First case of schizophrenia and OCD in TK2-related mitochondrial DNA depletion myopathy: a case report

Abstract

Introduction

Mitochondria generate energy in the form of adenosine triphosphate (ATP), integral in regulating cellular activities. Pathogenic variants in mitochondrial DNA occur when excess free radicals are produced during abnormal electron transport, causing cumulative oxidative stress and decline in mitochondrial function. The brain is particularly susceptible to oxidative damage due to its high oxygen consumption and low levels of antioxidant enzymes. This predisposes to neuropsychiatric manifestations, which may be exacerbated by psychotropics that further impair mitochondrial function.

Objectives

To highlight clinical clues that distinguish primary psychiatric disorders from neuropsychiatric manifestations of mitochondrial disease, and to outline key prescribing principles in this context.

Methods

Non-systematic review of the literature and report of a case study.

Results

We present a 59-year-old Chinese lady with papillary thyroid cancer, congenital alopecia and eczema, treated for schizophrenia and OCD for over 30 years before a diagnosis of possible TK2-related mitochondrial DNA depletion myopathy—the first reported case with neuropsychiatric features. Her psychiatric symptoms included contamination obsessions, cleaning compulsions, elementary auditory hallucinations, and negative symptoms, remaining stable on low-dose risperidone and fluoxetine without relapses. In 2023, she developed post-operative drowsiness and desaturation, with physical examination showing oculopharyngeal weakness and proximal myopathy. CK > 10,000, aldolase 96.6, EMG with myopathic changes, and biopsy suggested mitochondrial myopathy. Genetic testing revealed two TK2 variants, also present in her sister. Despite months of psychotropic non-compliance, she reported only intermittent hallucinations without OCD relapse.

Conclusions

Differentiating primary psychiatric disorders from neuropsychiatric symptoms of mitochondrial disease is crucial, as some psychotropics may worsen mitochondrial function. Literature reveals no clear guidelines and conflicting recommendations. Three predictors of organic pathology include: (a) multi-organ involvement, (b) cognitive impairment with negative symptoms, and (c) well-controlled symptoms on low-dose psychotropics. The absence of pharmacological guidelines highlights the need for research on psychotropic–mitochondrial interactions and potential adjunctive antioxidant or mitochondrial-targeted therapies. Meanwhile, safe prescribing should follow the principles of ‘start low, go slow’ with careful titration.

Clinical trial number

Not applicable.

Introduction

The mitochondria is the powerhouse of a cell, generating energy in the form of adenosine triphosphate (ATP), integral in regulating cellular activities including calcium homeostasis, oxidative phosphorylation and cell apoptosis [1]. Pathogenic variants in mitochondrial DNA are thought to arise from a combination of genetic susceptibility and cellular stressors, with excess production of oxygen-containing free radicals during abnormal electron transport contributing to cumulative oxidative stress and progressive mitochondrial dysfunction [2]. This is a complex process and not fully understood. When a large proportion of mitochondria is affected, mitochondrial disorders arise, typically affecting highly energy-dependent tissues such as muscle and brain. The brain is particularly susceptible to oxidative damage due to its substantial levels of oxygen consumption and high proportion of readily oxidized polyunsaturated fatty acids, which are not adequately protected by the low levels of antioxidant enzymes available [3]. Neuropsychiatric symptoms thus manifest when the central nervous system (CNS) is compromised. It is challenging, but essential to distinguish between a primary psychiatric disorder and neuropsychiatric manifestations of mitochondrial disease as there are significant treatment implications. Pharmacological treatment with psychotropics including antipsychotic and antidepressant drugs can potentially alter and impair mitochondria functions by causing more oxidative damage, thereby worsening the underlying illness [4].

We present the unique case of a patient who was treated for schizophrenia and obsessive-compulsive disorder (OCD) over 3 decades, before ultimately being diagnosed with possible TK2-related mitochondrial DNA depletion myopathy. This case report explores the neurobiological underpinnings of her psychiatric presentation, and highlights key principles for prescribing in the context of mitochondrial disorders.

Case presentation

This is a 59-year-old single Chinese lady on follow-up with the outpatient psychiatric service for simple schizophrenia and obsessive-compulsive disorder (OCD). When she first presented in her 20s, the main symptoms reported by her live-in sister were that of obsessions with cleanliness and contamination, with consequent compulsions of repetitive handwashing and long showers. In this same visit, psychotic symptoms explored reveals observations of patient talking to herself, suggesting a response to unseen stimuli, though there were no other evidence of psychosis. During the course of her disease, positive symptoms were rarely highlighted, besides the occasional auditory hallucinations which were described as mostly elementary sounds. She has never experienced any delusions or displayed grossly disorganized or catatonic behavior. It was only when negative symptoms, namely avolition, alogia, associality and diminished emotional expression, became increasingly pronounced that schizophrenia was diagnosed. By then, she was unable to hold her job as a seamstress and has remained unemployed since. In the past 30 years, she remained stable on low-dose antipsychotic treatment, oral Risperidone 0.5 mg nightly with no known relapses until her current presentation. Oral Fluoxetine 30 mg every morning was prescribed for treatment of OCD, which similarly controlled her symptoms well.

Besides her psychiatric conditions, the patient was also diagnosed with bilateral papillary thyroid cancer post-total thyroidectomy on daily Levothyroxine replacement, congenital alopecia and xerotic eczema. There is no family history of autoimmune conditions, psychiatric or mitochondrial diseases. Functionally, she is independent in her activities of daily living and community ambulant without aids.

In August 2023, the patient was electively admitted for a left lower lid entropion repair under local anesthesia with sedation. She was found to be drowsy on arrival in the induction room and desaturated during the procedure. Post-operatively, she remained at a Glasgow Coma Scale of 3 and was immediately admitted to the Intensive Care Unit, where non-invasive ventilation was started. When her condition was stabilized, physical examination showed significant findings for oculopharyngeal weakness (bilateral ptosis, dysphagia, dysphonia) and proximal myopathy. Investigations performed reveals high creatine kinase levels of > 10,000 and high aldolase levels of 96.6. Myositis profile and serum acetylcholine receptor antibodies were not suggestive of myositis or myasthenia gravis. A non-contrast MRI brain performed showed no significant abnormalities particularly in the anterior and temporal lobes (Fig. 1). Electromyography performed demonstrated some myopathic features suggestive of an underlying myopathic disorder with associated muscle membrane irritability. Henceforth, a muscle biopsy was conducted and findings were suspicious of an underlying mitochondrial myopathy. During the outpatient neurology follow-up, genetic screen was sent with consent and returned with 2 TK2 variants ‘c.116_120dup (p. Pro41Glyfs*14)’ likely pathogenic and ‘c.367C > G (p.Arg123Gly)’ variant of uncertain significance. A follow-up genetic test from her sister also showed 2 TK2 pathogenic variants. Deep phenotyping was unfortunately not performed in sister and there were no other available family members for further testing. An impression of likely TK2-related mitochondrial DNA depletion myopathy was made, and coenzyme q10 started.

When the patient was next seen in the psychiatric outpatient clinic in February 2025, it was highlighted that she had been non-compliant to her psychotropics for several months. Despite this, she only reported intermittent auditory hallucinations and no relapse symptoms of her OCD. Given the new diagnosis of mitochondrial myopathy, a literature search on psychotropic choice was performed but resulted in no clear guidelines found. As there were conflicting recommendations on the use of Risperidone [5, 6] and Fluoxetine [7, 8], these psychotropics were stopped and switched to low dose Sulpiride 100 mg daily and Mirtazapine 7.5 mg daily to treat residual symptoms. As of her last clinic visit in May 2025, patient no longer reports any psychotic or OCD symptoms.

Fig. 1.

Axial enhanced T2 weighted fluid-attenuated inversion recovery (FLAIR) images (A, B), sagittal T1 weighted reconstructed images (C, D) of the brain – no significant intracranial abnormalities detected

Discussion

The brain is the most highly energy-dependent organ in the body, relying heavily on mitochondria-generated cellular energy in the form of ATP. Besides energy metabolism, mitochondria are also integral in regulating neuronal processes and synaptic plasticity. Hence, mitochondrial malfunctions can cause abnormal brain development and cognitive impairment [9]. Notwithstanding neuropsychiatric manifestations, mitochondrial diseases present with a wide range of clinical symptoms as any organ system can be affected by mitochondrial dysfunction.

First presentation of neuropsychiatric symptoms in TK2-related mtDNA depletion myopathy

Disruption in the biochemical cascade of ATP production may occur due to increasing mitochondrial DNA (mtDNA) polymorphisms and nuclear DNA (nDNA) pathogenic variants [10]. Well-established syndromes resulting from defects of mtDNA include MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) and MERRF (myoclonus epilepsy with ragged red fibres). On the other hand, pathogenic variants of nDNA are all transmitted by Mendelian inheritance, and can lead to notable deficiencies in respiratory chain subunits such as coenzyme Q₁₀ (CoQ₁₀) and thymidine kinase 2 (TK2), as seen in our patient. TK2 is a nuclear-encoded mitochondrial enzyme essential for maintaining balanced mitochondrial deoxynucleotide pools and supporting mtDNA replication and repair, particularly in energy-dependent tissues such as muscle and brain [11]. Deficiency of TK2 leads to mtDNA depletion and impaired oxidative phosphorylation, resulting in a primary mitochondrial disorder that typically presents as a myopathy [12]. However, what makes this patient unusual is that TK2 pathogenic variants are typically associated with myopathic features including proximal weakness, ptosis and eventual respiratory failure. There are no known cases to our knowledge, of patients developing neuropsychiatric symptoms. It remains unclear why patients with TK2 pathogenic variants have preferential muscle involvement, when TK2 is a necessary enzyme for mtDNA maintenance in the brain. Saada et al. investigated the expression of mitochondrial deoxynucleotide carrier, mtDNA amount, and TK2 activity across various tissues, and hypothesized that muscle may be affected more than other organs due to its higher requirement for mitochondrial-encoded proteins, yet significantly lower activity of TK2. However, in a TK2 knock-out mouse model [13], severe reductions of mtDNA levels were observed throughout the brain and the mice displayed neurological impairment including ataxia, impaired motor coordination and gait and abnormal reflexes. Though it can be challenging to elicit psychiatric symptoms in animal studies, given the extensive brain involvement seen, it can be safe to assume the possibility of neuropsychiatric symptoms emerging as well. A more recent study in 2025 reported the first case of a patient with infantile TK2-depletion epileptic encephalomyopathy [14], in which 2 novel autosomal recessive TK2 variants were identified, and the patient demised at 18 months from rapidly evolving neurological symptoms and multiorgan failure. TK2-depletion syndromes were first identified in patients with primarily myopathic symptoms, and to date, only about 20 pathogenic TK2 pathogenic variants have been identified [15]. Perhaps the scarcity of case studies on TK2-depletion mitochondrial disease presenting with neuropsychiatric symptoms may may reflect the severe, often early-lethal neurological course, limiting survival into an age at which such symptoms can be recognized. Given the rarity of this condition and limited available literature, detailed phenotyping in surviving patients may reveal a broader clinical spectrum of TK2 deficiency, including neuropsychiatric manifestations.

Clinical clues for an organic pathology

It is widely established that many psychiatric conditions are associated with alterations in mitochondrial function. It can, however, be clinically challenging to differentiate between primary psychiatric disorders with neuropsychiatric symptoms secondary to mitochondrial disorders. This can result in treatment implications, as some psychotropics can worsen mitochondrial function, elaborated in later paragraphs. Before clinching a diagnosis, it is prudent that full organic workup is performed to rule out other diseases associated with mitochondrial damage such as Alzheimer’s disease, early-onset Parkinson’s disease and amyotrophic lateral sclerosis [16, 17]. An organic pathology was suspected in our patient’s case in view of her atypical presentation of psychiatric symptoms. Firstly, symptoms which cover multiple organ systems i.e. neurological, dermatological and endocrinology. In a comprehensive case series of 12 patients with psychiatric complications of mitochondrial disease [18], almost all presented with a history of multi-organ system involvement. The author highlighted the importance of excluding mitochondrial disorder in the context of a constellation of multi-systemic findings. Given that all organs and tissues subsist on the integral role of mitochondria for energy production, the downstream effects of mitochondrial dysfunction can cause various organ manifestations [19].

Secondly, the prominence of cognitive impairment and negative symptoms. Schneider’s first rank symptoms (FRSs) of schizophrenia have been extensively studied over the past decades, with data suggesting high predictive values among first-episode psychosis patients [20]. Besides the occasional auditory hallucinations, the patient had not reported FRSs of thought interferences, made acts or delusional perception. In a literature review on major mental illness amongst adult patients with mitochondrial disease, a common finding was progressive dementia and intellectual disability at a young age [21]. Correspondingly, magnetic resonance spectroscopy (MRS) studies suggest that the severity of negative and cognitive symptoms in patients with psychosis is correlated with ATP levels [22]. In the process of neurogenesis, the highly proliferative neuronal stem cells and neurons have high energy demands, which are supplied by mitochondria [23]. When there is mitochondrial dysfunction, neuronal differentiation and maturation are affected, causing neuronal circuits to be compromised, and problems with higher-order cognitive functions and thought processing become more significant [24].

Lastly, over the course of 20 years, our patient remained clinically stable on low doses of antipsychotics (Risperidone 0.5 mg/day) and antidepressants (Fluoxetine 30 mg/day) for treatment of schizophrenia and OCD respectively. Based on measurements of dopamine D₂ and serotonin 5-HT_2A receptor occupancy in position emission tomography (PET) studies, Risperidone 4 mg/day has been recommended at a suitable dose to achieve optimal antipsychotic effect [25]. As psychotic symptoms in mitochondrial disease may not arise from classical dopaminergic or glutamatergic theories in schizophrenia, but rather, from increased oxidative stress, enzymatic modifications and altered energy metabolism, low-dose antipsychotics may be sufficient to control symptoms [26]. Likewise in the treatment of OCD, better clinical responses are seen in high doses of selective serotonin reuptake inhibitors (SSRIs), at a dose of 40-60 mg/day for Fluoxetine [27]. Though the relationship between mitochondrial disease and OCD remains poorly studied, animal studies suggest that the involvement of mitochondria in oxidative stress metabolism may be related to the regulation of anxiety behaviors [28, 29]. Similarly, high dose antidepressants may not be necessary to control OCD symptoms.

Prescribing principles

It is essential to differentiate neuropsychiatric manifestations secondary to mitochondrial disorder from primary psychiatric conditions, as certain psychotropic medications may exacerbate mitochondrial dysfunction. A growing body of evidence suggests that antipsychotics can impair mitochondrial integrity by disrupting gene and protein expression involved in oxidative phosphorylation pathways [30–32], and by directly inhibiting the activity of electron transport chain complexes [33, 34]. However, much of this evidence arises from preclinical studies, primarily in animal models [34, 35], and translational applicability to human subjects remains an area requiring further exploration. In a rare Chinese study involving 80 patients with schizophrenia- 40 drug-naïve and 40 chronically treated- biochemical analyses demonstrated significantly increased oxidative stress markers among patients receiving long-term antipsychotic therapy [36]. These findings lend human-based support to concerns raised in preclinical research. Furthermore, the aforementioned retrospective case series of 12 adults with known mitochondrial disorders reported that 58% of patients remained stable with minimal or no psychotropic medication, relying instead on mitochondrial-targeted supplements alone [18]. This highlights the potential for conservative, mitochondria-sparing management strategies in selected cases.

The effects of antidepressants on mitochondrial function remain underexplored and are marked by inconsistent findings. While some studies suggest potential mitochondrial-enhancing properties, others indicate deleterious effects. For instance, Fluoxetine monotherapy has been shown to increase citrate synthase, a marker of mitochondria density in the striatum, along with enhanced respiratory chain complex I activity in the hippocampus [37]. However, these effects appear to vary with duration of use. In chronic Fluoxetine administration, no significant changes in citrate synthase activity were observed, and a reduction in respiratory chain complex IV activity was noted instead [38]. Additional proposed mechanisms for antidepressant-induced mitochondrial dysfunction include increased production of reactive oxygen species, leading to oxidative stress and loss of mitochondrial membrane potential [4].

In addition to psychotropic medications, there is emerging evidence supporting the potential role of antioxidant and mitochondrial-targeted therapies as adjunctive treatments in managing neuropsychiatric symptoms associated with mitochondrial dysfunction [39]. Such interventions may help regulate neuroplasticity and reduce the risk of progression to neurodegenerative disorders. In our patient with TK2-related mitochondrial DNA depletion myopathy, coenzyme Q10 (CoQ10), a key cofactor in the mitochondrial electron transport chain, was initiated. While current evidence does not clearly support CoQ10 as an effective treatment for OCD or schizophrenia specifically, it has shown promise in mitigating cognitive deficits through its antioxidant properties. By limiting oxidative damage, CoQ10 may potentially ameliorate negative symptoms and enhance overall cognitive function [40, 41]. Further research is warranted to better define the therapeutic value of mitochondrial supplements in neuropsychiatric disorders and guide their use in clinical practice.

Limitations

This report is limited by its single-case design, which precludes any conclusions about causality or generalizability. In addition, further neurological investigations such as electroencephalography and cerebrospinal fluid analysis were not performed, limiting the ability to exclude other central nervous system processes. Future studies and larger case series will be necessary to clarify the relationship between TK2-Related Mitochondrial DNA Depletion Myopathy and neuropsychiatric symptoms.

Conclusion

This report depicts the first known case of neuropsychiatric manifestations in a patient with TK2-related mitochondrial DNA depletion myopathy. Beyond the novelty of this presentation, the retrospective review of her clinical course offers important clinical clues suggestive of an underlying organic etiology. The current lack of pharmacological guidelines underscores the need for further research into the interactions between psychotropic medications and mitochondrial function. In the meantime, adherence to fundamental prescribing principles of “start low, go slow”, and careful titration based on clinical response remains essential for safe and effective management.

Author contributions

S.H Ngoh performed the initial literature review and wrote the main manuscript text. A.Gudi provided guidance, and assisted with vetting of manuscript. All authors reviewed the manuscript.

Funding

There was no funding obtained for the study. The authors have no conflicts of interest to disclose.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent for publication has been obtained from the patient for their personal and clinical details to be published in this study.

Competing interests

The authors declare no competing interests.