Pharmacogenomics and Psychiatric Clinical Care.

Approximately one in five individuals in the United States experiences mental health issues in any given year, and these disorders are consistently among the leading causes of years lived with disability. Unfortunately, many mental illnesses are lifelong conditions that require medication and therapy to improve quality of life, yet clinical trial data show that many patients fail to achieve remission or require several pharmacological interventions prior to remission. These results indicate a need to address the variability among patients in their response to medication, in addition to developing treatment plans tailored to the individual. One approach that may help explain patient variability in response to medication is pharmacogenetic testing. The current review shows the clinical use of pharmacogenetic testing in a small subset of gene variants and how they pertain to psychiatric illness and treatment. Recent evidence suggests that genetic testing for psychiatric illness can improve patient outcomes in addition to decreasing health care costs. [Journal of Psychosocial Nursing and Mental Health Services, 56(1), 22-31.].

Effect of L-Methylfolate Supplementation on Sleep for Patients with Reduced Methylenetetrahydrofolate Reductase Activity.

INTRODUCTION: Clinicians have limited options outside controlled substances to address sleep disturbance, which left untreated can negatively affect patient outcomes in cardiovascular health, mental health, immunologic function, and more. For some, genetic factors may influence sleep disturbances. L-methylfolate, the active form of folate, plays a critical role in regulation of monoamine neurotransmitters known to have significant impact on sleep regulation: dopamine, serotonin, norepinephrine. Single nucleotide polymorphisms of the enzyme methylene-tetrahydrofolate-reductase are common and can impact monoamine production. The goal of this study was to evaluate effects of L-methylfolate supplementation on sleep in a cohort with reduced methylene tetrahydrofolate reductase (MTHFR) activity. METHODS: A retrospective cohort of patients being treated with L-methylfolate in a concierge medical clinic setting was studied. Patients presenting with sleep complaints were evaluated using the Patient-Reported Outcomes Measurement Information System at baseline. Patients with known MTHFR polymorphisms at either C667T and/or A1298C were recommended 5 mg of L-methylfolate daily and were reevaluated at 2 wks, at 4 wks, and at 8 wks of supplementation. Statistical comparisons were made utilizing ANOVA and T-test comparisons. RESULTS: Ten were included in the final cohort: six male and four female, average age 43 ± 16 years. Beginning at wk 2, average sleep disturbance improved significantly by -6.94 points (p = 0.005) and by 8 wks, all patients had improvement with a -14.34 change in disturbance from baseline (p = 0.001). CONCLUSION: Improvement in sleep disturbance was seen in both low and intermediate function phenotypes. L-methylfolate may be useful for improving sleep in patients with MTHFR polymorphism.

GABA(A) receptor modulation during adolescence alters adult ethanol intake and preference in rats.

BACKGROUND: To address the hypothesis that GABA(A) receptor modulation during adolescence may alter the abuse liability of ethanol during adulthood, the effects of adolescent administration of both a positive and negative GABA(A) receptor modulator on adult alcohol intake and preference were assessed. METHODS: Three groups of adolescent male rats received 12 injections of lorazepam (3.2 mg/kg), dehydroepiandrosterone (DHEA, 56 mg/kg), or vehicle on alternate days starting on postnatal day (PD) 35. After this time, the doses were increased to 5.6 and 100 mg/kg, respectively, for 3 more injections on alternate days. Subjects had access to 25 to 30 g of food daily, during the period of the first 6 injections, and 18 to 20 g thereafter. Food intake of each group was measured 60 minutes after food presentation, which occurred immediately after drug administration on injection days or at the same time of day on noninjection days. When subjects reached adulthood (PD 88), ethanol preference was determined on 2 separate occasions, an initial 3-day period and a 12-day period, in which increasing concentrations of ethanol were presented. During each preference test, intake of water, saccharin, and an ethanol/saccharin solution was measured after each 23-hour access period. RESULTS: During adolescence, lorazepam increased 60-minute food intake, and this effect was enhanced under the more restrictive feeding schedule. DHEA had the opposite effect on injection days, decreasing food intake compared with noninjection days. In adulthood, the lorazepam-treated group preferred the 2 lowest concentrations of ethanol/saccharin more than saccharin alone compared with vehicle-treated subjects, which showed no preference for any concentration of ethanol/saccharin over saccharin. DHEA-treated subjects showed no preference among the 3 solutions. CONCLUSIONS: These data demonstrate that GABA(A) receptor modulation during adolescence can alter intake and preference for ethanol in adulthood and highlights the importance of drug history as an important variable in the liability for alcohol abuse.

Effects of positive and negative modulators of the γ-aminobutyric acid A receptor complex on responding under a differential-reinforcement-of-low-rate schedule of reinforcement in rats.

Relatively little is known about the behavioral effects of the neurosteroids compared with other drugs that modulate the γ-aminobutyric acid A (GABAA) receptor complex. This study examined the acute effects of pregnanolone and dehydroepiandrosterone (DHEA) in male rats responding under a differential-reinforcement-of-low-rate schedule of reinforcement. For comparison, three positive modulators of the GABAA receptor (lorazepam, ethanol, and pentobarbital), one negative modulator (ß-CCM), and one neutral modulator (flumazenil) were tested. Pregnanolone was also administered in combination with DHEA to test for antagonism between these substances. Pregnanolone, lorazepam, and pentobarbital produced increases in responding at intermediate doses, and ethanol and pentobarbital produced decreases in responding at the highest doses tested. However, all four drugs dose-dependently decreased reinforced responding by decreasing inter-response times. DHEA, ß-CCM, and flumazenil did not increase responding at intermediate doses or decrease reinforced responding. DHEA did not competitively antagonize the disruptive effects of pregnanolone. In summary, pregnanolone and DHEA produced effects on differential-reinforcement-of-low-rate responding that are similar to other positive and negative GABAA modulators, respectively, and do not produce these effects through a single binding site.

Partial mGlu5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects.

Cocaine abuse remains a public health concern for which pharmacotherapies are largely ineffective. Comorbidities between cocaine abuse, depression, and anxiety support the development of novel treatments targeting multiple symptom clusters. Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor 5 (mGlu5) subtype are currently in clinical trials for the treatment of multiple neuropsychiatric disorders and have shown promise in preclinical models of substance abuse. However, complete blockade or inverse agonist activity by some full mGlu5 NAM chemotypes demonstrated adverse effects, including psychosis in humans and psychotomimetic-like effects in animals, suggesting a narrow therapeutic window. Development of partial mGlu5 NAMs, characterized by their submaximal but saturable levels of blockade, may represent a novel approach to broaden the therapeutic window. To understand potential therapeutic vs adverse effects in preclinical behavioral assays, we examined the partial mGlu5 NAMs, M-5MPEP and Br-5MPEPy, in comparison with the full mGlu5 NAM MTEP across models of addiction and psychotomimetic-like activity. M-5MPEP, Br-5MPEPy, and MTEP dose-dependently decreased cocaine self-administration and attenuated the discriminative stimulus effects of cocaine. M-5MPEP and Br-5MPEPy also demonstrated antidepressant- and anxiolytic-like activity. Dose-dependent effects of partial and full mGlu5 NAMs in these assays corresponded with increasing in vivo mGlu5 occupancy, demonstrating an orderly occupancy-to-efficacy relationship. PCP-induced hyperlocomotion was potentiated by MTEP, but not by M-5MPEP and Br-5MPEPy. Further, MTEP, but not M-5MPEP, potentiated the discriminative-stimulus effects of PCP. The present data suggest that partial mGlu5 NAM activity is sufficient to produce therapeutic effects similar to full mGlu5 NAMs, but with a broader therapeutic index.

Comparison of dehydroepiandrosterone (DHEA) and pregnanolone with existing pharmacotherapies for alcohol abuse on ethanol- and food-maintained responding in male rats.

The present study compared two putative pharmacotherapies for alcohol abuse and dependence, dehydroepiandrosterone (DHEA) and pregnanolone, with two Food and Drug Administration (FDA)-approved pharmacotherapies, naltrexone and acamprosate. Experiment 1 assessed the effects of different doses of DHEA, pregnanolone, naltrexone, and acamprosate on both ethanol- and food-maintained responding under a multiple fixed-ratio (FR)-10 FR-20 schedule, respectively. Experiment 2 assessed the effects of different mean intervals of food presentation on responding for ethanol under a FR-10 variable-interval (VI) schedule, whereas Experiment 3 assessed the effects of a single dose of each drug under a FR-10 VI-80 schedule. In Experiment 1, all four drugs dose-dependently decreased response rate for both food and ethanol, although differences in the rate-decreasing effects were apparent among the drugs. DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding, whereas the reverse was true for naltrexone. Acamprosate decreased responding for both reinforcers with equal potency. In Experiment 2, different mean intervals of food presentation significantly affected the number of food reinforcers obtained per session; however, changes in the number of food reinforcements did not significantly affect responding for ethanol. Under the FR-10 VI-80 schedule in Experiment 3, only naltrexone significantly decreased both the dose of alcohol presented and blood ethanol concentration (BEC). Acamprosate and pregnanolone had no significant effects on any of the dependent measures, whereas DHEA significantly decreased BEC, but did not significantly decrease response rate or the dose presented. In summary, DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding under a multiple FR-10 FR-20 schedule, and were more selective for decreasing ethanol self-administration than either naltrexone or acamprosate under that schedule. Experiment 2 showed that ethanol intake was relatively independent of the interval of reinforcement in the food-maintained component, and Experiment 3 showed that naltrexone was the most effective drug at the doses tested when the interval for food reinforcement was low and maintained under a variable-interval schedule.

Substituted 1-Phenyl-3-(pyridin-2-yl)urea negative allosteric modulators of mGlu5: discovery of a new tool compound VU0463841 with activity in rat models of cocaine addiction.

Cocaine is a powerful and highly addictive stimulant that disrupts the normal reward circuitry in the central nervous system (CNS), producing euphoric effects. Cocaine use can lead to acute and life threatening emergencies, and abuse is associated with increased risk for contracting infectious diseases. Though certain types of behavioral therapy have proven effective for treatment of cocaine addiction, relapse remains high, and there are currently no approved medications for the treatment of cocaine abuse. Evidence has continued to accumulate that indicates a critical role for the metabotropic glutamate receptor subtype 5 (mGlu5) in the modulation of neural circuitry associated with the addictive properties of cocaine. While the small molecule mGlu5 negative allosteric modulator (NAM) field is relatively advanced, investigation into the potential of small molecule mGlu5 NAMs for the treatment of cocaine addiction remains an area of high interest. Herein we describe the discovery and characterization of a potent and selective compound 29 (VU0463841) with good CNS exposure in rats. The utility of 29 (VU0463841) was demonstrated by its ability to attenuate drug seeking behaviors in relevant rat models of cocaine addiction.

Effects of pregnanolone and flunitrazepam on the retention of response sequences in rats.

Neuroactive steroids produce effects similar to other GABA(A) modulators (e.g., benzodiazepines and barbiturates) and have a large therapeutic potential; however, a greater understanding of the effects of these substances on learning and memory is needed. To specifically assess the effects of a neurosteroid on memory, pregnanolone (1-18 mg/kg) was administered to male Long-Evans rats responding under a repeated acquisition and delayed-performance procedure in which different 4-response sequences were acquired and then retested after varying delays. Responding was maintained under a second-order fixed-ratio (FR) 2 schedule of food reinforcement, and incorrect responses (errors) produced a 5-sec timeout. For comparison purposes, both a high (flunitrazepam) and low efficacy agonist/antagonist (flumazenil) of the GABA(A) receptor complex were also administered both alone and in combination. Retention of each sequence was quantified as percent savings in errors-to-criterion and this dependent measure was shown to be sensitive to increases in delay. When administered 15 min prior to the end of either a 30- or 180-minute delay, pregnanolone produced both dose- and delay-dependent decreases in percent savings, response rate and accuracy; this effect was selective in that decreases in retention occurred at doses lower than those that disrupted response rate or accuracy. Flunitrazepam (0.056-1mg/kg) produced similar disruptions in retention and these disruptions were antagonized by 5.6 mg/kg of flumazenil. Both an ineffective (0.056 mg/kg) and an effective (0.18 mg/kg) dose of flunitrazepam also potentiated the dose- and delay-dependent disruptions in retention produced by pregnanolone. These data indicate that the neurosteroid pregnanolone disrupts retention in a manner similar to the benzodiazepine flunitrazepam, and suggests that the interaction of flunitrazepam and pregnanolone on retention may be mediated by the GABA(A) receptor complex.

Neurosteroid Binding Sites on the GABA(A) Receptor Complex as Novel Targets for Therapeutics to Reduce Alcohol Abuse and Dependence.

Despite the prevalence of alcohol abuse and dependence in the US and Europe, there are only five approved pharmacotherapies for alcohol dependence. Moreover, these pharmacotherapeutic options have limited clinical utility. The purpose of this paper is to present pertinent literature suggesting that both alcohol and the neurosteroids interact at the GABA(A) receptor complex and that the neurosteroid sites on this receptor complex could serve as new targets for the development of novel therapeutics for alcohol abuse. This paper will also present data collected by our laboratory showing that one neurosteroid in particular, dehydroepiandrosterone (DHEA), decreases ethanol intake in rats under a variety of conditions. In the process, we will also mention relevant studies from the literature suggesting that both particular subtypes and subunits of the GABA(A) receptor play an important role in mediating the interaction of neurosteroids and ethanol.