P, Scarpelli M, Vattemi G, Rizzuto N, et al. Neuropathology
of mitochondrial diseases. Biosci Rep 2007;27(1–3):23–30.
Finsterer J. Mitochondriopathies. Eur J Neurol 2004;11(3):163–86.
Finsterer J, Segall L. Drugs interfering with mitochondrial disorders. Drug Chem Toxicol
2010;33(2):138–51.
Fletcher MA, Zeng XR, Barnes Z, Levis S, Klimas NG. Plasma cytokines in women with
chronic fatigue syndrome. J Transl Med 2009;7:96.
Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC, et al.
Antidepressant drug effects and depression severity: a patient-level meta-analysis.
JAMA 2010;303(1):47–53.
Frances AJ, Egger HL. Whither psychiatric diagnosis. Aust N Z J Psychiatry 1999;33(2):
161–5.
Garakani A, Win T, Virk S, Gupta S, Kaplan D, Masand PS. Comorbidity of irritable bowel
syndrome in psychiatric patients: a review. Am J Ther 2003;10(1):61–7.
Gardner A, Boles RG. Is a “mitochondrial psychiatry” in the future? A review. Curr
Psychiatr Rev 2005;1(3):255–71.
Gardner A, Boles RG. Mitochondrial energy depletion in depression with somatization.
Psychother Psychosom 2008a;77(2):127–9.
Gardner A, Boles RG. Symptoms of somatization as a rapid screening tool for
mitochondrial dysfunction in depression. Biopsychosoc Med 2008b;22(2):7.
Gardner A, Pagani M. A review of SPECT in neuropsychiatric disorders: neurobiological
background, methodology, findings and future perspectives. Alasbimn J 2003;5(21)
[http://www2.alasbimnjournal.cl/alasbimn/CDA/sec_b/0,1206,SCID%253D4387,00.
html].
Gardner A, Pagani M, Wibom R, Nennesmo I, Jacobsson H, Hällström T. Alterations of
rCBF and mitochondrial dysfunction in major depressive disorder: a case report.
Acta Psychiatr Scand 2003a;107(3):233–9.
Gardner A, Johansson A, Wibom R, Nennesmo I, von Döbeln U, Hagenfeldt L, et al.
Alterations of mitochondrial function and correlations with personality traits in
selected major depressive disorder patients. J Affect Disord 2003b;76(1–3):55–68.
Gardner A, Kaplan BJ, Rucklidge JJ, Jonsson BH, Humble MB. The potential of nutritional
therapy. Science 2010;327(5963):268.
Gold DR, Cohen BH. Treatment of mitochondrial cytopathies. Semin Neurol 2001;21(3):
309–25.
Goodman DW, Thase ME. Recognizing ADHD in adults with comorbid mood disorders:
implications for identification and management. Postgrad Med 2009;121(5):
20–30.
Gros DF, Antony MM, McCabe RE, Swinson RP. Frequency and severity of the symptoms
of irritable bowel syndrome across the anxiety disorders and depression. J Anxiety
Disord 2009;23(2):290–6.
A. Gardner, R.G. Boles / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 730–743
Gu Y, Wang C, Roifman CM, Cohen A. Role of MHC class I in immune surveillance of
mitochondrial DNA integrity. J Immunol 2003;170(7):3603–7.
Gupta S, Aggarwal S, See D, Starr A. Cytokine production by adherent and nonadherent mononuclear cells in chronic fatigue syndrome. J Psychiatr Res 1997;31(1):
149–56.
Gür A, Karakoç M, Nas K, Cevik R, Denli A, Saraç J. Cytokines and depression in cases
with fibromyalgia. J Rheumatol 2002;29(2):358–61.
Haas RH, Parikh S, Falk MJ, Saneto RP, Wolf NI, Darin N, et al. Mitochondrial Medicine
Society's Committee on Diagnosis. The in-depth evaluation of suspected mitochondrial disease. Mol Genet Metab 2008;94(1):16–37.
Härtel C, Strunk T, Bucsky P, Schultz C. Effects of vitamin C on intracytoplasmic cytokine
production in human whole blood monocytes and lymphocytes. Cytokine 2004;27(4–5):
101–6.
Hasselmann O, Blau N, Ramaekers VT, Quadros EV, Sequeira JM, Weissert M. Cerebral
folate deficiency and CNS inflammatory markers in Alpers disease. Mol Genet
Metab 2010;99(1):58–61.
Hershey AD, Powers SW, Vockell AL, Lecates SL, Ellinor PL, Segers A, et al. Coenzyme
Q10 deficiency and response to supplementation in pediatric and adolescent
migraine. Headache 2007;47(1):73–80.
Hohlfeld R, Kerschensteiner M, Stadelmann C, Lassmann H, Wekerle H. The
neuroprotective effect of inflammation: implications for the therapy of multiple
sclerosis. Neurol Sci 2006;27(Suppl 1):S1–7.
Hokama Y, Campora CE, Hara C, Kuribayashi T, Le Huynh D, Yabusaki K. Anticardiolipin
antibodies in the sera of patients with diagnosed chronic fatigue syndrome. J Clin
Lab Anal 2009;23(4):210–2.
Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in
patients with mitochondrial myopathies. Nature 1988;331(6158):717–9.
Houshmand M, Gardner A, Hällström T, Müntzing K, Oldfors A, Holme E. Different tissue
distribution of a mitochondrial DNA duplication and the corresponding deletion in
a patient with a mild mitochondrial encephalomyopathy: deletion in muscle,
duplication in blood. Neuromuscul Disord 2004;14(3):195–201.
Hsu MC, Harris RE, Sundgren PC, Welsh RC, Fernandes CR, Clauw DJ, et al. No consistent
difference in gray matter volume between individuals with fibromyalgia and agematched healthy subjects when controlling for affective disorder. Pain 2009;143(3):
262–7.
Huang CN, Jee SH, Hwang JJ, Kuo YF, Chuang LM. Autoimmune IDDM in a sporadic
MELAS patient with mitochondrial tRNA(Leu(UUR)) mutation. Clin Endocrinol
(Oxf) 1998;49(2):265–70.
Hudson G, Chinnery PF. Mitochondrial DNA polymerase-gamma and human disease.
Hum Mol Genet 2006;15(Spec No 2):R244–52.
Hudson JI, Arnold LM, Keck Jr PE, Auchenbach MB, Pope Jr HG. Family study of
fibromyalgia and affective spectrum disorder. Biol Psychiatry 2004;56(11):884–91.
Insel TR, Wang PS. The STAR D trial: revealing the need for better treatments. Psychiatr
Serv 2009;60(11):1466–7.
Ishikawa S, Mima T, Aoki C, Yoshio-Hoshino N, Adachi Y, Imagawa T, et al. Abnormal
expression of the genes involved in cytokine networks and mitochondrial function
in systemic juvenile idiopathic arthritis identified by DNA microarray analysis. Ann
Rheum Dis 2009;68(2):264–72.
Isotani H, Fukumoto Y, Kawamura H, Furukawa K, Ohsawa N, Goto Y, et al.
Hypoparathyroidism and insulin-dependent diabetes mellitus in a patient with
Kearns–Sayre syndrome harbouring a mitochondrial DNA deletion. Clin Endocrinol
(Oxf) 1996;45(5):637–41.
Janowsky DS. Bipolar disorder- and major depression—relevant abstracts from the 2009
9th World Congress of Biological Psychiatry Meeting. Curr Psychiatry Rep 2009;11(6):
509–11.
Jeffree RL, Wills EJ, Harper C. An unusual myopathy: speckled muscle fibers due to
enlarged mitochondria. Muscle Nerve 2007;36(1):118–22.
Jesudason EP, Masilamoni JG, Jebaraj CE, Paul SF, Jayakumar R. Efficacy of DL-alpha lipoic
acid against systemic inflammation-induced mice: antioxidant defense system.
Mol Cell Biochem 2008;313(1–2):113–23.
Judd LL, Akiskal HS, Maser JD, Zeller PJ, Endicott J, Coryell W, et al. A prospective 12-year
study of subsyndromal and syndromal depressive symptoms in unipolar major
depressive disorders. Arch Gen Psychiatry 1998;55(8):694–700.
Karry R, Klein E, Ben Shachar D. Mitochondrial complex I subunits expression is altered
in schizophrenia: a postmortem study. Biol Psychiatry 2004;55(7):676–84.
Kasahara T, Kubota M, Miyauchi T, Noda Y, Mouri A, Nabeshima T, et al. Mice with
neuron-specific accumulation of mitochondrial DNA mutations show mood
disorder-like phenotypes. Mol Psychiatry 2006;11(6):577–93 523.
Kasahara T, Kubota M, Miyauchi T, Ishiwata M, Kato T. A marked effect of
electroconvulsive stimulation on behavioral aberration of mice with neuronspecific mitochondrial DNA defects. PLoS ONE 2008;3(3):e1877.
Kato T, Stine OC, McMahon FJ, Crowe RR. Increased levels of a mitochondrial DNA
deletion in the brain of patients with bipolar disorder. Biol Psychiatry 1997;42(10):
871–5.
Kato K, Sullivan PF, Evengård B, Pedersen NL. A population-based twin study of
functional somatic syndromes. Psychol Med 2009;39(3):497–505.
Katyare SS, Rajan RR. Effect of long-term in vivo treatment with imipramine on the
oxidative energy metabolism in rat brain mitochondria. Comp Biochem Physiol C
Pharmacol Toxicol Endocrinol 1995;112(3):353–7.
Kendler KS, Muñoz RA, Murphy G. The development of the Feighner criteria: a historical
perspective. Am J Psychiatry 2010;167(2):134–42.
Kenis G, Maes M. Effects of antidepressants on the production of cytokines. Int J
Neuropsychopharmacol 2002;5(4):401–12.
Khanzode SD, Dakhale GN, Khanzode SS, Saoji A, Palasodkar R. Oxidative damage and
major depression: the potential antioxidant action of selective serotonin re-uptake
inhibitors. Redox Rep 2003;8(6):365–70.
741
Kiliçaslan SM, Ayvali C, Tastan H. A microscopic study of kidney tissue in Familial
Mediterranean Fever patients. Cell Biochem Funct 2007;25(4):363–7.
Kim JH, Suh SI, Seol HY, Oh K, Seo WK, Yu SW, et al. Regional grey matter changes in
patients with migraine: a voxel-based morphometry study. Cephalalgia 2008;28(6):
598–604.
Kim J, Xu M, Xo R, Mates A, Wilson GL, Pearsall 4th AW, et al. Mitochondrial DNA
damage is involved in apoptosis caused by pro-inflammatory cytokines in human
OA chondrocytes. Osteoarthritis Cartilage 2010;18(3):424–32.
Klein DN. Classification of depressive disorders in the DSM-V: proposal for a twodimension system. J Abnorm Psychol 2008;117(3):552–60.
Koçer A, Memisogullari R, Domaç FM, Ilhan A, Koçer E, Okuyucu S, et al. IL-6 levels in
migraine patients receiving topiramate. Pain Pract 2009;9(5):375–9.
Kodama K, Suzuki M, Toyosawa T, Araki S. Inhibitory mechanisms of highly purified
vitamin B2 on the productions of proinflammatory cytokine and NO in endotoxininduced shock in mice. Life Sci 2005;78(2):134–9.
Koene S, Kozicz TL, Rodenburg RJ, Verhaak CM, de Vries MC, Wortmann S, et al. Major
depression in adolescent children consecutively diagnosed with mitochondrial
disorder. J Affect Disord 2009;114(1–3):327–32.
Komulainen T, Hinttala R, Kärppä M, Pajunen L, Finnilä S, Tuominen H, et al. POLG1 p.
R722H mutation associated with multiple mtDNA deletions and a neurological
phenotype. BMC Neurol 2010;10:29.
Kovács GG, Höftberger R, Majtényi K, Horváth R, Barsi P, Komoly S, et al.
Neuropathology of white matter disease in Leber's hereditary optic neuropathy.
Brain 2005;128(Pt 1):35–41.
Kuchinad A, Schweinhardt P, Seminowicz DA, Wood PB, Chizh BA, Bushnell MC.
Accelerated brain gray matter loss in fibromyalgia patients: premature aging of the
brain? J Neurosci 2007;27(15):4004–7.
Kuhlmann T, Goldschmidt T, Antel J, Wegner C, König F, Metz I, et al. Gender differences
in the histopathology of MS? J Neurol Sci 2009;286(1–2):86–91.
Lange G, Holodny AI, DeLuca J, Lee HJ, Yan XH, Steffener J, et al. Quantitative assessment
of cerebral ventricular volumes in chronic fatigue syndrome. Appl Neuropsychol
2001;8(1):23–30.
Langhorst J, Junge A, Rueffer A, Wehkamp J, Foell D, Michalsen A, et al. Elevated human
beta-defensin-2 levels indicate an activation of the innate immune system in
patients with irritable bowel syndrome. Am J Gastroenterol 2009;104(2):404–10.
Le Goff P. Is fibromyalgia a muscle disorder? Joint Bone Spine 2006;73(3):239–42.
Lee S, Ng KL, Tsang A. Prevalence and correlates of depression with atypical symptoms
in Hong Kong. Aust N Z J Psychiatry 2009;43(12):1147–54.
Lerman-Sagie T, Leshinsky-Silver E, Watemberg N, Luckman Y, Lev D. White matter
involvement in mitochondrial diseases. Mol Genet Metab 2005;84(2):127–36.
Lestienne P, Ponsot G. Kearns–Sayre syndrome with muscle mitochondrial DNA
deletion. Lancet 1988;1(8590):885.
Liebregts T, Adam B, Bredack C, Röth A, Heinzel S, Lester S, et al. Immune activation in
patients with irritable bowel syndrome. Gastroenterology 2007;132(3):913–20.
Lindberg G, Törnblom H, Iwarzon M, Nyberg B, Martin JE, Veress B. Full-thickness
biopsy findings in chronic intestinal pseudo-obstruction and enteric dysmotility.
Gut 2009;58(8):1084–90.
Lister RE. An open, pilot study to evaluate the potential benefits of coenzyme Q10 combined
with Ginkgo biloba extract in fibromyalgia syndrome. J Int Med Res 2002;30(2):195–9.
Luft R. The development of mitochondrial medicine. Proc Natl Acad Sci USA 1994;1
(19):8731–8.
Luft R, Ikkos D, Palmieri G, Ernster L, Afzelius B. A case of severe hypermetabolism of
nonthyroid origin with a defect in the maintenance of mitochondrial respiratory
control: a correlated clinical, biochemical, and morphological study. J Clin Invest
1962;41:1776–804.
Lutz J, Jäger L, de Quervain D, Krauseneck T, Padberg F, Wichnalek M, et al. White and
gray matter abnormalities in the brain of patients with fibromyalgia: a diffusiontensor and volumetric imaging study. Arthritis Rheum 2008;58(12):3960–9.
MacLennan SC, Wade FM, Forrest KM, Ratanayake PD, Fagan E, Antony J. High-dose
riboflavin for migraine prophylaxis in children: a double-blind, randomized,
placebo-controlled trial. J Child Neurol 2008;23(11):1300–4.
Maes M, Bosmans E, Suy E, Vandervorst C, De Jonckheere C, Raus J. Immune
disturbances during major depression: upregulated expression of interleukin-2
receptors. Neuropsychobiology 1990-1991;24(3):115–20.
Maes M, Smith R, Scharpe S. The monocyte–T-lymphocyte hypothesis of major
depression. Psychoneuroendocrinology 1995;20(2):111–6.
Maes M, De Vos N, Pioli R, Demedts P, Wauters A, Neels H, et al. Lower serum vitamin E
concentrations in major depression. Another marker of lowered antioxidant
defenses in that illness. J Affect Disord 2000;58(3):241–6.
Maes M, Yirmyia R, Noraberg J, Brene S, Hibbeln J, Perini G, et al. The inflammatory &
neurodegenerative (I&ND) hypothesis of depression: leads for future research and
new drug developments in depression. Metab Brain Dis 2009a;24(1):27–53.
Maes M, Mihaylova I, Kubera M, Uytterhoeven M. Lower plasma Coenzyme Q10 in
depression: a marker for treatment resistance and chronic fatigue in depression
and a risk factor to cardiovascular disorder in that illness. Neuro Endocrinol Lett
2009b;30(4):462–9.
Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Coenzyme
Q10 deficiency in myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS)
is related to fatigue, autonomic and neurocognitive symptoms and is another risk
factor explaining the early mortality in ME/CFS due to cardiovascular disorder.
Neuro Endocrinol Lett 2009c;30(4):470–6.
Magis D, Ambrosini A, Sándor P, Jacquy J, Laloux P, Schoenen J. A randomized doubleblind placebo-controlled trial of thioctic acid in migraine prophylaxis. Headache
2007;47(1):52–7.
Mak AD. Prevalence and correlates of bipolar II disorder in major depressive patients at
a psychiatric outpatient clinic in Hong Kong. J Affect Disord 2009;112(1–3):201–5.
742
A. Gardner, R.G. Boles / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 730–743
Makay B, Emiroglu N, Unsal E. Depression and anxiety in children and adolescents with
familial Mediterranean fever. Clin Rheumatol 2010;29(4):375–9.
Mancuso M, Orsucci D, Coppedè F, Nesti C, Choub A, Siciliano G. Diagnostic approach to
mitochondrial disorders: the need for a reliable biomarker. Curr Mol Med 2009;9(9):
1095–107.
Mao P, Reddy PH. Is multiple sclerosis a mitochondrial disease? Biochim Biophys Acta
2010;1802(1):66–79.
Mathew RJ, Weinman ML, Mirabi M. Physical symptoms of depression. Br J Psychiatry
1981;139:293–6.
Maurer IC, Schippel P, Volz HP. Lithium-induced enhancement of mitochondrial
oxidative phosphorylation in human brain tissue. Bipolar Disord 2009;11(5):
515–22.
McKenzie M, Liolitsa D, Hanna MG. Mitochondrial disease: mutations and mechanisms.
Neurochem Res 2004;29(3):589–600.
Merikangas KR, He JP, Brody D, Fisher PW, Bourdon K, Koretz DS. Prevalence and
treatment of mental disorders among US children in the 2001–2004 NHANES.
Pediatrics 2010;125(1):75–81.
Mezuk B, Eaton WW, Albrecht S, Golden SH. Depression and type 2 diabetes over the
lifespan: a meta-analysis. Diabetes Care 2008;31(12):2383-90. Comment in:
Diabetes Care 2009;32(5):e56; author reply e57.
Miguel-Carrasco JL, Mate A, Monserrat MT, Arias JL, Aramburu O, Vázquez CM. The role
of inflammatory markers in the cardioprotective effect of L-carnitine in L-NAMEinduced hypertension. Am J Hypertens 2008;21(11):1231–7.
Miller AH. Depression and immunity: a role for T cells? Brain Behav Immun 2010;24(1):
1–8.
Miwa K, Fujita M. Increased oxidative stress suggested by low serum vitamin E
concentrations in patients with chronic fatigue syndrome. Int J Cardiol 2009;136(2):
238–9.
Mizukami K, Sasaki M, Suzuki T, Shiraishi H, Koizumi J, Ohkoshi N, et al. Central nervous
system changes in mitochondrial encephalomyopathy: light and electron microscopic study. Acta Neuropathol 1992;83(4):449–52.
Morrissey SP, Borruat FX, Miller DH, Moseley IF, Sweeney MG, Govan GG, et al. Bilateral
simultaneous optic neuropathy in adults: clinical, imaging, serological, and genetic
studies. J Neurol Neurosurg Psychiatry 1995;58(1):70–4.
Mullick MS, Nahar JS, Haq SA. Psychiatric morbidity, stressors, impact, and burden in
juvenile idiopathic arthritis. J Health Popul Nutr 2005;23(2):142–9.
Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial
dysfunction. Int J Clin Exp Med 2009;2(1):1-16.
Nahon E, Israelson A, Abu-Hamad S, Varda SB. Fluoxetine (Prozac) interaction with the
mitochondrial voltage-dependent anion channel and protection against apoptotic
cell death. FEBS Lett 2005;579(22):5105–10.
Nierenberg AA, Miyahara S, Spencer T, Wisniewski SR, Otto MW, Simon N, et al. Clinical
and diagnostic implications of lifetime attention-deficit/hyperactivity disorder
comorbidity in adults with bipolar disorder: data from the first 1000 STEP-BD
participants. Biol Psychiatry 2005;57(11):1467–73.
Nordquist N, Oreland L. Serotonin, genetic variability, behaviour, and psychiatric
disorders—a review. Ups J Med Sci 2010;115(1):2-10.
Oexle K, Oberle J, Finckh B, Kohlschütter A, Nagy M, Seibel P, et al. Islet cell antibodies in
diabetes mellitus associated with a mitochondrial tRNA(Leu(UUR)) gene mutation.
Exp Clin Endocrinol Diabetes 1996;104(3):212–7.
Öhman L, Isaksson S, Lindmark AC, Posserud I, Stotzer PO, Strid H, et al. T-cell activation
in patients with irritable bowel syndrome. Am J Gastroenterol 2009;104(5):
1205–12.
Okasha A, Okasha T. Notes on mental disorders in Pharaonic Egypt. Hist Psychiatry
2000;11:413–24.
Oldfors A, Fyhr IM, Holme E, Larsson NG, Tulinius M. Neuropathology in Kearns–Sayre
syndrome. Acta Neuropathol 1990;80(5):541–6.
Owen AJ, Batterham MJ, Probst YC, Grenyer BF, Tapsell LC. Low plasma vitamin E levels
in major depression: diet or disease? Eur J Clin Nutr 2005;59(2):304–6.
Ozawa T. Genetic and functional changes in mitochondria associated with aging.
Physiol Rev 1997;77(2):425–64.
Palace J. Inflammation versus neurodegeneration: consequences for treatment. J Neurol
Sci 2007;259(1–2):46–9.
Palace J. Multiple sclerosis associated with Leber's hereditary optic neuropathy. J Neurol
Sci 2009;286(1–2):24–7.
Parashos IA, Tupler LA, Blitchington T, Krishnan KR. Magnetic-resonance morphometry
in patients with major depression. Psychiatry Res 1998;84(1):7-15.
Parikh S, Cohen BH, Gupta A, Lachhwani DK, Wyllie E, Kotagal P. Metabolic testing in the
pediatric epilepsy unit. Pediatr Neurol 2008;38(3):191–5.
Parikh S, Saneto R, Falk MJ, Anselm I, Cohen BH, Haas R. A modern approach to the
treatment of mitochondrial disease. Curr Treat Options Neurol 2009;11(6):414–30.
Patarca R. Cytokines and chronic fatigue syndrome. Ann NY Acad Sci 2001;933:
185–200.
Perez F, Anne O, Debruxelles S, Menegon P, Lambrecq V, Lacombe D, et al. Leber's optic
neuropathy associated with disseminated white matter disease: a case report and
review. Clin Neurol Neurosurg 2009;111(1):83–6.
Perini F, D'Andrea G, Galloni E, Pignatelli F, Billo G, Alba S, et al. Plasma cytokine levels in
migraineurs and controls. Headache 2005;45(7):926–31.
Pettegrew JW, Levine J, McClure RJ. Acetyl-L-carnitine physical-chemical, metabolic,
and therapeutic properties: relevance for its mode of action in Alzheimer's disease
and geriatric depression. Mol Psychiatry 2000;5(6):616–32.
Piao YS, Tang GC, Yang H, Lu DH. Clinico-neuropathological study of a Chinese case of
familial adult Leigh syndrome. Neuropathology 2006;26(3):218–21.
Quiroz JA, Gray NA, Kato T, Manji HK. Mitochondrially mediated plasticity in the
pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology
2008;33(11):2551–65.
Regenold WT, Phatak P, Marano CM, Gearhart L, Viens CH, Hisley KC. Myelin staining of
deep white matter in the dorsolateral prefrontal cortex in schizophrenia, bipolar
disorder, and unipolar major depression. Psychiatry Res 2007;151(3):179–88 30.
Regenold WT, Phatak P, Makley MJ, Stone RD, Kling MA. Cerebrospinal fluid evidence of
increased extra-mitochondrial glucose metabolism implicates mitochondrial
dysfunction in multiple sclerosis disease progression. J Neurol Sci 2008;275(1–2):
106–12.
Rodriguez MC, MacDonald JR, Mahoney DJ, Parise G, Beal MF, Tarnopolsky MA.
Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders.
Muscle Nerve 2007;35(2):235–42.
Roitman S, Green T, Osher Y, Karni N, Levine J. Creatine monohydrate in resistant
depression: a preliminary study. Bipolar Disord 2007;9(7):754–8.
Rosenberg RN. Mitochondrial medicine. Book review. Arch Neurol 2006;63(10):1505.
Rousseau G. Depression's forgotten genealogy: notes towards a history of depression.
Hist Psychiatry 2000;11(41 Pt 1):71-106.
Rubinsztein DC. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 2006;443(7113):780–6.
Sabunciyan S, Kirches E, Krause G, Bogerts B, Mawrin C, Llenos IC, et al. Quantification of
total mitochondrial DNA and mitochondrial common deletion in the frontal cortex
of patients with schizophrenia and bipolar disorder. J Neural Transm 2007;114(5):
665–74.
Sándor PS, Di Clemente L, Coppola G, Saenger U, Fumal A, Magis D, et al. Efficacy of
coenzyme Q10 in migraine prophylaxis: a randomized controlled trial. Neurology
2005;64(4):713–5.
Sarandol A, Sarandol E, Eker SS, Erdinc S, Vatansever E, Kirli S. Major depressive
disorder is accompanied with oxidative stress: short-term antidepressant
treatment does not alter oxidative–antioxidative systems. Hum Psychopharmacol
2007;22(2):67–73.
Sarchielli P, Alberti A, Baldi A, Coppola F, Rossi C, Pierguidi L, et al. Proinflammatory
cytokines, adhesion molecules, and lymphocyte integrin expression in the internal
jugular blood of migraine patients without aura assessed ictally. Headache 2006;46(2):
200–7.
Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of
supporting evidence. Am J Psychiatry 1965;122(5):509–22.
Schmelzer C, Lorenz G, Lindner I, Rimbach G, Niklowitz P, Menke T, et al. Effects of
Coenzyme Q10 on TNF-alpha secretion in human and murine monocytic cell lines.
Biofactors 2007a;31(1):35–41.
Schmelzer C, Lorenz G, Rimbach G, Döring F. Influence of coenzyme Q_{10} on release of
pro-inflammatory chemokines in the human monocytic cell line THP-1. Biofactors
2007b;31(3–4):211–7.
Schmelzer C, Lindner I, Rimbach G, Niklowitz P, Menke T, Döring F. Functions of
coenzyme Q10 in inflammation and gene expression. Biofactors 2008;32(1–4):
179–83.
Schmidt-Wilcke T, Luerding R, Weigand T, Jürgens T, Schuierer G, Leinisch E, et al.
Striatal grey matter increase in patients suffering from fibromyalgia—a voxel-based
morphometry study. Pain 2007;132(Suppl 1):S109–16.
Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine
prophylaxis. A randomized controlled trial. Neurology 1998;50(2):466–70.
Scholte HR, Luyt-Houwen IE, Vaandrager-Verduin MH. The role of the carnitine system
in myocardial fatty acid oxidation: carnitine deficiency, failing mitochondria and
cardiomyopathy. Basic Res Cardiol 1987;82(Suppl 1):63–73.
Schon EA, Bonilla E, DiMauro S. Mitochondrial DNA mutations and pathogenesis. J
Bioenerg Biomembr 1997;29(2):131–49.
Schwartz M, Vissing J. New patterns of inheritance in mitochondrial disease. Biochem
Biophys Res Commun 2003;310(2):247–51.
Sciacco M, Prelle A, Comi GP, Napoli L, Battistel A, Bresolin N, et al. Retrospective
study of a large population of patients affected with mitochondrial disorders:
clinical, morphological and molecular genetic evaluation. J Neurol 2001;248(9):
778–88.
Shao L, Martin MV, Watson SJ, Schatzberg A, Akil H, Myers RM, et al. Mitochondrial
involvement in psychiatric disorders. Ann Med 2008;40(4):281–95.
Simon GE, VonKorff M, Piccinelli M, Fullerton C, Ormel J. An international study of the
relation between somatic symptoms and depression. N Engl J Med 1999;341(18):
1329–35.
Smeitink JA. Mitochondrial disorders: clinical presentation and diagnostic dilemmas. J
Inherit Metab Dis 2003;26(2–3):199–207.
Souza ME, Polizello AC, Uyemura SA, Castro-Silva O, Curti C. Effect of fluoxetine on rat
liver mitochondria. Biochem Pharmacol 1994;48(3):535–41 3.
Sparaco M, Bonilla E, DiMauro S, Powers JM. Neuropathology of mitochondrial
encephalomyopathies due to mitochondrial DNA defects. J Neuropathol Exp
Neurol 1993;52(1):1-10.
Sparaco M, Simonati A, Cavallaro T, Bartolomei L, Grauso M, Piscioli F, et al. MELAS:
clinical phenotype and morphological brain abnormalities. Acta Neuropathol
2003;106(3):202–12.
Sparaco M, Feleppa M, Lipton RB, Rapoport AM, Bigal ME. Mitochondrial dysfunction
and migraine: evidence and hypotheses. Cephalalgia 2006;26(4):361–72.
Spinazzola A, Zeviani M. Disorders from perturbations of nuclear-mitochondrial
intergenomic cross-talk. J Intern Med 2009;265(2):174–92.
Sprague AH, Khalil RA. Inflammatory cytokines in vascular dysfunction and vascular
disease. Biochem Pharmacol 2009;78(6):539–52.
Steiner TJ, Hering R, Couturier EG, Davies PT, Whitmarsh TE. Double-blind placebocontrolled trial of lithium in episodic cluster headache. Cephalalgia 1997;17(6):
673–5.
Steingard RJ, Renshaw PF, Hennen J, Lenox M, Cintron CB, Young AD, et al. Smaller
frontal lobe white matter volumes in depressed adolescents. Biol Psychiatry
2002;52(5):413–7.
A. Gardner, R.G. Boles / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 730–743
Stine OC, Luu SU, Zito M, Casanova M. The possible association between affective
disorder and partially deleted mitochondrial DNA. Biol Psychiatry 1993;33(2):
141–2.
Stockmeier CA, Mahajan GJ, Konick LC, Overholser JC, Jurjus GJ, Meltzer HY, et al.
Cellular changes in the postmortem hippocampus in major depression. Biol
Psychiatry 2004;56(9):640–50.
Su KG, Banker G, Bourdette D, Forte M. Axonal degeneration in multiple sclerosis: the
mitochondrial hypothesis. Curr Neurol Neurosci Rep 2009;9(5):411–7.
Sullivan PF, Kendler KS. Typology of common psychiatric syndromes. An empirical
study. Br J Psychiatry 1998;173:312–9.
Szuster-Ciesielska A, Slotwinska M, Stachura A, Marmurowska-Michalowska H, DubasSlemp H, Bojarska-Junak A, et al. Accelerated apoptosis of blood leukocytes and
oxidative stress in blood of patients with major depression. Prog Neuropsychopharmacol Biol Psychiatry 2008;32(3):686–94.
Tanahashi C, Nakayama A, Yoshida M, Ito M, Mori N, Hashizume Y. MELAS with the
mitochondrial DNA 3243 point mutation: a neuropathological study. Acta
Neuropathol 2000;99(1):31–8.
Tarnopolsky MA. The mitochondrial cocktail: rationale for combined nutraceutical therapy
in mitochondrial cytopathies. Adv Drug Deliv Rev 2008;60(13–14):1561–7.
Thompson LM. Neurodegeneration: a question of balance. Nature 2008;452(7188):
707–8.
Törnblom H, Lindberg G, Nyberg B, Veress B. Full-thickness biopsy of the jejunum
reveals inflammation and enteric neuropathy in irritable bowel syndrome.
Gastroenterology 2002;123(6):1972–9.
Tousoulis D, Drolias A, Antoniades C, Vasiliadou C, Marinou K, Latsios G, et al.
Antidepressive treatment as a modulator of inflammatory process in patients with
heart failure: effects on proinflammatory cytokines and acute phase protein levels.
Int J Cardiol 2009;134(2):238–43.
Turconi AC, Benti R, Castelli E, Pochintesta S, Felisari G, Comi G, et al. Focal cognitive
impairment in mitochondrial encephalomyopathies: a neuropsychological and
neuroimaging study. J Neurol Sci 1999;170(1):57–63.
Van Alboom E, Louis P, Van Zandijcke M, Crevits L, Vakaet A, Paemeleire K. Diagnostic
and therapeutic trajectory of cluster headache patients in Flanders. Acta Neurol
Belg 2009;109(1):10–7.
Vasic N, Walter H, Höse A, Wolf RC. Gray matter reduction associated with
psychopathology and cognitive dysfunction in unipolar depression: a voxelbased morphometry study. J Affect Disord 2008;109(1–2):107–16.
Veress B, Nyberg B, Törnblom H, Lindberg G. Intestinal lymphocytic epithelioganglionitis: a unique combination of inflammation in bowel dysmotility: a histopathological and immunohistochemical analysis of 28 cases. Histopathology 2009;54(5):
539–49.
Vermeulen RC, Scholte HR. Exploratory open label, randomized study of acetyl- and
propionylcarnitine in chronic fatigue syndrome. Psychosom Med 2004;66(2):276–82.
743
Vernon SD, Whistler T, Cameron B, Hickie IB, Reeves WC, Lloyd A. Preliminary evidence
of mitochondrial dysfunction associated with post-infective fatigue after acute
infection with Epstein Barr virus. BMC Infect Dis 2006;6:15.
Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, et al. Mitochondrial DNA
mutation associated with Leber's hereditary optic neuropathy. Science 1988;242(4884):
1427–30.
Wallace DJ, Linker-Israeli M, Hallegua D, Silverman S, Silver D, Weisman MH. Cytokines
play an aetiopathogenetic role in fibromyalgia: a hypothesis and pilot study.
Rheumatology (Oxf) 2001;40(7):743–9.
Weinbach EC, Costa JL, Nelson BD, Claggett CE, Hundal T, Bradley D, et al. Effects of
tricyclic antidepressant drugs on energy-linked reactions in mitochondria.
Biochem Pharmacol 1986;35(9):1445–51.
Whatley SA, Curti D, Marchbanks RM. Mitochondrial involvement in schizophrenia and
other functional psychoses. Neurochem Res 1996;21(9):995-1004.
Wilens TE, Biederman J, Wozniak J, Gunawardene S, Wong J, Monuteaux M. Can adults
with attention-deficit/hyperactivity disorder be distinguished from those with
comorbid bipolar disorder? Findings from a sample of clinically referred adults. Biol
Psychiatry 2003;54(1):1–8.
Winokur G. All roads lead to depression: clinically homogeneous, etiologically
heterogeneous. J Affect Disord 1997;45(1–2):97-108.
Winokur A, Maislin G, Phillips JL, Amsterdam JD. Insulin resistance after oral glucose
tolerance testing in patients with major depression. Am J Psychiatry 1988;145(3):
325–30.
Yeretssian G, Labbé K, Saleh M. Molecular regulation of inflammation and cell death.
Cytokine 2008;43(3):380–90.
Zeviani M, Moraes CT, DiMauro S, Nakase H, Bonilla E, Schon EA, et al. Deletions of
mitochondrial DNA in Kearns–Sayre syndrome. Neurology 1988;38(9):1339–46.
Zhang DM, Zhou ZG, Weng JP, Li LR, Deng H, Zhang C, et al. Etiological dissection in
common anti-islet autoantibody-negative patients with type 1 diabetes [abstract in
English]. Zhonghua Yi Xue Za Zhi 2004;84(15):1247–51.
Zhang Z, Cherryholmes G, Mao A, Marek C, Longmate J, Kalos M, et al. High plasma
levels of MCP-1 and eotaxin provide evidence for an immunological basis of
fibromyalgia. Exp Biol Med (Maywood) 2008a;233(9):1171–80.
Zhang WH, Wang H, Wang X, Narayanan MV, Stavrovskaya IG, Kristal BS, et al.
Nortriptyline protects mitochondria and reduces cerebral ischemia/hypoxia injury.
Stroke 2008b;39(2):455–62.
Ziaei S, Kazemnejad A, Sedighi A. The effect of vitamin E on the treatment of menstrual
migraine. Med Sci Monit 2009;15(1):CR16–9.
Zimmerman M, Galione JN, Chelminski I, McGlinchey JB, Young D, Dalrymple K, et al. A
simpler definition of major depressive disorder. Psychol Med 2010;40(3):451–7.
Zou K, Deng W, Li T, Zhang B, Jiang L, Huang C, et al. Changes of brain morphometry in
first-episode, drug-naïve, non-late-life adult patients with major depression: an
optimized voxel-based morphometry study. Biol Psychiatry 2010;67(2):186–8.