PHARMACOGENETIC TESTING IN TREATMENT-RESISTANT PANIC DISORDER: A PILOT STUDY
Authors: Freire *Rafael , Fidry Marcos , Zugliani Morena , Cabo Mariana , Faria Clara , Nardi Antonio 
Published: February 2025

Background

Pharmacological treatment is considered effective in the treatment of panic disorder (PD). However, about 20 to 40% of PD patients do not respond to the first pharmacological treatment. Trials with multiple drugs are often required before response to treatment is achieved. Pharmacogenetic testing is a promising new tool to aid clinicians in finding the right medication and the right dose for each patient. It could be especially useful in the treatment of treatment-resistant patients with PD.

Aims and Objectives

Ascertain the usefulness of pharmacogenetic testing in treatment-resistant PD.

Methods

20 PD patients who did not respond to treatment-as-usual (TAU) were included in this study. Only patients who were on medications with known efficacy for PD, on adequate dose, and received treatment for at least 8 weeks were considered eligible. Patients with Clinical Global Impression – Improvement (CGI-I) of 1 (very much improved) or 2 (much improved) were considered responders, patients with scores higher than 2 were considered non-responders. The key enzymes’ genetic polymorphisms evaluated were: CYP2D6, CYP2C19, CYP2C9, CYP1A2, CYP3A4, CYP3A5, CYP2B6, FKBP5, HTR2A, ANKK1, HTR1A, HTR2C, DRD2, GRIK4, ADRA2A, OPRM1, COMT, SLC6A4 e ABCB1, FKBS, GSK3B, EPHX1, UGT1A4, UGT2B15, MC4R, SCN1A, SLC6A4, MTHFR (rs1801131 e rs1811133). We retrospectively compared the recommendations of the pharmacogenetic analysis with the treatment the patient actually received.

Results

The recommendation from the pharmacogenetic analysis regarding the actual prescribed drug was “use according to the label” in 40% of the cases, “use with attention” in 55% of the cases and “use with caution and attention” in 5% of the cases. Pharmacogenetic testing indicated reduced chance of response to the prescribed drug in 30% of the subjects, while they indicated very low serum levels of the prescribed drug (fast metabolism) in 20% of the subjects. The CYP3A4 and CYP2D6 activity was normal for most patients. CYP2C19 phenotype indicated slower enzyme activity in 25%, faster enzyme activity in 40%, and normal enzyme activity in 35% of patients. The pharmacogenetic tests predicted a small reduction of methylenetetrahydrofolate reductase (MTHFR) enzyme activity in 75% of the patients.

Discussion and Conclusion

If the pharmacogenetic was made before the treatment, if would have interfered on the medication choice and changed treatment outcome only in 5% of the subjects. Since the polymorphism associated with low MTHFR activity was very prevalent, this finding raises the question of a possible association between this polymorphism and treatment resistance in PD. Low MTHFR activity was associated with treatment resistance in mood disorders. Administering L-methylfolate would bypass the enzyme and correct the vitamin deficiency in the intracellular level, making these patients treatment responsive. Given the findings from the current study, pharmacogenetic tests would not have aided clinicians in finding the right pharmacological treatments for each patient. High prevalence of CYP2C19 and MTHFR polymorphisms in PD patients requires further study.

References

Baldwin, D.S., Anderson, I.M., Nutt, D.J., Allgulander, C., Bandelow, B., Den Boer, J.A., Christmas, D.M., Davies, S., Fineberg, N., Lidbetter, N., Malizia, A., McCrone, P., Nabarro, D., O’ Neill, C., Scott, J., Van Der Wee, N., Wittchen, H.U., 2014. Evidence-based pharmacological treatment of anxiety disorders, post- traumatic stress disorder and obsessive-compulsive disorder: A revision of the 2005 guidelines from the British Association for Psychopharmacology. J. Psychopharmacol. 28, 403–439. https://doi.org/10.1177/0269881114525674

Bjelland, I., Tell, G.S., Vollset, S.E., Refsum, H., Ueland, P.M., 2003. Folate, vitamin B12, homocysteine, and the MTHFR 677C→ T polymorphism in anxiety and depression. The Hordaland Homocysteine Study. Arch. Gen. Psychiatry. https://doi.org/10.1001/archpsyc.60.6.618

Blaya, C., Salum, G.A., Lima, M.S., Leistner-Segal, S., Manfro, G.G., 2007. Lack of association between the Serotonin Transporter Promoter Polymorphism (5-HTTLPR) and Panic Disorder: a systematic review and meta-analysis. Behav Brain Funct 3, 41. https://doi.org/1744-9081-3-41 [pii]\n10.1186/1744-9081-3- 41

Caldirola, D., Perna, G., 2015. Is there a role for pharmacogenetics in the treatment of panic disorder? Pharmacogenomics. https://doi.org/10.2217/pgs.15.66

Freire, R.C., Hallak, J.E., Crippa, J.A., Nardi, A.E., 2011. New treatment options for panic disorder: clinical trials from 2000 to 2010. Expert Opin. Pharmacother. https://doi.org/10.1517/14656566.2011.562200 Froese, D.S., Huemer, M., Suormala, T., Burda, P., Coelho, D., Gué ant, J.L., Landolt, M.A., Kož ich, V., Fowler, B., Baumgartner, M.R., 2016. Mutation Update and Review of Severe Methylenetetrahydrofolate Reductase Deficiency. Hum. Mutat. https://doi.org/10.1002/humu.22970

He, Q., Mei, Y., Liu, Y., Yuan, Z., Zhang, J., Yan, H., Shen, L., Zhang, Y., 2019. Effects of Cytochrome P450 2C19 Genetic Polymorphisms on Responses to Escitalopram and Levels of Brain-Derived Neurotrophic Factor in Patients with Panic Disorder. J. Clin. Psychopharmacol. https://doi.org/10.1097/JCP.0000000000001014