What’s Perfusion Got to Do With It?

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Stubborn or difficult to treat bipolar depression presents a particular challenge in psychiatry, often defying conventional algorithm-driven treatment such as complex lifestyle changes, counseling, behavioral therapy, and medications. This article examines the case of a patient with refractory bipolar depression who failed to respond to the conventional algorithm over 2 years. By integrating measures of perfusion acquired by Brain SPECT imaging into the initial assessment, we illuminate how that technique provided actionable insights, which informed a newer treatment that directly targets the same disturbed perfusion.

Brain SPECT imaging is a cost-effective and clinically valuable tool for assessing cerebral perfusion, one of the few direct measures of neurophysiological state. In this case, initial SPECT imaging revealed significant perfusion abnormalities, which can be a signal that additional oral pharmacologic interventions will worsen the episode (Figure 1).

Figure 1. Upon Admission to the Clinic, Before Any Brain Stimulation

The imaging results suggested that a treatment path of external brain stimulation was a more appropriate therapeutic option. To avoid hospitalization and other adverse consequences associated with electroconvulsive therapy (ECT), we chose another form of brain stimulation that we call “combination therapy,” providing the patient with the benefits of high-intensity transcranial magnetic stimulation (TMS) at 1 Hz. Because high-intensity (slow) TMS is typically too painful for clinical use, the combination therapy relies upon procedural sedation induced with moderate doses of ketamine.¹

This approach not only mitigated discomfort but also leveraged the complementary mechanisms of both interventions. While both TMS and ketamine-based treatments hold promise, in the clinic they are less impactful than we need.

TMS's Role

Low-frequency (1 Hz) TMS reliably increases cerebral perfusion and it typically induces inhibitory effects on cortical excitability.^2-5

Improved perfusion enhances oxygen and nutrient delivery to neural tissue while facilitating waste removal, supporting recovery of regions affected by (neuro)psychiatric conditions. Its antidepressant impact is limited: "Evidence on its efficacy in the short-term is adequate, although the clinical response is variable."⁶ Over the short-term, TMS seems to lead towards remission in about 20% to 24% of chronic depression cases.⁷

Ketamine's Role

Ketamine acts as an NMDA-glutamate receptor antagonist, reducing excitatory neurotransmission and stabilizing overactive neuronal activity implicated in mood disorders. Additionally, ketamine promotes synaptogenesis and enhances neuroplasticity, contributing to its rapid antidepressant effects. It provides short-lived relief from dysphoria.⁸ The ketamine-based medications do not seem to offer long-lasting antidepressant effects: "The effects of ketamine lasted no more than one week after treatment and clearly disappeared after two weeks. Ketamine did, however, cause more [adverse] effects than placebo. The effects of esketamine were seen at 24 hours and could last up to 4 weeks with repeated doses."⁹

Combination Therapy’s Role

Integrated or coadministered TMS and ketamine reliably yields a lasting remission in over 85% of patients.¹⁰

Figure 2. Upon the Completion of the Acute Course of Brain Stimulation in Our Clinic

Regarding our case study, after our patient's clinical recovery and consequent return to his own premorbid lifestyle, we acquired these images, which show a dramatic improvement of neurophysiologic state (Figure 2). Specifically, results from a valid Personality Assessment Inventory and Beck Depression Inventory showed substantial decreases in symptoms related to mood (PAI Time 1 DEP T score 79 vs Time 2 T = 65; Time 1 MAN T = 79 vs Time 2 T = 61; Time 1 BDI = 36 vs Time 2 = 13) even though life stress indices remained elevated and essentially unchanged.

The combination therapy of TMS and ketamine potentiates the distinct impacts of the 2 separate constituents into an enhanced therapeutic outcome, particularly in individuals with varieties of treatment-resistant depression.^11,12 We propose that increased perfusion is the common theme for assessment and treatment.

Mechanism of Action: TMS

Approximately 1 Hz TMS has been shown to increase regional perfusion, contributing to its therapeutic effects by enhancing neurovascular support.^2,3 An increase of perfusion in deficient areas hypothetically not only aids in nutrient delivery but also should facilitate the removal of metabolic byproducts, potentially supporting brain function and recovery in areas affected by neuropsychiatric conditions.

The effects of TMS on cortical excitability depend on parameters such as the frequency and site of stimulation. For example, 1 Hz TMS is recognized for its ability to induce inhibitory effects on certain brain regions, effectively reducing cortical hyperactivity often seen in neuropsychiatric conditions like clinical depression.^4,5

Mechanism of Action: Ketamine

Perfusion. The antidepressant response to ketamine is associated with perfusion changes in reward-system regions, specifically ventral basal ganglia and medial prefrontal cortex.¹³

NMDA-glutamate receptor antagonism. Ketamine antagonizes the NMDA-glutamate receptor, which results in decreased excitatory neurotransmission.¹⁴ The reduction in pathological excitability is believed to aid in the resetting of dysfunctional neural circuits involved in depression.¹⁵

Neuroplasticity. The acute antidepressant effects of ketamine are also linked to its promotion of synaptogenesis and enhancement of neuroplasticity. Ketamine has been shown to increase synaptic connections and improve neural plasticity, which can help restore healthy neural connectivity and function. These neuroplastic changes are thought to underpin the quick improvements in mood and cognitive function seen in patients with depression.^14,16

Taken as a whole, the findings underscore the potential of both TMS and ketamine as innovative treatments for aspects of depressive illness. Each modality works through distinct yet complementary pathways to modulate brain activity and improve mental health outcomes.

Possible Mechanism of Action of Combination Therapy

Plasticity and tissue recruitment. The increased perfusion from TMS hypothetically supports the synaptic changes and tissue recruitments induced by ketamine, facilitating more effective and long-lasting neural circuit remodeling. TMS is already used to induce plasticity, which serves to facilitate more effective and long-lasting neural circuit remodeling.¹⁷ The improvement of aberrant focal perfusion by TMS may serve to reinforce the synaptic changes, tissue recruitments, and alterations of perfusion induced by ketamine.¹³

Synergistic modulation. By combining TMS's ability to increase perfusion and to modulate cortical activity and connectivity with ketamine's rapid modulation of excitatory neurotransmission and promotion of neuroplasticity, the combination therapy delivers a more comprehensive approach to rebalancing dysfunctional brain networks.¹⁸ Ketamine has been shown to affect connectivity in the salience network,¹⁹ while TMS can modulate activity in the default mode network.²⁰ These observations were recently clarified by the finding “that ketamine causes spontaneously active neurons to become suppressed while previously silent neurons become spontaneously activated.”²¹

Considering these mechanisms together in the same process suggests that the improved perfusion from TMS could enhance the substrate availability necessary for synaptic remodeling, thereby amplifying the neuroplastic effects of ketamine and potentially leading to more sustained therapeutic outcomes.²² Additionally, ketamine offers a complementary advantage by addressing concerns of overstimulation of neural tissue (and iatrogenic pain emanating from the substance of the scalp, skull, and meninges) at higher TMS intensities while mitigating dysphoria.²³

Concluding Thoughts

When traditional treatments fail or are likely to fail to relieve suffering, modern clinicians can turn to a range of explanatory models. The various models are grounded in phenomenological descriptions, biochemical assessments, structural imaging, and various functional brain imaging techniques, including electromagnetic methods, perfusion imaging, and metabolic imaging.

Perfusion imaging, such as Brain SPECT imaging, has been an essential tool in our clinical practice. Our observations support the hypothesis that the effectiveness of combination therapy—integrating coadministered TMS and ketamine—is driven by the impact of 1 Hz TMS on regional brain perfusion. This combination therapy provides a comprehensive approach to treating depression by addressing multiple physiological factors underlying the condition.

1. TMS increases cerebral blood flow, enhancing the brain's metabolic environment and fostering neuroplasticity. Meanwhile, ketamine’s distinct mechanisms also promote neuroplasticity, making it especially effective for addressing persistent chronic depressive illness. Both treatments influence functional connectivity within brain networks associated with depression. Ketamine primarily affects connectivity in the salience network, while TMS helps regulate abnormal activity in the default mode network.
2. Ketamine offers a rapid onset of action, particularly effective in relieving acute dysphoric suffering.⁸
3. Improved effectiveness in acute treatment and reduced long-term relapse rates.¹⁰

Although newer treatments may seem appealing at first glance, modernized versions of time-tested tools—such as Brain SPECT Imaging (readily available since 1976), TMS (successfully applied in 1985), and ketamine (first administered in 1966)—consistently demonstrate clinical efficacy. When evaluating diagnostic and treatment options, it is essential to strike a balance between traditional textbook approaches and the latest advancements in medical science. Our clinical experience with the integration of these proven technologies, targeting perfusion, provides highly effective tools for directly addressing treatment-resistant depression.

While a fully satisfying explanation for most cases of mental illness remains elusive, we do have decades of experience with diagnostic testing and the components of combination therapy, culminating in 15 years of practical application with combination therapy itself. We believe this qualifies it as an evidence-based practice, defined as “the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients.”²⁴ In our experience, when combination therapy is implemented as recommended, outcomes tend to be more positive and predictable, with the vast majority of previously treatment-resistant cases achieving satisfactory clinical results.

Dr Best is the director of the Neuroscience Center in Deerfield, Illinois. Dr Pavel was the director of PathFinder Brain SPECT, and a professor of radiology and nuclear medicine at the University of Illinois Medical Center. This article is published posthumously; Dr Pavel passed away in 2021.

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