Posttraumatic Stress Disorder Subtypes Invalid

Mehta et al¹ concluded that certain polymorphisms in FKBP5, a gene related to the glucocorticoid receptor (GR), determine specific types of hypothalamic-pituitary-adrenal axis dysfunction within posttraumatic stress disorder (PTSD) and that these polymorphisms are associated with biologically distinct subtypes of PTSD. These novel claims are unsound.

The essential error consists in the drawing of categorical conclusions from dimensional analyses. A statistically significant triple interaction among allele carrier status, PTSD status, and baseline serum cortisol concentration or change in cortisol concentration with dexamethasone administration does not identify a specific dysfunction or a PTSD subtype. Further to the fictive status of these proposals, operational definitions of the supposed subtypes of PTSD were not given.

Inspection of the endocrine data reveals that all the group mean post-dexamethasone plasma cortisol concentrations were in the range of 4.2 to 5.5μg/dL (to convert to nanomoles per liter, multiply by 27.588) (Mehta et al Table 1 and Figure 1B). No group displayed a trend to“increased dexamethasone suppression” or“GR supersensitivity.” Based on the means and variances (the latter being undefined but apparently standard deviations in Table 1 and standard errors in Figure 1), many cases in all groups would be regarded as cortisol nonsuppressors.^{2 - 3} A further concern is that the significant potential confound of variation in dexamethasone pharmacokinetics among groups^{4 - 6} was ignored.

The claims of hypothalamic-pituitary-adrenal axis“dysfunction” or“putative biomarkers” lack face validity. The baseline cortisol concentration differences (Figure 1A) are physiologically minor; likewise, any difference between groups in cortisol concentration change after dexamethasone administration is trivial (Figure 1B). To characterize these small dimensional differences as“specific types of hypothalamic-pituitary-adrenal axis dysfunction” is inaccurate, because no evidence of“dysfunction” was presented. No operational definitions of the supposed hypothalamic-pituitary-adrenal axis dysfunctions or putative biomarkers were given. Evidence of“dysfunction” would require, in addition, normative data obtained with the local assay for cortisol. There is no reason to think that any of the results shown would differ significantly from those expected in normal subjects.

Finally, inconsistencies in characterizing the phenotype should be noted. Mehta et al repeatedly equivocated on the terms posttraumatic stress disorder, PTSDsymptoms, and probablePTSD. In fact, the ad hoc diagnosis of PTSD was a proxy judgment derived from a symptom screening scale that has less than 80% specificity in relation to gold-standard diagnoses of PTSD and that considers only 2 weeks of symptom duration instead of 4 weeks as required by standard criteria.^{7 - 8} Therefore, there is no basis to imply, as in the title, that these findings apply to the clinical disorder called PTSD. At best, the findings apply only to symptoms.

Thus, this report suffers from serious deficiencies in design and in critical interpretation. The evidence does not support the conclusions.