Connectivity between mitochondrial functions and psychiatric disorders


Jana Hroudová, MPharm, Department of Psychiatry, 1st Faculty of Medicine, Charles University in Prague, Ke Karlovu 11, 121 08 Prague 2, Czech Republic. Email:


Mitochondria provide most of the energy production in cells. They are involved in the regulation of free radicals, calcium buffering, and redox signaling and take part in the intrinsic pathway of apoptosis. Mutations or polymorphisms of mitochondrial DNA, mitochondria-mediated oxidative stress, decrease of adenosine triphosphate production, changes of intracellular calcium and oxidative stress are concerned in various diseases. There is increasing evidence that impaired functions of mitochondria are associated with mood disorders. It is suggested that disturbed energetic metabolism and/or reactive oxygen species production take part in the pathophysiology of mood disorders and could participate in the therapeutic effects or side-effects of antidepressants and mood stabilizers.


MITOCHONDRIA ARE SMALL cellular structures consisting of outer and inner membranes, an intermembrane space and an intracellular matrix. The outer membrane covers the organelle, the inner membrane folds and forms cristae. This settlement extends the surface and enables plenty of chemical reactions. In the mitochondrial matrix, the enzymes of tricarboxylic acid cycle (TCA, also known as citric acid cycle or Krebs cycle) are localized. It is the central pathway of metabolism; its main function is oxidation of acetyl-CoA derived from carbohydrates, amino acids and fatty acids. The TCA is organized into a supramolecular complex that interacts with mitochondrial membranes and the electron transport chain (ETC).1 Therefore, most of the TCA enzymes provide other additional ‘moonlighting’ functions, e.g. they stabilize the mitochondrial DNA (mtDNA) or are associated with mitochondrial RNA (mtRNA) translation, oxidative stress, iron metabolism and tumor suppression.2

Mitochondria provide energy for cellular processes, converting metabolites and producing adenosine-5′-triphosphate (ATP). Thus, they are sometimes called ‘powerhouses’ of cells and the highest number of mitochondria is present in organs demanding the most of energy – brain, liver and muscles. ETC and processes of oxidative phosphorylation (OXPHOS), responsible for energy production, are localized in the inner membrane. The ETC consists of five protein complexes. Three of them (complex I, III and IV) pump protons outwardly through the membrane into the matrix. According to chemiosmotic theory,3 most of the ATP synthesis comes from the electrochemical gradient across the inner membranes of mitochondria by ATP synthase (complex V). Complex I, the main entrance into ETC, catalyzes the two electron reductions by reduced nicotinamide adenine dinucleotide (NADH) of coenzyme Q10; complex II, side entry into ETC, oxidizes succinate to fumarate and reduces koenzyme Q10 by flavin adenine dinucleotide (FADH). Electrons are continuously transported to complex III and finally complex IV enables the conversion of O2 to H2O. Activity of ETC is modulated by coenzyme Q10 at complex III and by cytochrome c at complex IV (cytochrome c oxidase [COX]).

Energy saved in ATP is used in synaptic ion homeostasis and phosphorylation reactions. ATP is essential for the excitability and survival of neurons, OXPHOS is involved in synaptic signaling and is related to changes of neuronal structure and function. Therefore, mitochondria are included in neurotransmitter exocytosis, recovery and in ion homeostasis in presynaptic nerve terminals. The major role is given to complex I (NADH dehydrogenase [ubiquinone], EC in controlling mitochondrial OXPHOS; its abnormality can result in mitochondrial dysfunction.4 Thus, many mitochondrial diseases originate from complex I deficiencies, e.g. Leber's hereditary optic neuropathy, severe and fatal lactic acidosis and various neuromuscular neuropathies.5


The unique property of mitochondria is the possession of their DNA (mtDNA), which is maternally inherited. The human mitochondrial genome contains only 37 structural genes, 13 of them encode polypeptides (the rest of the genes encode ribosomal and transfer RNA). Mitochondrial proteins are encoded by both nuclear and mitochondrial DNA. All 13 mtDNA-encoded polypeptides form subunits of respiratory chain complexes I, III, IV and V. Complex II is encoded only by nuclear DNA (nDNA).6,7

There are several differences between mitochondrial and nuclear DNA. mtDNA is very compact, introns are rarely present, and more than 90% are the sequence-encoding genes. There are neither repairing mechanisms nor histones. In the nucleus, there are plenty of preventing and repairing mechanisms, which protect DNA from damage. In addition, nDNA is protected by histones. In mitochondria, mechanisms of the protection and the possibilities of mtDNA have not yet been sufficiently clarified. It is presumed mtDNA is more sensitive to oxidative changes due to the proximity of the inner mitochondrial membrane, where oxidative agents arise. Superoxide anion radical, hydroxyl radical and products of lipid peroxidation can cause mtDNA mutations and mtDNA damage. Polymorphisms of mtDNA can influence mitochondrial functions as well. Pathogenic mtDNA mutations fall into tree categories: (i) rearrangement mutations8– inherited (primarily insertions) or spontaneous (primarily deletions); (ii) polypeptide gene missense mutations;9 and (iii) protein synthesis (rRNA and tRNA) gene mutations.10,11 Mitochondrial mutations can alter functions of mitochondria – apoptosis, calcium buffering and signaling as well as OXPHOS can be influenced. According to increasing evidence of mtDNA-associated diseases, clinical manifestations have been linked to affect the brain, heart, skeletal muscles, renal, and endocrine systems.11

Interestingly, the exclusive maternal inheritance is reflected in a proportion of cases where the disease is passed through the maternal line. Despite this, the majority of patients with mitochondrial mutations have no family history.12

Reactive oxygen species

The important role of mitochondria is regulation of reactive oxygen species (ROS): superoxide anion radical (O2•-), hydrogen peroxide (H2O2) and the hydroxyl radical (OH). Mitochondrial respiration is considered as the major source of cellular ROS and therefore mitochondria are the prime target of cell oxidative damage.13 In the inner membrane, side reactions of the electron transport chain with molecular oxygen directly generate the superoxide anion radical. It can be further transformed by dismutases to hydrogen peroxide, which can further react to form hydroxyl radical.14 ROS are generated at pathological as well as at normal physiological conditions.15 In spite of this, oxygen free radical superoxide and mitochondrial-derived ROS have been frequently implicated in a number of diseases and disorders, including aging, neurodegenerative diseases, schizophrenia, cancers, joint diseases, atheroma, asthma, etc.11,16–18

Interestingly, monoamine oxidase A and B (MAO-A and MAO-B) are localized in the outer mitochondrial membrane. These enzymes produce H2O2 by oxidation of monoamine substrates and induce oxidative stress resulting in neuronal degeneration.19 Similarly, glutamate and other excitatory amino acids, producing ROS, are sources of oxidative stress20 and might be involved in the pathogenesis of neuronal damage, and impaired cellular calcium homeostasis.21,22

Cytoplasmic calcium

Other important mitochondrial functions are regulation of intracellular calcium and redox signaling (Fig. 1). Mitochondria have the ability to remove Ca2+ from the cytoplasm and accumulate it in their matrix. They participate in many Ca2+-mediated signaling processes and regulate rapid changes of intracellular calcium concentrations. The mitochondrial calcium uniporters and antiporters have been characterized, but Ca2+ processes and Ca2+-handling systems have not been sufficiently clarified. It is suggested Ca2+ levels are involved in the regulation of ATP production. First, it was thought that the main regulator of ATP production was considered to be relative concentrations of energetically high phosphates. Mitochondrial Ca2+ transport was found to be important only in buffering cytosolic Ca2+ by acting as a sink under conditions of Ca2+ overload.23,24 Nowadays, it is considered that ATP production is regulated by several mechanisms: intramitochondrial Ca2+ levels belong to one of them. Ca2+ regulates activities of dehydrogenases: glycerophosphate dehydrogenase, pyruvate dehydrogenase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase. Via these enzymes Ca2+ levels lead to increased ATP production, production of glycogen, and glucose oxidation.24

Figure 1.

The role of mitochondria in neuroplasticity. Principal mechanisms leading to neuronal impairment and cell death are composed of decreased adenosine-5′-triphosphate (ATP) production, increased production of reactive oxygen and nitrogen species (RONS), initiation of apoptotic processes and impaired calcium homeostasis. Exhaustion of energy supplies and decreased ATP production lead to impairment of ATP-dependent processes and therefore to changed cellular functions. Insufficient function of Na+, K+- ATPases leads to disturbances of ion transmembrane gradients, efflux of K+, and influx of Na+, Cl- and Ca2+. Increased extracellular concentrations of K+ mediate depolarization of membranes and change the functions of amino acids transporters. Voltage-gated ion channels (VGIC) and ligand-dependent calcium channels (LGIC) are activated and mediate increased cytosolic calcium concentrations. Intracellular calcium causes functional changes of amino acid transporters and enhances the increased extracellular concentrations of excitatory amino acid, glutamate especially, and extends neurotoxicity. Increased levels of synaptic glutamate can be mediated by release of glutamate from astrocytes. The activation of ionotropic glutamate receptors leads to higher Ca2+ influx into the cell, which is followed by increased activation of phospholipases, proteases, and endonucleases. For example, activation of phospholipase A2 (PLA2) by calcium releases membrane arachidonic acid (AA), which induces production of superoxide. High intracellular calcium levels cause overload of mitochondrial calcium, increase reactive oxygen species (ROS) production, and inhibit ATP production. Activation of calcium-dependent protein phosphatases (e.g. calcineurin) causes translocation of proapoptotic factor Bad into the mitochondria and triggers apoptosis by sequestration of antiapoptotic factors Bcl-2 and Bcl-xL. Release of cytochrome c (cyt c) and other proapoptotic factors from the intermembrane space of mitochondria induce the formation of apoptosome, and consequently triggers activation of caspases and apoptosis. Apoptosis-inducing factor (AIF) is another factor released by mitochondria. Disengaged AIF is transported into the nucleus and triggers caspases-independent apoptosis. Mitochondria in the brain are also a target of nitric oxide (NO) action. Bax, Bak, Bad, proapoptotic factors of Bcl-2 family; Bcl-2, antiapoptotic factor of Bcl-2 family; BDNF, brain-derived neurotrophic factor; CaM, calmodulin; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding; Δψm, potential on the inner mitochondrial membrane; EAAT, excitatory amino acid transporter; ER, endoplasmic reticulum; Glu, glutamate; MAO, monoamine oxidase; nNOS, neuronal nitric oxide synthase; PKA, protein kinase A; PLC, phospholipase C.

The overload of calcium in mitochondria is a crucial step of excitotoxicity. It leads to mitochondrial damage, activation of mitochondrial permeability transition (MPT), the release of proapoptotic proteins, and production of ROS.25,26


Mitochondria are concerned with apoptosis – the best characterized type of programmed cell death (PCD). PCD involves a complex network of biochemical pathways and is present at physiologically normal processes. During the development of the nervous system, newborn neurons grow and axons and dendrites form synapses; many newly generated neurons undergo PCD.27 In spite of this, PCD is widely present in a range of pathological conditions, mood disorders and neurodegenerative diseases included.28,29 The insults that trigger the PCD are variable, and include moderate overactivation of glutamate receptors, mitochondrial dysfunction, Ca2+ overload, oxidative stress, and DNA damage.30 The biochemical activation of apoptosis occurs through two main pathways: intrinsic and extrinsic apoptotic pathway. The extrinsic pathway involves death receptors (e.g. Fas); and the intrinsic pathway of apoptosis involves mitochondria.30,31 The mitochondrial process is controlled by proapoptotic (Bax, Bak, Bad) and antiapoptotic proteins (Bcl-2, Bcl-xL, Bcl-w),32 which are balanced. If proapoptotic proteins are activated, they change their conformations and oligomerize to form mitochondrial outer membrane pores. Consequently, other proapoptotic proteins are released, such as cytochrome c and Smac (second mitochondrial-derived activator of caspase) and trigger the caspase cascade leading to apoptosis.33 Recently, the connectivity among PCD, Ca2+ levels and antiapoptotic protein Bcl-2 has been discussed. Bcl-2 and other antiapoptotic proteins are suggested to reduce endoplasmic reticulum Ca2+ levels and therefore involve the mitochondria as downstream effectors of apoptosis. Conversely, Bax and apoptotic proteins enhance loading of the Ca2+ store and trigger apoptotic effector systems, mitochondria included.34


Mitochondrial distribution and activity are key factors in neuronal morphogenesis – synaptogenesis, developmental and synaptic plasticity and axogenesis. During the development, neuronal stem cells proliferate and differentiate into neurons; subsequently axons and dendrites form synapses.35,36 It seems, due to ATP production and the importance of mitochondria in synaptic ion homeostasis and phosphorylation reactions, mitochondria would be accumulated at sites where ATP consumption and Ca2+ concentration are higher. It was reported that mitochondria are more abundant in the regions of growing axons than in the non-growing axons. Mitochondrial net movement is anterograde in growing axons and is retrograde in non-growing axons. Shortly before axogenesis, mitochondria congregate at the base of the neurite that is destined to become the axon. Nerve growth factor (NGF) was found as one of the signals inducing accumulation of mitochondria in the active growing cone.37 Interestingly, when the ATP production is impaired and cells provide an alternative source of energy, axogenesis is abolished although growth of dendrites remains relatively unaffected.35

There are changes in mitochondrial energy metabolism occurring in brain cells during CNS development. During embryonic and early postnatal development, fats are primarily used, and, later on, glucose becomes fuel. This fact supports the role of mitochondria in biochemical requirements of highly proliferative neuronal stem cells and postmitotic neurons. During neuronal differentiation, the number of mitochondria per cell increases, but the velocity at which individual mitochondria move decreases as neurite outgrowth slows and synaptogenesis occurs.38,39

It was demonstrated that neuronal activity is influenced by the mitochondrial functions, and defective trafficking and dysfunction of mitochondria from axon terminals is implicated in the pathogenesis of axonal degeneration.40,41 In addition, dendritic mitochondria are essential in the morphogenesis and plasticity of spines and synapses.42 Recent findings suggest roles for mitochondria as mediators of at least some effects on glutamate and brain-derived neurotrophic factor (BDNF) on synaptic plasticity.37 BDNF promotes synaptic plasticity, in part, by enhancing mitochondrial energy production. It increases glucose utilization and increases mitochondrial respiratory coupling at complex.43,44

Mitochondria are dynamic organelles; their function is modulated by fission, fusion and moving within the axons and dendrites.29 Their structure, functions and properties differ in axons and dendrites.42,45 Transport and positioning of mitochondria is essential for neuronal homeostasis and the mitochondrial movement is a part of regulation by intracellular signals.


A growing body of evidence suggests that mitochondrial dysfunction is important in patients with psychiatric disorders, such as major depressive disorder (MDD), bipolar disorder (BD), schizophrenia (SZ), psychosis, anxiety disorder and borderline personality disorders.46–48 From the genetic point of view, sequence variations in the mitochondrial genome have also been implicated in the pathogenesis of both BD and SZ.49 More evidence comes from studies using positron emission tomography (PET), magnetic resonance spectroscopy (MRS), single photon emission computer tomography (SPECT) and proton echo-planar spectroscopic imaging (PEPSI).

Mitochondrial changes include dysfunction of the OXPHOS as well as mitochondrial-related gene expression. Mitochondrial abnormalities in genome were found in SZ50 and BD;51,52 expression of mitochondria-related genes was altered in post-mortem brains of patients with BD or SZ. Conversely, mitochondrial diseases are frequently comorbid with psychotic symptoms and misdiagnosed BD or SZ.53 The hypothesis of mitochondrial variants in SZ, BD and MDD is supported with inheritance of mtDNA. It is matrilineal and higher rates of maternal offspring with mental diseases were found in comparison to father rates. This was observed in family studies, not in the general population. It supports the hypothesis that the origin of these diseases can be related to mitochondrial dysfunctions.

Affective disorders

According to Kato et al.,51,54,55 mtDNA polymorphisms/mutations or mtDNA deletions caused by mutations of nuclear genes could cause mitochondrial dysregulation of calcium, leading to the symptoms of bipolar affective disorder. Mitochondrial changes then alter energy metabolism, change concentration of phosphomonoesters and production of lipids. Abnormal cellular energy and phospholipid metabolism was found using proton or phosphorus MRS.56 Lower creatine and phosphocreatine, as well as choline-containing compounds (glycerophosphocholine and phosphocholine), were found in post-mortem studies of left dorsolateral prefrontal cortex in medication-free patients suffering from BD.57,58 MRS studies also demonstrated increased lactate, decreased pH, phosphocreatine, and ATP levels; and a shift toward glycolytic energy production.54,59 Studies using 2-D PEPSI confirmed altered brain metabolism in medication-free patients suffering from BD. Patients exhibited increased grey matter lactate and γ-aminobutyric acid (GABA) levels; phosphocreatine, creatine or choline-containing compounds were not altered.60 Post-mortem studies of patients with bipolar disorder have identified anatomical and neuropathological abnormalities, including ventricular enlargement, decreased gray matter volume, and reductions of number, size and/or density of neurons and glial cells.61–63 Analyses using PET and SPECT demonstrate variable loss of monoamines in depressive patients.64 PET analyses of brain energy metabolism suggested mitochondrial deficits in idiopathic psychiatric disorders. Data demonstrated reduced ATP production rate and increased mitochondrial deletions in patients compared to controls. Patients suffering from depression exhibited reduced glucose utilization in the prefrontal cortex, anterior cingulated gyrus and caudate nucleus.65


Similarly, altered energy metabolism was found in patients with schizophrenia; brain imaging studies revealed decreased metabolism in prefrontal cortex66 and altered metabolism in additional brain regions – temporal and parietal cortices, thalamus, basal ganglia and cerebellum.67,68 The PET studies demonstrated decreased energy metabolism.67,6931P-MRS study showed impaired high-energy phosphate and phospholipid metabolism;70–72 furthermore, regional deficits of phospholipids, phosphomonoesters, inorganic phosphate73,74 and N-acetyl aspartate75,76 have been described in the first episode of the disease in drug-naïve schizophrenics.

Impaired function of OXPHOS (especially of complex I) was observed in the brains of schizophrenic patients as well as in their blood platelets and lymphocytes.77,78 The pathology of complex I corresponds with the diversity and similarities in clinical symptoms of mental psychiatric disorders;79 two single nucleotide polymorphisms in a nuclear encoded subunit of complex I, NADH dehydrogenase [ubiquinone] flavoprotein 2, were found to be associated with schizophrenia as well as with bipolar disorder; furthermore, genetic variations of NADH-ubiquinone oxidoreductase chain 3 in bipolar disorder and NADH dehydrogenase subunit 4 in schizophrenia were observed, both encoded by mtDNA.80,81 Post-mortem studies of schizophrenics revealed altered respiratory chain complexes: complex I + III were lower both in basal ganglia and temporal cortex; complex II (succinate dehydrogenase) was found to be increased in putamen and nucleus accumbens. Activity of complex IV, which is suggested to be an indicator of neuronal activity,82 was found changed, depending on the brain area: decreased in caudate nucleus and frontal cortex; and increased in putamen and nucleus accumbens.83–85 However, negative correlations were found between the COX activity and emotional and intellectual impairment, without any correlation to motor impairment.86


Although a wide range of pharmacologically different antidepressants and mood stabilizers is available, molecular mechanisms of their therapeutic effects have not yet been sufficiently clarified.


It was thought that depression is connected with the deficit of monoamines in key areas of the brain. However, the therapeutic response to antidepressants is time-dependent; therefore effects of antidepressants are linked to cellular adaptations, including regulation of neurotransmitter receptors, signal transduction cascades, and changes in gene expression.87

An in vitro study examined the influence of pharmacologically different antidepressants and mood stabilizers both on mitochondrial monoamine oxidase88,89 and on respiratory chain complexes; in isolated pig brain mitochondria, imipramine, desipramine, amitriptyline, citalopram, and mirtazapine were found to be complex I inhibitors.90 In other studies, NADH inhibition of imipramine and clomipramine was compared to classic uncouplers, e.g. oligomycin.90,91 Imipramine enhanced oxidative phosphorylation;92 changes in respiratory rates were accompanied by a selective increase in the intramitochondrial cytochrome. In isolated rat liver mitochondria, nefazodone was found to be an inhibitor of mitochondrial complexes I and IV; buspirone inhibited complex I but had no effect on complex IV. Trazodone did not affect either complex I or complex IV,93 but was found to decrease oxygen consumption and to reduce Na+, K+-ATPase activity. It acts also as an uncoupler of oxidative phosphorylation.94

Effects of antidepressants on apoptotic markers, e.g. cytochrome c release and DNA fragmentation, seem to be different. Various antidepressants exhibited potential anticancer properties and caused cytotoxic effects. Evidence demonstrated overexpression of mitochondrial antiapoptotic factors Bcl-2 and Bcl-xL in HL-60 cells, which prevent apoptosis induced by these imipramine, clomipramine and citalopram.95 Paroxetine, fluoxetine and clomipramine caused increased levels of apoptotic markers and led to apoptosis in glioma and neuroblastoma cells, whereas imipramine and mianserin did not.96 Desipramine induced apoptosis in rat glioma cells by activation of caspases, without any change of mitochondrial membrane potential Δψm.97 Fluoxetine and amitriptyline protected PC12 cells from cell death induced by hydrogen peroxide.98 Amitriptyline and tranylcypromine prevented the loss of mitochondrial Δψm, overexpression of Bax, reduction in Bcl-2 level, cytochrome c release, caspase-3 activation, and formation of ROS. In contrast, fluoxetine seemed to have an additive toxic effect to 1-methyl-4-phenylpyridinium (MPP+) against neuronal cell damage by increasing mitochondrial damage and oxidative stress.99 Nortriptyline was identified as a strong inhibitor of MPT and was observed as a potential inhibitor of neuronal cell death; it protected isolated mitochondria against PCD, inhibited release of apoptotic mitochondrial factors and caspases, increased Ca2+ retention in mitochondria and delayed the Ca2+-induced loss of Δψm, further leading to neuronal cell death.100,101

Mood stabilizers

Lithium, several antiepileptics (lamotrigine, carbamazepine, valproate) as well as some atypical antipsychotics (olanzapine, quetiapine, aripiprazole) are used as mood-stabilizing drugs. They exert a large variety of effects on the molecular level and it is not unambiguous which of them are related to therapeutic effects.

Lithium interferes in the protein kinase C (PKC) pathway and inhibits glycogen synthase kinase 3 activity; in mitochondria induces upregulation of Bcl-2, expression of BDNF and subsequent activation of its receptor TrkB102–104 and has neuroprotective effects associated with inactivation of N-methyl-D-aspartic acid (NMDA) receptors.105 Additionally, in isolated brain mitochondria, lithium caused desensitization to calcium, antagonized permeability transition, and diminished cytochrome c release.106 Valproate (VPA), the second most used mood-stabilizing drug, has the same biochemical target, intervenes similarly to lithium in the PKC signaling pathway and activates the mitogen-activated protein kinase (MAPK) signaling pathway that is crucial for neurotrophic effects of VPA.88 Studies have shown effects of mood-stabilizing drugs on mitochondria. In isolated rat liver mitochondria, VPA inhibited oxidative phosphorylation.107 In isolated pig brain mitochondria, both lithium and valproate inhibited respiratory chain complexes I and IV.90 According to a study performed in rats,108 VPA reversed the decreased activity of citrate synthase caused by amphetamine and lithium prevented the inhibition. The cytoprotective effect of lithium and VPA was observed after 7 days of pretreatment of human SH-SY5Y cells against cytotoxicity resulting from oxidative stress evoked by rotenone and H2O2. This effect was not observed after 1 day of pretreatment.109 Chronic treatment of SH-SY5Y cells prevents reduction of methamphetamine-induced reduction of cytochrome c, mitochondrial antiapoptotic Bcl-2/Bax ratio and mitochondrial COX activity.110 Interestingly, long-term lithium and VPA did not protect SH-SY5Y cells against endoplasmic reticulum stress-induced cytotoxicity.109 Lithium and carbamazepine could facilitate activation of CREB and VPA and lamotrigine did not affect BDNF-mediated signalling.111 Thus, these mood stabilizers likely decrease the vulnerability of mitochondrial functions caused by oxidative stress and have neuroprotective effects.109

Lamotrigine causes the blockade of sodium channels,112 and is not likely to be responsible for mood-stabilizing effects. Studies in rodents showed that lamotrigine increases hippocampal activity,113 serotonin and dopamine levels, and decreases glutamate.114,115 Furthermore, lamotrigine prevented the toxicity caused by rotenone and MPP+ in rat PC12 cells by suppressing the MPT formation, which leads to cytochrome c release and subsequent apoptosis. However, lamotrigine seems to have a neuroprotective effect due to mitochondrial respiratory complex I inhibition.116

Carbamazepine interferes in the adenylate cyclase pathway: inhibits adenylate cyclase, and the synthesis of cAMP;117 and chronic treatment with carbamazepine protects against NMDA-mediated toxicity.118 Interestingly, a recent study performed with epileptic children examined the influence of carbamazepine and lamotrigine on mitochondrial functions – both drugs influenced respiratory chain complexes and significantly affected ATP production (carbamazepine decreased the production, contrary to the stimulatory effect of lamotrigine).119


Administration of antipsychotics involved mitochondrial functions, OXPHOS especially. Haloperidol, chlorpromazine, fluphenazine as well as risperidone and clozapine inhibit the activity of complex I (dose-dependent inhibition) in the human brain of schizophrenics. Haloperidol and fluphenazine caused general inhibition of complex I, and this effect was not observed with clozapine.120,121 Prolonged treatment of rats or mice with haloperidol caused reduced activity of complex I in the frontal cortex, hippocampus, midbrain and striatum; clozapine reduced complex I activity in the hippocampus and frontal cortex; and risperidone caused complex loss in the hippocampus, striatum and frontal cortex. In isolated rat liver mitochondria, clozapine and olanzapine inhibited complex I very slightly and risperidone and quetiapine inhibited less than typical neuroleptics (chlorpromazine, thioridazine).122 These findings correlated with the extrapyramidal side-effects of antipsychotics;123 thus, complex I inhibition may be associated with the side-effects of these drugs.124 The activity of complex II was found to be reduced or unchanged after the chronic antipsychotic treatment.123,125 In human brain specimens, both typical and atypical antipsychotics had no significant effect on the activities of complex II + III and complex IV.90 Chlorpromazine at high concentrations slightly inhibited COX.126


Mitochondrial dysfunctions lead to impaired energy metabolism, perturbed calcium homeostasis, increased ROS, oxidative stress and apoptosis. Therefore, impaired functions of mitochondria contribute to a wide range of diseases, including psychiatric disorders. The role of mitochondria in the pathophysiology of SZ, BD and MDD is supported by studies investigating genomic differences, changes of energy metabolism and mitochondrial changes included. Variations in the mitochondrial genome as well as defects of ETC have been implicated in the pathogenesis of psychiatric diseases.49,101

Antidepressants and mood stabilizers are suggested to cause changes in intracellular pathways and improve energy metabolism. Variability in intracellular processes probably participates in interindividual differences of the response to treatment with antidepressant or in drug resistance. Further studies of effects of mood disorders, antidepressants and mood stabilizers on the molecular level are necessary to understand their roles in signaling pathways and influences on energy metabolism of neurons. They are expected to be helpful both in the search for biological markers of mood disorders or predictors of efficiency of the treatment with antidepressants and in the search of new psychotropics.


This research was supported by grant No. MSM0021620849 from the Ministry of Education, Youth and Sports of the Czech Republic and by grant No. 41310 from the Grant Agency of Charles University in Prague.