Use of Electroconvulsive Therapy and Ketamine in a POLG-Related Disorder

POLG is a nuclear gene that encodes a subunit of the enzyme that is involved in replicating mitochondrial DNA, DNA polymerase gamma. Mutations in this gene can result in a variety of genetic conditions known as POLG-related disorders. These disorders can present at any age with a broad spectrum of symptoms including psychiatric, endocrine, and neurological issues.¹ Psychiatric disorders that are seen in people with confirmed POLG-related disorder include mood disorders such as depression and bipolar disorder as well as anxiety disorders. Diagnosis of POLG-related disorder is usually made based on clinical findings and molecular genetic studies.²

Case Report

This is the case of a 68-year-old man with hypertension, dyslipidemia, tinnitus, type 2 diabetes mellitus, and a long-standing history of depression who had tried different antidepressants such as citalopram, venlafaxine, and duloxetine. He presented to the emergency department (ED) with manic symptoms while under treatment with mirtazapine. Consequently, he was diagnosed with bipolar disorder and started on lithium. This diagnosis aligned with his significant family history of bipolar disorder. Following discharge, he had multiple visits to the ED and complained of insomnia and restlessness. He was started on low-dose trazodone in the outpatient setting to help with his sleep issues. Although his sleep initially improved, he presented again to the ED with worsening of insomnia, irritability, muscle weakness, and increased falls. On physical examination, he had ptosis, external ophthalmoplegia, proximal muscle weakness, and myalgia. His blood work showed rhabdomyolysis and elevated creatine kinase. The neurology service also noted areflexia, and his nerve conduction study/electromyography study showed moderate to severe sensorimotor axonal polyneuropathy and epileptiform discharges. Brain magnetic resonance imaging showed areas of increased fluid-attenuated inversion recovery signal hyperintensity in the subcortical white matter, and his electrocardiogram was normal.

After he was seen by the medical genetic specialist, a concern was raised about an underlying mitochondrial disorder. While waiting for molecular testing, he was admitted to the psychiatry department, and, given his family history of bipolar disorder and response to valproic acid (VPA), he was started on this medication. As he was endorsing depressive symptoms, he was also started on a low dose of lamotrigine. Molecular testing via a mitochondrial disorder gene panel revealed compound heterozygous pathogenic variants in the gene POLG that confirmed POLG-related disorder. Because VPA was contraindicated, it was discontinued, and he was referred to the psychology service for psychotherapy for depression.

Given that his depressive symptoms did not respond to psychotherapy, the psychiatry service explored the possibility of ketamine therapy. There is a dearth of evidence on using ketamine in POLG-related disorder, but, following consultation with medical genetics and anesthesia services, ketamine therapy was initiated. He received a total of 12 ketamine therapy sessions, 6 sessions at 0.5 mg/kg and 6 sessions at 0.75 mg/kg. Ketamine therapy only provided limited short-term benefits for the patient; therefore, electroconvulsive therapy (ECT) was considered as the next step. Following consultation with medical genetics and anesthesia services, he was scheduled for ECT. He received 4 sessions of right unilateral ECT and noticed improvements in his depressive symptoms and was discharged and scheduled to receive ECT as an outpatient. His medication at discharge included lamotrigine 25 mg twice daily, olanzapine 5 mg at bedtime, folic acid 1 mg daily, linagliptin 5 mg daily, magnesium 150 mg twice daily, and vitamin B₁₂ 1,200 mcg daily.

Discussion

The clinical manifestations of pathogenic POLG variants are linked to impaired mitochondrial DNA replication and repair in organs with high metabolic demand such as the liver and brain. Medications with mitochondrial toxicity may worsen mitochondrial dysfunction in POLG-related disorders. Although psychiatric symptoms are common among patients with POLG-related disorders, they are not usually the predominant characteristics. Symptoms that should raise suspicion for POLG-related disorders include the presence of neurological symptoms such as seizure, ataxia, and myopathy.³ Among psychotropic medications that are contraindicated in POLG-related disorder, VPA has the most evidence against its use.⁴

This case highlights the importance of considering POLG-related disorders in the differential diagnosis of a patient who presents with psychiatric symptoms associated with neurological and metabolic issues. Ketamine therapy and ECT are 2 treatment modalities that may be considered in an individual with POLG-related disorder with mood symptoms.

Article Information

Published Online: October 13, 2026. https://doi.org/10.4088/PCC.26cr04238
© 2026 Physicians Postgraduate Press, Inc.
Prim Care Companion CNS Disord 2026;28(5):26cr04238
Submitted: March 24, 2026; accepted May 28, 2026.
To Cite: Hafizi S, Kaushik V, Ramkissoon R. Use of electroconvulsive therapy and ketamine in a POLG-related disorder. Prim Care Companion CNS Disord 2026;28(5): 26cr04238.
Author Affiliations: Department of Psychiatry, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada (all authors).
Corresponding Author: Sina Hafizi, MD, Department of Psychiatry, PsycHealth Centre, PZ433-771 Bannatyne Ave, University of Manitoba, Winnipeg, MB R3T 2N2 Canada ([email protected]).
Financial Disclosure: None.
Funding/Support: None.
Patient Consent: The patient provided written informed consent to publish the case report, and information has been de-identified to protect anonymity.
Additional Information: Microsoft Word (Version 2603) with Copilot was used to enhance the readability of the article. The authors have reviewed the content and take full responsibility for the contenKetamine therapy and ECT are 2 treatment modalities that may be considered in patients with a POLG-related disorder and mood symptoms.t of the article.