Improving PTSD Treatment with Pharmacogenetics

Improving PTSD Treatment with Pharmacogenetics

Post Traumatic Stress Disorder (PTSD) is a mental health condition that is characterized by nightmares and flashbacks of past traumatic events, avoidance of reminders of trauma, hypervigilance and sleep disturbance. PTSD is often associated with other psychiatric illnesses such as severe anxiety and depression and may be accompanied by psychotic episodes. PTSD can afflict not only violent crime victims, combat veterans, and first responders, but also people working in other high stress occupations such as hospital nurses and journalists.

PTSD is treated by both medications and psychosocial interventions. Individuals living with PTSD often resort to drugs and alcohol, which can lead to substance abuse and worsening of psychosis. Psychotherapy, with or without the use of medication, is considered to be the first line treatment of PTSD. To support psychological counseling, medication management can also be used for better control of anxiety, depression, sleep, drug and alcohol cravings.
Successful treatment of PTSD depends on patients’ response and adherence to treatment and engagement through cognitive behavioural therapy (CBT). All medications have side effects but may be particularly severe in people with inherently reduced drug metabolism. Accumulation of a drug in the blood may lead to side effects thereby reducing treatment adherence. On the other extreme, when a medication is cleared too fast it may not improve symptoms and increases the risk of treatment failure. In this summary we will highlight how the genetics of PTSD patients can impact drug response.
Meta analyses of medications used for management of PTSD related symptoms indicate effective pharmacotherapies, including selective serotonin reuptake inhibitors (SSRIs) such as paroxetine, sertraline, fluoxetine, and other agents. Recently, cannabinoids have also been used to improve sleep in PTSD patients.
For PTSD-related symptoms, SSRIs are considered the first line of treatment. It is important to note that up to 25% of people in Canada may have reduced response to sertraline because of an inherently enhanced clearance by CYP2C19. For patients who are rapid or ultrarapid CYP2C19 metabolizers, the Clinical Pharmacogenetics Consortium guideline recommends initiating therapy at the recommended starting dose and to consider alternative medication not metabolized by CYP2C19 if the patient does not respond to the recommended maintenance dose. Up to 10% of people are poor CYP2C19 metabolizers and may not tolerate sertraline which may lead to a change in medication to paroxetine or fluoxetine. On the other hand, both paroxetine and fluoxetine are metabolized by the CYP2D6 enzyme, an enzyme which is also subject to a lot of variability between individuals. The Clinical Pharmacogenetics Implementation guidelines can therefore help select an appropriate SSRI according to the patient’s inherited drug metabolism (pharmacogenetics).

If a PTSD patient with psychosis does not respond to SSRIs then an antipsychotic such as risperidone, quetiapine or olanzapine could be added.
Risperidone is metabolized by the CYP2D6 enzyme – patients with enhanced CYP2D6 activity may have inadequate response, while poor metabolizers may experience significant side effects.

Quetiapine is mostly metabolized by the CYP3A4/5 enzymes. Notably, >85% of Caucasians are poor CYP3A5 metabolizers, also sometimes referred as CYP3A5 “non-expressors”, and are considered normal. However, most people of African origin express a functional CYP3A5, resulting in reduced quetiapine concentration in the blood. For the ethnically diverse North American population, knowing a patient’s pharmacogenetic profile can provide insights on which of these antipsychotic medications would be more effective and well tolerated by the patient.
Olanzapine is mostly metabolized by the CYP1A2 enzyme, which is one of the most “inducible” cytochrome enzymes. CYP1A2 activity is greatly induced in smokers, therefore, response to olanzapine is reduced in PTSD patients who smoke.
For treatment of sleep disruption and nightmares, prazosin has been found to be efficacious. Prazosin is metabolized by demethylation and conjugation and is therefore less susceptible to have altered response in patients with a different pharmacogenetic profile.

Research is currently underway to evaluate the potential use of cannabinoids for treatment of PTSD associated sleep disruption and nightmares, amongst other symptoms. Although the use of cannabinoids in PTSD patients may worsen psychosis, it may help to reduce anxiety and improve sleep. Cannabionoids currently being evaluated include cannabis for medical purposes, tetrahydrocannabinol (THC) and nabilone. Nabilone is a synthetic cannabinoid similar to delta9-THC and was originally approved for managing nausea symptoms. Nabilone is metabolized by numerous enzymes, including CYP2C9 and CYP3A4. Patients with reduced CYP2C9 or CYP3A4 activity may have higher exposure, and as a result could be at higher risk of nabilone related side effects.
In summary, pharmacogenetic testing such as Pillcheck, can provide critical insights on person’s metabolic drug profile and guide therapy choices for patients with PTSD and PTSD associated symptoms.

Selected References

Watts BV, Schnurr PP, Mayo L, Young-Xu Y, Weeks WB, Friedman MJ. Meta-analysis of the efficacy of treatments for posttraumatic stress disorder. J Clin Psychiatry. 2013 Jun;74(6):e541-50.

Zhou Y, Ingelman‐Sundberg M, Lauschke VM. Worldwide Distribution of Cytochrome P450 Alleles: A Meta‐analysis of Population‐scale Sequencing Projects. Clin Pharmacol Ther. 2017 Oct; 102(4): 688–700.

Hicks, JK at al., Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors Clin Pharmacol Ther. 2015 Aug; 98(2): 127–134.

Gueorguieva, I, Jackson, K, Wrighten, S.A, Sinha, V.P, & Chien, J.Y Desipramine, substrate for CYP2D6 activity: population pharmacokinetic model and design elements of drug–drug interaction trials Br J Clin Pharmacol. 2010 Oct; 70(4): 523–536.

Pietrzak, R. H., Goldstein, R. B., Southwick, S. M., & Grant, B. F. (2011). Prevalence and Axis I comorbidity of full and partial posttraumatic stress disorder in the United States: results from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions. Journal of anxiety disorders, 25(3), 456-465.

Campbell, D. G., Felker, B. L., Liu, C. F., Yano, E. M., Kirchner, J. E., Chan, D., … & Chaney, E. F. (2007). Prevalence of depression–PTSD comorbidity: Implications for clinical practice guidelines and primary care-based interventions. Journal of general internal medicine, 22(6), 711-718.

Lindley, S. E., Carlson, E., & Sheikh, J. (2000). Psychotic symptoms in posttraumatic stress disorder. CNS spectrums, 5(9), 52-57.

Share this post