Complex Case Study: Treatment Resistant Depression

Brain Biopsy Findings Link Major Depressive Disorder to Neuroinflammation, Oxidative Stress, and Neurovascular Dysfunction

The patient first experienced depressive mood symptoms at age 15. At that time, he had begun to feel as though he couldn’t experience emotions and was “dead inside.” By age 19, his mood was depressed and irritable often, and he experienced loss of pleasure from activities he previously enjoyed. However, his academic performance and personal achievement, first in school and then at work, remained stellar.

At age 29, the patient found himself easily fatigued despite excessive sleep. His energy was persistently low. His capacity to be productive at work was drastically reduced. He was psychiatrically hospitalized for a major depressive episode and was treated aggressively with a combination of psychotherapy and pharmacotherapy, which continued going forward.

By age 35, the patient could not sustain work because of persistent mood symptoms and cognitive dysfunction. Over the next four years, an MRI of the brain, neuropsychological testing, an EEG, and sleep studies were performed. The results of these tests were unremarkable until the patient was 38, when he was told that he was suffering neurological complications of Lyme disease. Before being referred to NYU Langone, he was treated elsewhere with antibiotics, acupuncture, over-the-counter supplements, transcranial magnetic stimulation, and hyperbaric oxygen. All were of no benefit. At age 39, after 10 years of treatment, he terminated psychotherapy. He then sought neuropsychiatric evaluation with Scott Hirsch, MD, assistant professor of neurology and psychiatry at NYU Langone Medical Center. 

On presentation, his affect was dysphoric, and he was easily frustrated. He demonstrated rumination and expressed intense anxiety and hopelessness. He had lost interest in most of the activities he had previously enjoyed. He exhibited slow processing speed, yet seemed highly intelligent. Segmental neurological examination was unremarkable. There was no evidence of myoclonus, dystonia, dyskinesia, or tics. 

Despite the patient’s cognitive complaints, neuropsychological testing revealed high scores on all measures (90th to 99.7th percentile) except processing speed, on which his score was only average. His Montgomery-Asberg Depression Scale (MADRS) score was 25. His Beck Depression Inventory (BDI-II) score was 27. His Beck Anxiety Inventory (BAI) score was 22.

A three-day ambulatory electroencephalogram was normal. Brain magnetic resonance imaging (MRI) showed scattered white matter foci of increased signal. Single photon emission computed tomography (SPECT) showed moderate to severe frontal hypoperfusion. Comprehensive serological and cerebrospinal fluid assays for infectious agents, systemic autoimmune diseases, and antineuronal antibodies were all unremarkable.

The clinical presentation and history were consistent with the working diagnosis of major depressive disorder (MDD). Given the severity of the symptoms, Dr. Hirsch referred the patient to Norman Sussman, MD, professor of psychiatry and director of NYU Langone’s Treatment-Resistant Depression Program. Because of the patient’s extensive history of unsuccessful treatment with antidepressant medications, treatment was aimed at providing symptomatic relief using nonpsychiatric medications with reported benefits in treating mood disorders. The patient had been taking the antidepressants fluoxetine and bupropion, as well as quetiapine, clonazepam, and an amphetamine. Bupropion, which is known to cause cognitive impairment, was discontinued. Although clonazepam can also impair memory and reaction times, it was not stopped because the patient reported deriving significant symptom relief from the drug. After the first visit, Dr. Sussman added memantine to the regimen with the rationale that its glutamatergic effects could prove helpful.

However, given the abnormal nonspecific brain MRI and SPECT imaging findings, there was also concern about a low-grade encephalitic process, such as seronegative autoimmune encephalitis, that might be treatable. As a result, the patient was also referred to Souhel Najjar, MD, clinical associate professor of neurology at NYU Langone’s Comprehensive Epilepsy Center, for further evaluation.

Accordingly, a brain biopsy was obtained and was used to exclude an encephalitic process. Histological examination showed mild nonspecific inflammation without lymphocytic infiltration, with mild perivascular macrophage histiocytic infiltration and mild to moderate subcortical astrogliosis. Ultrastructural analysis revealed lipofuscin granule accumulation exclusively within the neurovascular unit, indicative of oxidative stress leading to blood-brain barrier dysfunction. While the medical literature had previously documented increased central nervous system oxidative stress in MDD, this was the first demonstrated evidence of oxidative injury of the neurovascular endothelium. Because of the confirmed presence of inflammation, intravenous immunoglobulin (IVIG) pulse therapy was started and continued twice weekly for nine months. Three months after initiation of IVIG, intravenous minocycline was started because of its anti-inflammatory and antidepressant effects demonstrated in animal models of depression.

Ten months after initiation of IVIG, a repeat SPECT scan showed complete normalization of frontal hypoperfusion. Of note, the psychotropic regimen remained essentially constant over this 10-month period. At the time of a neuropsychiatric reevaluation 13 months after starting IVIG, the patient reported significant improvement in his mood and much better control of his anxiety. His wife reported a positive personality change in her husband. He was much more active in general and more appropriately engaged with his family. He was more interested in socializing, and he became an active participant in raising his child. In fact, he was excited to report that he and his wife were expecting a second child. Motivation and energy were reported as better. Reductions in the MADRS (from 25 to 15), the BDI-II (27 to 15), and the BAI (22 to 3) were also noted.

Eighteen months after starting IVIG, the patient reported the best-sustained improvement inmood symptoms he could remember; his MADRS score was 8. Of note, in the Treatment-Resistant Depression Program, Dr. Sussman was documenting the patient’s clinical course separately from Dr. Najjar’s treatment with IVIG and minocycline. These assessments independently validated the patient’s clinical improvement.

For more information, see the case study report published in Biological Psychiatry.