Psychosomatics 47:1-7, February 2006
doi: 10.1176/appi.psy.47.1.1
© 2006 Academy of Psychosomatic Medicine
Review of the Literature on Major Mental Disorders in Adult Patients With Mitochondrial Diseases
Omar Fattal, M.D., M.P.H.,
Kumar Budur, M.D.,
Aaron J. Vaughan, B.S., and
Kathleen Franco, M.D., M.S.
Received September 21, 2004; revised December 13, 2004, January 19, 2005; accepted March 7, 2005. From The Cleveland Clinic Foundation, Cleveland OH. Send correspondence and reprint requests to Dr. Franco, P57, 9500 Euclid Ave., Cleveland, OH 44195. e-mail: FrancoK{at}ccf.org
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ABSTRACT
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Mitochondria are intracellular organelles crucial to the production cellular energy. Mitochondrial disease results from a malfunction in this biochemical cascade. These disorders can affect any organ system, producing diverse signs and symptoms, including psychiatric ones. Several authors argue that mitochondrial dysfunction is related to the pathophysiology of bipolar disorder and schizophrenia. Also, the authors retrieved 19 case reports that describe patients with mitochondrial diseases and psychiatric disorders. Most of these patients have psychiatric presentations that preceded the diagnosis of mitochondrial disease. The most common physical findings are fatigue, muscle weakness with or without atrophy, and hearing loss.
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INTRODUCTION
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Mitochondria are intracellular organelles containing DNA (mtDNA) inherited solely through the mother, and playing a crucial role in ATP production through oxidative phosphorylation (OXPHOS), a process carried out by the respiratory chain complexes I, II, III, IV, and V.1–4 They are also involved in amino acid, lipid, and steroid metabolism. Mitochondria serve as calcium buffers, sources of free radicals, and regulators of apoptosis.1,3 Mitochondrial disease or disorder describes a malfunction in the biochemical cascade of energy production, resulting from disruption of either mtDNA or nuclear DNA.1–3
Brain, skeletal muscle, and cardiac muscle have high aerobic activity, requiring high mitochondrial content, and are more likely to be affected in mitochondrial disease.3 Because any organ system can be affected by mitochondrial disease, patients can have a wide range of clinical presentations. Some presentations are clustered into syndromes such as MELAS (mitochondrial encephalomyopathy lactic acidosis and strokelike episodes) or CPEO (chronic progressive external ophthalmoplegia), but many remain largely heterogeneous.1,3,4 Mitochondrial diseases can be inherited through the maternal line or can be sporadic.3 Diagnosis is based on clinical and laboratory findings such as mutations in mtDNA1,2 or ragged red fibers (RRF) on muscle biopsy.2
Treatment of mitochondrial diseases is challenging.5–7 Some authors classify the treatments into nonpharmacological (nutritional and exercise) and pharmacological categories,5 whereas others classify the treatment according to the mode of action of the agents used: bypassing the defect, supplementing the energy source, increasing the antioxidant capacity of the cell, eliminating cytotoxic byproducts, and supplementing precursors for defective electron-transport chain enzymes.6,7 Gene therapy and genetic counseling are also considered an important aspect of the treatment.7 Only a few articles address diagnosis and treatment of the diverse psychiatric symptoms associated with mtDNA mutations. To date, the literature describes trends or commonalities, without much information regarding etiology.
We reviewed the literature addressing psychiatric presentations of mitochondrial diseases to better understand associations, trends, or markers that can alert physicians to possible diagnosis of mitochondrial disease and potential treatments.
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METHODS
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We performed a MEDLINE search (1966–2004) using the key words "mitochondrial diseases," "mental disorders," "depressive disorders," "anxiety disorders," "schizophrenia," and "psychotic disorders." We searched articles published in English and those identified from bibliographies of retrieved articles. Although of interest to some mitochondrial researchers, we excluded articles addressing only cognitive impairment or dementia and those solely including patients younger than 18 years old. We also reviewed the relevant articles discussing the treatment aspects of psychiatric symptoms in patients with mitochondrial disorders.
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RESULTS
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Several authors suggest mitochondrial dysfunction precedes bipolar disorder, or at least a subtype of bipolar disorder. Kato and Takahashi8 identified 35 Japanese patients with bipolar disorder and tested their leukocyte mtDNA for deletions, finding that only two patients had the 4977 base-pair (bp) deletion. They also tested 29 normal volunteers and did not find the deletion in any of them. The authors suggested that there might be a relationship between deletions in mtDNA in the brain and bipolar disorder; however the results from this study should be carefully interpreted because the sample is small; the presence of a deletion, in itself, does not confirm a cause-and-effect relationship; and its prevalence in the general population is unknown.8
Konradi et al.9 reported decreased expression of nuclear gene coding for enzymatic complexes responsible for oxidative phosphorylation and reduced expression of nuclear genes related to proteasome degradation in the hippocampi of nine subjects with bipolar disorder. Although this was a very small study, these results were not found in the control subjects. The authors proposed that abnormalities like low pH found in brains of bipolar-disorder patients are secondary to mitochondrial dysfunction.9
Kato and Kato10 proposed that altered intracellular calcium regulation and defective energy metabolism of mitochondrial dysfunction merges into the pathophysiology of bipolar disorder. This theory was based on findings in patients with bipolar disorder such as regional alterations of brain pH, white-matter hyperintensities, low phosphocreatine and ATP, possible maternal inheritance, and increased mtDNA 4977 bp and similar deletions. Also, multiple case reports in the literature describe patients comorbid for bipolar and mitochondrial disorders.10
Gardner et al.11 identified 28 patients with major depressive disorder and coexisting physical complaints of muscular pain, hearing loss, and visual problems. Muscle biopsies on these patients indicated significantly more mtDNA deletions and lower mitochondrial ATP production rate (MAPR) than in control subjects. They found a correlation between this decrease in the MAPR and the Somatic Anxiety, Psychasthenia, and Suspicion sections of the Karolinska Scales of Personality that are believed to be associated with major depression.11
Reduced cellular energy secondary to impaired mitochondria,12 particular mtDNA substitutions,13 fewer mitochondria in the striatum,14 and impaired mitochondrial (COX) activity in the caudate nucleus,15 have all been associated with an increased risk of schizophrenia.
Ben-Shachar et al.16 classified the mitochondrial abnormalities of schizophrenia into three broad categories: 1) mitochondrial morphological aberrations; 2) mitochondrial oxydative phosphorylation(OXPHOS) system malfunction; and 3) abnormal mitochondrial-related gene expression.
On autopsy, brain tissue of schizophrenic patients shows a reduction in the number and density of mitochondria in the frontal cortex, striatum, and substantia nigra.14 Interestingly, when divided into drug-off and drug-on groups, the patients who were on antipsychotic treatment had more normal mitochondrial morphology and density.14
The mitochondrial OXPHOS system of schizophrenia patients exhibits reduced Complex IV activity in the frontal cortex and caudate nucleus, an elevation of Complex IV in the putamen, and no changes elsewhere in the brain.16 In another study, low Complex IV activity was highly associated with increased emotional and intellectual impairment, but not motor impairment.17 Significantly reduced activity of Complexes I–III is reported in the frontal and temporal cortex as well as the basal ganglia of patients with schizophrenia.18,19
Complex I activity is significantly increased in platelets of patients with predominantly positive symptoms of schizophrenia and reduced in patients with "residual" schizophrenia, as compared with control subjects.16 However, others report significant reduction in Complex I activity of platelets and lymphocytes for schizophrenic patients after lengthy treatment with antipsychotics.18 There is also strong evidence, in vivo and in vitro, that dopamine, long known to initiate psychotic symptoms, plays a predominant role in the mitochondrial respiratory system of patients suffering from schizophrenia.16
Finally, mitochondrial gene expression indicates increased cytochrome oxidase subunit II in post-mortem frontal cortex tissue of schizophrenic patients.20 Odawara,21 however, did not find the A3243G mutation in the mtDNAof the 300 patients with schizophrenia who were randomly tested for this mutation.
At least 19 case reports (12 men, 7 women) connect mitochondrial disease with psychiatric problems (Table 1). Four met comorbid criteria for mitochondrial disease and major depressive disorder (MDD).22–25 There is one case of MDD with psychosis,26 one case of bipolar disorder,27 eight cases of psychosis,28–35 and one patient with personality change;36 three cases with mutation in mt tRNA had anxiety disorders.23
Four articles reported improvement of psychiatric symptoms after treatment with coenzyme Q10.22,25,29,37 In one of these, Onishi25 reported on a 23-year-old man with depression that did not respond to antidepressants but did improve after 2 months of 90 mg/day of Q10.22 In the second paper, a patient with depression and mitochondrial disease had improvement in her fatigue after 5 months of treatment with Q10.25 In the third paper, Q10 helped prevent recurrence of stroke-like episodes, headaches, tinnitus, and psychotic symptoms in a patient with MELAS.29 Finally, Shinkai et al.37 described a 48-year-old female patient with MELAS who had delusions of persecution and aggressive behavior that responded to 70 mg/day of Q10 for 3 months. In another adult man with MELAS and schizophrenia, mutism improved after administration of nicotinic acid and Q10 for several days.28
An adult man with an mtDNA 3243 point mutation and one episode of psychosis with auditory hallucinations and delusions of persecution, responded to 1 week of low-dose haloperidol treatment. He later developed mutism and blunted affect that did not respond to haloperidol but did respond to 1-month treatment with the antioxidant idebenone at 160 mg per day.33
Another man with mitochondrial disorder and psychotic depression responded to low-dose flupenthixol when tricyclic agents and ECT failed. After an additional 5 months of treatment with Q10, his fatigue lifted.25
Stewart and Naylor, in 1990,27 reported a female patient with Kearns-Sayre syndrome and bipolar disorder, who improved with a combination of imipramine and lithium.
Saijo et al.32 reported a case of a 19-year-old man with MELAS who developed delirium, with auditory and visual hallucinations, associated with increased lactate levels in blood and cerebrospinal fluid (CSF). His symptoms resolved after treatment with oral sodium dichloroacetate, which lowered his lactate levels.
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DISCUSSION
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Roughly three-quarters of the case reports summarized in Table 1 indicate the onset of psychiatric symptoms several years to a decade before the diagnosis of mitochondrial disease was actually made, suggesting that clinicians may not consider this rare disease earlier. Although diverse in description, most of these patients did not have a "classic" course of the psychiatric disorder. A common finding was progressive dementia at an early age,28–31 a drop in IQ,32,33 and abnormalities on neuropsychological testing.26
Almost all patients had numerous physical complaints starting before, during, or after the onset of the psychiatric symptoms. The presence of several physical signs or disorders can be an important "red flag." The most common physical symptoms were muscle weakness, with or without atrophy and hearing loss. Also, seizures, diabetes, Wolff-Parkinson-White syndrome, headaches, and short stature are frequently found.
Few reports asked about possible consanguinity. On physical exam, measuring height and assessing muscle mass can also be very informative. For diagnostic evaluation, simple studies like an audiogram, ECG, and fasting blood glucose can be helpful in assessing new patients. Also helpful is finding an elevated lactate level in blood or CSF.
The lactate/pyruvate ratio and measures of acetylcarnitine and organic/amino acids in urine and blood are also useful. Ragged red fibers obtained by muscle biopsy can point to mitochondrial disease. CT and MRI of the brain, in many of the cases we reviewed, commonly identified diffuse atrophy that had progressed over time. In many cases, however, the CT and MRI of the brain were normal.
It is worth mentioning here that diagnosing mitochondrial disorders is inherently difficult and challenging. This is largely due to the ubiquitous presence of mitochondria in the body, the dual control of the respiratory chain (nucleus and mitochondria), heterogeneous clinical presentations, and varying age at onset of symptoms.38
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CONCLUSION
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In conclusion, psychiatrists should consider mitochondrial diseases as a possible diagnosis in their patients with atypical presentation of psychiatric symptoms, particularly when they are accompanied by multiple comorbid physical symptoms. These reports all allude to a possible relationship between some psychiatric diseases (or subtypes of psychiatric diseases) with mitochondrial disease. The question remains whether the occurrence of psychiatric symptoms in these patients is just a coincidence or is more directly related to the mitochondrial disease, itself. Additional reports and further research in this area are clearly needed, with emphasis on diagnostic assessments and true risks and benefits of evidenced-based treatments.
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ABSTRACT
INTRODUCTION
