Neuroimaging biomarkers of treatment response in anxiety disorders

Mazen Elkhayat
Honours Psychology, Neuroscience and Behaviour (Mental Health Specialization), Class of 2023, McMaster University
elkhayam@mcmaster.ca

BACKGROUND

Anxiety disorders are the most prevalent psychiatric conditions across the human lifespan, with an estimated lifetime prevalence of 31.9%.^1,2 They are also the sixth leading cause of disability worldwide.³  Despite the significant functional impairment caused by anxiety disorders, patients are often treated as outpatients and subsequently receive less medical attention and treatment monitoring than patients with less prevalent disorders, but are usually treated as inpatients with consistent monitoring, such as schizophrenia or bipolar disorder.⁴ Moreover, treatment response is highly heterogeneous, with somewhere between 40% and 50% of patients failing to respond to either pharmacological or psychotherapeutic treatments.¹ Therefore, it is essential that patients are assigned to a treatment that is effective for them, considering the variability of treatment response and the fact that patients are not as closely monitored as opposed  to other conditions. Recent research has revealed reliable biomarker indicators of treatment response obtained from neuroimaging techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). These neuroimaging biomarkers could be used to objectively assess whether patients are responding well to current treatment, or whether they should be placed on another treatment plan.

FEAR NEUROCIRCUITRY IN ANXIETY DISORDERS

The identification of neuroimaging biomarkers, or detectable brain regions and networks that have some predictive value for determining the course of a disorder and/or treatment would not have been possible without prior research into the neuroanatomy underlying anxiety disorders. One of the lead unifying theories of this field of research is the fear neurocircuitry hypothesis proposed by Gorman et al.^5,6 This hypothesis centers around the amygdala, which has been implicated in many disorders involving emotional dysregulation. The amygdala processes emotions associated with fear and coordinates autonomic and behavioural responses accordingly.⁶ These functions are carried out via connections to other brain regions. Projections from the central nucleus of the amygdala communicate information regarding emotions experienced during anxiety to its many efferents, such as the hypothalamus. The hypothalamus then activates the hypothalamic-pituitary-adrenal (HPA) axis, leading to the release of cortisol and autonomic arousal, and the locus ceruleus which increases norepinephrine release, resulting in increased blood pressure, heart rate and behavioural fear responses.⁶ This response can be adaptive during some short-term periods of stress, such as when facing an imminent threat, however, it has negative long-term consequences, such as the psychological symptoms of anxiety and high blood pressure⁷. To prevent overactivation of this fear response, the activity of the amygdala is regulated via reciprocal connections to areas such as the prefrontal cortex (PFC) and its adjacent regions, especially the anterior cingulate cortex (ACC), which plays a critical role in emotional regulation. These regions and their connections are disturbed during anxiety disorders, leading to misinterpretation of neutral sensory information as threatening, the subsequent inappropriate activation of the amygdala and the rest of the fear circuitry.⁸ Therefore, research aiming to identify biomarkers of treatment response focuses on the amygdala and its associated regulatory regions.

METHODS OF DETERMINING NEUROIMAGING BIOMARKERS OF TREATMENT RESPONSE

The two main treatments for anxiety disorders are pharmacotherapy and cognitive-behavioural therapy (CBT). Pharmacotherapy involves administering drugs that aim to restore normal levels of neurotransmitters in the fear neurocircuitry outlined above. Benzodiazepines are the most common drug class for treating many anxiety disorders, such as generalized anxiety disorder (GAD). Benzodiazepines focus on enhancing the effects of the inhibitory neurotransmitter Gamma-Aminobutyric acid (GABA).⁸ Leicht and colleagues sought to investigate the effects of a common benzodiazepine, Alprazolam, more commonly known as Xanax, on fear neurocircuitry in panic disorder.⁹ Injections of the neuropeptide cholecystokinin-tetrapeptide (CCK-4) were used to induce panic symptoms in participants during fMRI scans before and after alprazolam administration. It was found that alprazolam significantly increased functional connectivity, or the co-activation patterns, between the ACC, the rest of the PFC and the amygdala. All three regions contain α2 and/or α3 subunits in their GABA receptors, which are important targets for benzodiazepine anxiolytic action.⁹ As mentioned previously, the ACC and the PFC regulate and often inhibit the activity of the amygdala, reducing fear responses.

CBT has also been shown to alter brain physiology in similar ways. CBT aims to change dysfunctional thoughts associated with fear, often by teaching coping mechanisms or relaxation techniques during the real or imagined presentation of anxiety-provoking stimuli. At a physiological level, this may encourage the use of regulatory regions, such as the ACC and PFC, to inhibit amygdala activation, thereby reducing anxiety.⁵  The physiological effects of CBT during the treatment of anxiety disorders are not only comparable to those produced by pharmaceutical medication, but they may occur at an even faster rate. Prasko et al. used PET scans to compare treatment response in panic disorder patients after either CBT or selective serotonin reuptake inhibitor (SSRI) pharmacotherapy, another common drug class used to treat anxiety.¹⁰ Increased metabolism, a measure of activity, in regulatory PFC regions was observed for both groups, along with improvements in psychopathology symptom ratings. However, patients receiving CBT experienced a faster reduction in symptoms compared to those receiving SSRI drug treatment.¹⁰ Several other studies also confirm the reliability of the PFC and the adjacent ACC in assessing treatment response in anxiety disorders after CBT. Sakai et al. also observed increased metabolism in the PFC in patients with panic disorder after CBT.¹¹ Sandman et al. found increased connectivity between the PFC and the amygdala after CBT for social anxiety disorder (SAD).¹² These findings emphasize the validity of using neuroimaging biomarkers to assess treatment response in patients undergoing psychological therapies such as CBT.

Recent evidence suggests that biomarkers of treatment response may not only be used to assess the efficacy of the current treatment plan but may even predict patients’ responses before undergoing treatment. Kujawa et al. found a significant correlation between baseline PFC activity and better treatment responses in patients with generalized, social and/or separation anxiety disorder.¹³ Patients with higher PFC activity before treatment went on to have better treatment response and symptom reduction after CBT or SSRI treatment.¹³ Frick and colleagueswere able to use baseline ACC activity to predict treatment response in SAD patients with 81% accuracy.¹⁴ Patients with high baseline ACC activity had better responses to a combination of SSRIs and CBT, whereas patients with low baseline ACC activity had better responses to CBT without SSRIs.¹⁴ This provides evidence for the predictive value of neuroimaging biomarkers, which could help determine more effective treatment plans by ensuring patients are assigned to treatments that they will respond appropriately to.

CONCLUSION

In anxiety disorders, treatment response is highly variable and difficult to predict. Patients and clinicians alike could spend considerable amounts of time and resources on a treatment plan that the patient is not responding well to. Brain regions that regulate the activity of the amygdala, mainly the PFC and the adjacent ACC, as well as the functional connectivity between these areas, are reliable indicators of treatment response. The discovery of these neuroimaging biomarkers could give rise to a new era of precision psychiatry, in which patients receive personalized, evidence-based treatments based on predictive biomarkers. Treatment response can be evaluated objectively to ensure the treatments that they are assigned to are effective.¹

1. Strawn J, Levine A. Treatment response biomarkers in anxiety disorders: From neuroimaging to neuronally-derived extracellular vesicles and beyond. Biomarkers in Neuropsychiatry. 2020;3:100024.
2. Merikangas K, He J, Burstein M, Swanson S, Avenevoli S, Cui L et al. Lifetime Prevalence of Mental Disorders in U.S. Adolescents: Results from the National Comorbidity Survey Replication–Adolescent Supplement (NCS-A). Journal of the American Academy of Child & Adolescent Psychiatry. 2010;49(10):980-89.
3. Baxter A, Vos T, Scott K, Ferrari A, Whiteford H. The global burden of anxiety disorders in 2010. Psychological Medicine. 2014;44(11):2363-2374.
4. Epidemiology of anxiety disorders in the 21st century. Dialogues in Clinical Neuroscience. 2015;17(3):327-35.
5. de Carvalho M, Dias G, Cosci F, de-Melo-Neto V, Bevilaqua M, Gardino P et al. Current findings of fMRI in panic disorder: Contributions for the fear neurocircuitry and CBT effects. Expert Review of Neurotherapeutics. 2010;10(2):291-303.
6. Gorman J. Neuroanatomical hypothesis of panic disorder, revised. American Journal of Psychiatry. 2000;157(4):493-505.
7. Mucci N, Giorgi G, De Pasquale Ceratti S, Fiz-Pérez J, Mucci F, Arcangeli G. Anxiety, stress-related factors, and blood pressure in young adults. Frontiers in psychology. 2016 Oct 28;7:1682.
8. Gomez A, Barthel A, Hofmann S. Comparing the efficacy of benzodiazepines and serotonergic anti-depressants for adults with generalized anxiety disorder: a meta-analytic review. Expert Opinion on Pharmacotherapy. 2018;19(8):883-894.
9. Leicht G, Mulert C, Eser D, Sämann P, Ertl M, Laenger A et al. Benzodiazepines counteract rostral anterior cingulate cortex activation induced by cholecystokinin-tetrapeptide in humans. Biological Psychiatry. 2013;73(4):337-344.
10. Prasko J, Horacek J, Paskova B, Belohlavek O, Hoschl C, Skrdlantova L et al. The change of regional brain metabolism (18 FDG PET) in panic disorder during the treatment with cognitive behavioral therapy or antidepressants. Neuroendocrinology Letters. 2004;25(5):340-348.
11. Sakai Y, Kumano H, Nishikawa M, Sakano Y, Kaiya H, Imabayashi E et al. Changes in cerebral glucose utilization in patients with panic disorder treated with cognitive–behavioral therapy. NeuroImage. 2006;33(1):218-226.
12. Sandman C, Young K, Burklund L, Saxbe D, Lieberman M, Craske M. Changes in functional connectivity with cognitive behavioral therapy for social anxiety disorder predict outcomes at follow-up. Behaviour Research and Therapy. 2020;129:103612.
13. Kujawa A, Swain J, Hanna G, Koschmann E, Simpson D, Connolly S et al. Prefrontal reactivity to social signals of threat as a predictor of treatment response in anxious youth. Neuropsychopharmacology. 2015;41(8):1983-1990.
14. Frick A, Engman J, Wahlstedt K, Gingnell M, Fredrikson M, Furmark T. Anterior cingulate cortex activity as a candidate biomarker for treatment selection in social anxiety disorder. BJPsych Open. 2018;4(3):157-159.