Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial.

Importance: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment. Objective: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes. Design, Setting, and Participants: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications. Interventions: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978). Main Outcomes and Measures: The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters. Results: Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = .02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = .45). Conclusions and Relevance: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission. Trial Registration: ClinicalTrials.gov Identifier: NCT03170362.

Olfactory-mediated fear-potentiated startle.

Recently, R. Richardson, A. Vishney, and J. Lee (1999) reported that ambient odor cues that were previously paired with footshock potentiate the acoustic startle response in rats. The authors of the present study extend those findings by using a discrete 4-s amyl acetate odor paired with footshock to address several parametric issues that might be important for using odorants as conditioned stimuli (CSs) in this paradigm. Amyl acetate (5%) had no significant effect on startle in untrained rats but did potentiate startle in rats that received 1, 2, 5, or 10 odor-shock pairings. Fear-potentiated startle decreased but was still significant up to 40 days after conditioning and could be measured in test trials separated by as little as 30 s. The magnitude of potentiated startle decreased with decreasing concentrations of amyl acetate (5%-5 x 10-9%). The anxiolytic compound buspirone (10 mg/kg) significantly attenuated olfactory-mediated fear-potentiated startle.

Glutamate receptor antagonist infusions into the basolateral and medial amygdala reveal differential contributions to olfactory vs. context fear conditioning and expression.

The basolateral amygdala's involvement in fear acquisition and expression to visual and auditory stimuli is well known. The involvement of the basolateral and other amygdala areas in fear acquisition and expression to stimuli of other modalities is less certain. We evaluated the contribution of the basolateral and medial amygdala to olfactory and to context fear and fear conditioning by infusing into these areas the NMDA receptor antagonist AP5, the AMPA/kainate receptor antagonist NBQX, or vehicle prior to either odor-shock pairings or fear-potentiated startle testing. Pre-training AP5 infusions into the basolateral amygdala disrupted fear conditioning to the odor but not the context conditioned stimulus (CS). Pre-test NBQX infusions disrupted fear-potentiated startle to the odor but not context CS. Neither compound blocked fear conditioning when infused into the medial amygdala prior to training, but pre-test NBQX infusions did block fear-potentiated startle. The results confirm and extend recent findings suggesting a role for the basolateral amygdala in olfactory fear and fear conditioning, reveal an unexpected dissociation of the basolateral amygdala's involvement in discrete cue versus context fear and fear conditioning, and implicate for the first time the medial amygdala in fear-potentiated startle.

Second-order olfactory-mediated fear-potentiated startle.

Recently, we reported that discrete (4-sec) olfactory cues paired with footshock serve as effective conditioned stimuli (CSs) for potentiating the acoustic startle response in rats using the fear-potentiated startle paradigm. Because odors are such salient cues for the rat, and because of the robust olfactory conditioning observed previously, the current studies investigated second-order fear conditioning using olfactory and visual cues. In Experiments 1 and 2, we used a small number of first-order and second-order training trials on separate days to investigate second-order fear-potentiated startle. Significant potentiated startle was observed in animals receiving Paired/Paired training in both studies, but surprisingly, control animals in the Unpaired/Paired group (Exp. 1) also showed significant potentiated startle to a light S2 at testing. These findings are addressed in the Discussion. Overall, the results of both experiments suggest that olfactory cues serve as efficient S1 and S2 stimuli in second-order fear-potentiated startle paradigms when only a small number of first and second-order training trials are presented.

"You will eat all of that!": a retrospective analysis of forced consumption episodes.

The present research was initiated to examine the prevalence of forced consumption and its role in subsequent food rejection. A forced consumption episode was defined as a situation where Person(s) A forced or demanded Person B to consume a specific substance against Person B's will. An initial survey of 407 college students revealed that over 69% of them had experienced at least one forced consumption episode. One hundred forty individuals completed a follow-up questionnaire exploring various characteristics of their most memorable forced consumption scenario. Specifically, the most common type of forced consumption (76%) involved an authority figure (e.g. parent, teacher) forcing a child to consume a novel, disliked, or aversive food. In this authority figure scenario, respondents recalled the episode as involving interpersonal conflict and negative affect, and identified the most aversive aspects of this scenario as lack of control and feelings of helplessness. Furthermore, most respondents (72%) reported that they would not willingly eat the target food today. In sum, the forced consumption episode appears to be a unique situation in which distasteful food combines with interpersonal conflict to result in long-lasting food rejection.