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.

The dual orexin/hypocretin receptor antagonist, almorexant, in the ventral tegmental area attenuates ethanol self-administration.

Recent studies have implicated the hypocretin/orexinergic system in reward-seeking behavior. Almorexant, a dual orexin/hypocretin R(1) and R(2) receptor antagonist, has proven effective in preclinical studies in promoting sleep in animal models and was in Phase III clinical trials for sleep disorders. The present study combines behavioral assays with in vitro biochemical and electrophysiological techniques to elucidate the role of almorexant in ethanol and sucrose intake. Using an operant self-administration paradigm, we demonstrate that systemic administration of almorexant decreased operant self-administration of both 20% ethanol and 5% sucrose. We further demonstrate that intra-ventral tegmental area (VTA) infusions, but not intra-substantia nigra infusions, of almorexant reduced ethanol self-administration. Extracellular recordings performed in VTA neurons revealed that orexin-A increased firing and this enhancement of firing was blocked by almorexant. The results demonstrate that orexin/hypocretin receptors in distinct brain regions regulate ethanol and sucrose mediated behaviors.

Autonomic dysregulation in young girls with Rett Syndrome during nighttime in-home recordings.

This study was designed to specifically characterize the autonomic phenotype of cardiorespiratory dysregulation during the nighttime in young girls with MECP2 mutation-confirmed Rett Syndrome (RS), studied in their home environment. Computerized breath-to-breath and beat-to-beat characterization of at-home continuously recorded respiratory inductance plethysmography of chest/abdomen and ECG (VivoMetrics, Inc.) was obtained during overnight recordings in 47 girls with MECP2 mutation-confirmed RS and 47 age-, gender-, and ethnicity-matched screened controls (ages 2-7 years). We determined that although the breathing and heart rate appear more regular during the night compared to the day, young girls with RS demonstrate apparent nocturnal irregularities. Comparing daytime versus nighttime, breathing was more irregular, with an increased breathing frequency (and irregularity), mean amplitude of respiratory inductance plethysmography sum (AMP)/T(I), and heart rate and decreased AMP in girls with RS. Comparing girls with RS versus controls during nighttime recording, breathing was more irregular, with an increased breathing frequency (and irregularity), mean AMP/T(I), and heart rate. An increased uncoupling between measures of breathing and heart rate control indicates malregulation in the autonomic nervous system, and is apparent during the day as well as the night. This uncoupling may represent a mechanism that renders the girls with RS more vulnerable to sudden death.

Differential modulation of neural network and pacemaker activity underlying eupnea and sigh-breathing activities.

Many networks generate distinct rhythms with multiple frequency and amplitude characteristics. The respiratory network in the pre-Bötzinger complex (pre-Böt) generates both the low-frequency, large-amplitude sigh rhythm and a faster, smaller-amplitude eupneic rhythm. Could the same set of pacemakers generate both rhythms? Here we used an in vitro respiratory brainslice preparation. We describe a subset of synaptically isolated pacemakers that spontaneously generate two distinct bursting patterns. These two patterns resemble network activity including sigh-like bursts that occur at low frequencies and have large amplitudes and eupneic-like bursts with higher frequency and smaller amplitudes. Cholinergic neuromodulation altered the network and pacemaker bursting: fictive sigh frequency is increased dramatically, whereas fictive eupneic frequency is drastically lowered. The data suggest that timing and amplitude characteristics of fictive eupneic and sigh rhythms are set by the same set of pacemakers that are tuned by changes in the neuromodulatory state.

Autonomic nervous system dysregulation: breathing and heart rate perturbation during wakefulness in young girls with Rett syndrome.

This study characterizes cardiorespiratory dysregulation in young girls with MECP2 mutation-confirmed Rett syndrome (RS). Respiratory inductance plethysmography of chest/abdomen and ECG was obtained during daytime wakefulness in 47 girls with MECP2 mutation-confirmed RS and 47 age-, gender-, and ethnicity-matched controls (ages 2-7 y). An in-home breath-to-breath and beat-to-beat characterization was conducted and revealed that breathing was more irregular, with an increased breathing frequency, mean airflow, and heart rate in RS versus controls. There was a decreased correlation between normal breathing and heart rate variability, and an exaggerated increase in heart rate response to breathholds in RS versus controls. We conclude that girls with RS have cardiorespiratory dysregulation during breathholds as well as during "normal" breaths and during breaths before and subsequent to breathholds. This dysregulation may offer insight into the mechanisms that render girls with RS more vulnerable to sudden death.

Pattern-specific synaptic mechanisms in a multifunctional network. I. Effects of alterations in synapse strength.

Many neuronal networks are multifunctional, producing different patterns of activity in different circumstances, but the mechanisms responsible for this reconfiguration are in many cases unresolved. The mammalian respiratory network is an example of such a system. Normal respiratory activity (eupnea) is periodically interrupted by distinct large-amplitude inspirations known as sighs. Both rhythms originate from a single multifunctional neural network, and both are preserved in the in vitro transverse medullary slice of mice. Here we show that the generation of fictive sighs were more sensitive than eupnea to reductions of excitatory synapse strength caused by either the P/Q-type (alpha1A-containing) calcium channel antagonist omega-agatoxin TK or the non-N-methyl-D-aspartate (NMDA) glutamate receptor antagonist 6-cyano-7-nitroquinoxalene-2,3-dione (CNQX). In contrast, the NMDA receptor antagonist MK-801, while also inhibiting eupnea, increased the occurrence of sighs. This suggests that among the glutamatergic synapses subserving eupneic rhythmogenesis, there is a specific subset-highly sensitive to agatoxin and insensitive to NMDA receptor blockade-that is essential for sighs. Blockade of N-type calcium channels with omega-conotoxin GVIA also had pattern-specific effects: eupneic activity was not affected, but sigh frequency was increased and postsigh apnea decreased. We hypothesize that N-type (alpha1B) calcium channels selectively coupled to calcium-activated potassium channels contribute to the generation of the postsigh apnea.

Pattern-specific synaptic mechanisms in a multifunctional network. II. Intrinsic modulation by metabotropic glutamate receptors.

The in vitro respiratory network contained in the transverse brain stem slice of mice simultaneously generates fast (approximately 15 min(-1)) and slow ( approximately 0.5 min(-1)) rhythmic activities corresponding to fictive eupnea ("normal" breathing) and fictive sighs. We show that these two activity patterns are differentially controlled through the modulatory actions of metabotropic glutamate receptors (mGluRs). Sighs were selectively inhibited by agonists of the group III mGluRs according to a pharmacological profile most consistent with activation of mGluR8. Sighs were also blocked by the supposedly inactive L-isomer of the widely used N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonopentanoic acid (L-AP5, 5 microM), an effect that was abolished in the presence of group III mGluR antagonists. Excitatory postsynaptic potentials (EPSPs) were recorded in pre-Bötzinger Complex neurons after stimulation of the contralateral ventral respiratory group (VRG); evoked EPSP amplitude was variably reduced after bath application of the group III agonist L-serine-O-phosphate (L-SOP), with an average reduction of 15%. Therefore although group III mGluRs do play a role in regulating synapse strength, this seems to be only a minor factor in the regulation of synapses made by midline-crossing axons. Intrinsic modulation of the respiratory central pattern generator by mGluRs appears to be an essential component of the multifunctionality that characterizes this network.

Commentary on the definition of eupnea and gasping.

Despite clear qualitative differences, it has proven difficult to identify criteria that reliably differentiate eupnea and gasping--particularly when multiple species or experimental preparations are considered. From a motor control perspective, this is unsurprising. Three organizational rules are common to nearly all rhythmic activities: (1) the basic rhythm is produced by a small network of cells, (2) the activity of this network in isolation often differs dramatically from the behavior of the whole animal, and (3) the rhythmogenic networks responsible for related behaviors are not fixed and independent but dynamically modifiable and overlapping. In this context, it becomes clear that the definition of a particular pattern and the investigation of the mechanisms underlying its production are inseparable. Rather than attempting to rigidly apply criteria developed using any one experimental preparation, the classification of respiratory patterns must evolve alongside our understanding of how each pattern is produced-a process that is only aided by investigations using a variety of experimental preparations.

Respiratory rhythm generation: converging concepts from in vitro and in vivo approaches?

The timing and activation pattern of breathing movements are determined by the respiratory network. This network is amenable to a variety of in vivo and in vitro approaches, which offers a unique opportunity to investigate multiple organizational levels. It is only recently, however, that concepts obtained under in vivo and in vitro conditions are being integrated into a coherent model of breathing behavior. For example, the pre-Bötzinger complex as an essential site for rhythm generation was first identified in vitro, but has since been verified in vivo. Conversely, timing signals provided by other central and peripheral neuronal areas have so far been investigated in vivo, but it is now possible to address these issues with more complex in vitro preparations. Several key issues remain unresolved. For example, to what extent is the respiratory pattern controlled independently of the underlying rhythm? Answers to this and other questions require a dissection of mechanisms that is only possible through a complementary combination of experimental approaches.