Meta-analysis of the comparative efficacy of benzodiazepines and antidepressants for psychic versus somatic symptoms of generalized anxiety disorder.

BACKGROUND: Benzodiazepines and antidepressants are effective agents for the treatment of generalized anxiety disorder (GAD), with the HAM-A frequently used as a primary outcome measure. The GAD literature is inconsistent regarding which medications are more effective for somatic versus psychic symptoms of GAD, and treatment guidelines do not advocate for prescribing based on subtype. This meta-analysis aimed to determine whether benzodiazepines and antidepressants have a differential impact on the somatic versus psychic subscales of the HAM-A in GAD. METHODS: An electronic search was undertaken for randomized controlled trials of either benzodiazepines or antidepressants for GAD that reported treatment response using the HAM-A subscales. Data were extracted by independent reviewers. A random effects assessment of weighted mean difference with 95% confidence intervals and subgroup difference was applied. All analysis was done on SPSS 26. An assessment of bias, and of quality of evidence was performed. RESULTS: 24 randomized controlled trials met the inclusion criteria: 18 antidepressant trials, 5 benzodiazepine trials and 1 of both. 14 studies were assessed as having between some and high risk of bias, while 10 were assessed as having low risk of bias. Benzodiazepines (WMD of 1.81 [CI 1.03, 2.58]) were significantly more effective than antidepressants (WMD of 0.83 [CI 0.64, 1.02]) for reducing somatic symptoms of GAD (Chi2 = 5.81, p = 0.02), and were also more effective (WMD of 2.46 [CI 1.83, 3.09]) in reducing psychic symptoms than antidepressants (WMD of 1.83 [CI 1.55, 2.10]), although this comparison did not reach statistical significance (Chi2 = 3.31, p = 0.07). CONCLUSION: The finding that benzodiazepines were significantly more effective than antidepressants for somatic symptoms needs to be weighed up against potential benefits of antidepressants over benzodiazepines. It may be useful for future treatment guidelines for GAD to explicitly consider symptom subtype.

Meta-analysis: Risk of hyperhidrosis with second-generation antidepressants.

BACKGROUND: Our goal was to quantify the risk of hyperhidrosis associated with commonly used antidepressant agents and examine the impact of medication class, pharmacodynamics, and dose on risk of hyperhidrosis. METHODS: We conducted a PubMed search to identify all double-blind, randomized, placebo-controlled trials examining the efficacy of second-generation antidepressant medications in the treatment of adults with a depressive disorder, anxiety disorders, or obsessive-compulsive disorder. We used a random-effects meta-analysis to examine the pooled risk ratio of hyperhidrosis reported as a side effect in adults treated with second-generation antidepressants compared to placebo. We used stratified subgroup analysis and metaregression to examine the effects of medication type, class, dosage, indication, and receptor affinity profile on the measured risk of hyperhidrosis. RESULTS: We identified 76 trials involving 28,544 subjects. There was no significant difference in the risk of hyperhidrosis between serotonin-norepinephrine reuptake inhibitors (SNRI) [risk ratio (RR) = 3.17, 95% CI: 2.63-3.82] and selective serotonin reuptake inhibitors (SSRI) (RR = 2.93, 95% CI: 2.46-3.47) medications compared to placebo. All antidepressant medications were associated with a significantly increased risk of hyperhidrosis except fluvoxamine (RR = 0.56, 95% CI: 0.12-2.53), bupropion (RR = 1.23, 95% CI: 0.57-2.67), and vortioxetine (RR = 1.35, 95% CI: 0.79-2.33). The dose of SSRI/SNRI medications was not significantly associated with the risk of hyperhidrosis. Increased risk of hyperhidrosis was associated with increased affinity of SSRI/SNRI medications to the dopamine transporter. CONCLUSION: Risk of hyperhidrosis was significantly increased with most antidepressant medications but was associated with dopamine transporter affinity.

Measurement of Clozapine, Norclozapine, and Amisulpride in Plasma and in Oral Fluid Obtained Using 2 Different Sampling Systems.

BACKGROUND: There is a poor correlation between total concentrations of proton-accepting compounds (most basic drugs) in unstimulated oral fluid and in plasma. The aim of this study was to compare clozapine, norclozapine, and amisulpride concentrations in plasma and in oral fluid collected using commercially available collection devices [Thermo Fisher Scientific Oral-Eze and Greiner Bio-One (GBO)]. METHODS: Oral-Eze and GBO samples and plasma were collected in that order from patients prescribed clozapine. Analyte concentrations were measured by liquid chromatography-tandem mass spectrometry. RESULTS: There were 112 participants [96 men, aged (median, range) 47 (21-65) years and 16 women, aged 44 (21-65) years]: 74 participants provided 2 sets of samples and 7 provided 3 sets (overall 2 GBO samples not collected). Twenty-three patients were co-prescribed amisulpride, of whom 17 provided 2 sets of samples and 1 provided 3 sets. The median (range) oral fluid within the GBO samples was 52 (13%-86%). Nonadherence to clozapine was identified in all 3 samples in one instance. After correction for oral fluid content, analyte concentrations in the GBO and Oral-Eze samples were poorly correlated with plasma clozapine and norclozapine (R = 0.57-0.63) and plasma amisulpride (R = 0.65-0.72). Analyte concentrations in the 2 sets of oral fluid samples were likewise poorly correlated (R = 0.68-0.84). Mean (SD) plasma clozapine and norclozapine were 0.60 (0.46) and 0.25 (0.21) mg/L, respectively. Mean clozapine and norclozapine concentrations in the 2 sets of oral fluid samples were similar to those in plasma (0.9-1.8 times higher), that is, approximately 2- to 3-fold higher than those in unstimulated oral fluid. The mean (±SD) amisulpride concentrations (microgram per liter) in plasma (446 ± 297) and in the Oral-Eze samples (501 ± 461) were comparable and much higher than those in the GBO samples (233 ± 318). CONCLUSIONS: Oral fluid collected using either the GBO system or the Oral-Eze system cannot be used for quantitative clozapine and/or amisulpride therapeutic drug monitoring.

The implications of methylphenidate use by healthy medical students and doctors in South Africa.

BACKGROUND: The use of medical stimulants to sustain attention, augment memory and enhance intellectual capacity is increasing in society. The use of Methylphenidate for cognitive enhancement is a subject that has received much attention in the literature and academic circles in recent times globally. Medical doctors and medical students appear to be equally involved in the off-label use of Methylphenidate. This presents a potential harm to society and the individual as the long-term side effect profile of this medication is unknown. DISCUSSION: The implication of the use of Methylphenidate by medical students and doctors has not been fully explored. This article considers the impact of this use on the traditional role of medicine, society, the patient and suggests a way forward. We discuss the salient philosophy surrounding the use of cognitive enhancement. We query whether there are cognitive benefits to the use of Methylphenidate in healthy students and doctors and whether these benefits would outweigh the risks in taking the medication. Could these benefits lead to tangible outcomes for society and could the off label-use of Methylphenidate potentially undermine the medical profession and the treatment of patients? If cognitive benefits are proven then doctors may be coerced explicitly or implicitly to use the drug which may undermine their autonomy. The increased appeal of cognitive enhancement challenges the traditional role of medicine in society, and calls into question the role of a virtuous life as a contributing factor for achievement. In countries with vast economic disparity such as South Africa an enhancement of personal utility that can be bought may lead to greater inequities. SUMMARY: Under the status quo the distribution of methylphenidate is unjust. Regulatory governmental policy must seek to remedy this while minimising the potential for competitive advantage for the enhanced. Public debate on the use of cognitive enhancement is long overdue and must be stimulated. The use of Methylphenidate for cognitive enhancement is philosophically defendable if long-term research can prove that the risks are negligible and the outcomes tangible.

Depression-like phenotype following chronic CB1 receptor antagonism.

Rimonabant was the first clinically marketed cannabinoid (CB)(1) receptor antagonist developed to treat obesity. Unfortunately, CB(1) receptor antagonism produced adverse psychiatric events in patients. To determine whether this occurs pre-clinically, we investigated the effects of rimonabant in rodent models of mood disorders. Chronic treatment with rimonabant increased immobility time in the rat forced swim test and reduced the consumption of sucrose-sweetened water in an assay postulated to model anhedonia. These responses were similar to the effects elicited by chronic mild stress in these behavioral models, which, taken together, are indicative of a depression-like phenotype. Additionally, chronic treatment with rimonabant produced decreases in frontal cortex serotonin levels, marked reductions in hippocampal cell proliferation, survival, and BDNF levels, and elevations in the concentrations of pro-inflammatory cytokines including interferon gamma and TNF alpha. These preclinical findings mimic clinical reports and implicate possible mechanisms responsible for the unfavorable psychiatric events reported following chronic rimonabant use.

WS-50030 [7-{4-[3-(1H-inden-3-yl)propyl]piperazin-1-yl}-1,3-benzoxazol-2(3H)-one]: a novel dopamine D2 receptor partial agonist/serotonin reuptake inhibitor with preclinical antipsychotic-like and antidepressant-like activity.

The preclinical characterization of WS-50030 [7-{4-[3-(1H-inden-3-yl)propyl]piperazin-1-yl}-1,3-benzoxazol-2(3H)-one] is described. In vitro binding and functional studies revealed highest affinity to the D(2) receptor (D(2L) K(i), 4.0 nM) and serotonin transporter (K(i), 7.1 nM), potent D(2) partial agonist activity (EC(50), 0.38 nM; E(max), 30%), and complete block of the serotonin transporter (IC(50), 56.4 nM). Consistent with this in vitro profile, WS-50030 (10 mg/kg/day, 21 days) significantly increased extracellular 5-HT in the rat medial prefrontal cortex, short-term WS-50030 treatment blocked apomorphine-induced climbing (ID(50), 0.51 mg/kg) in a dose range that produced minimal catalepsy in mice and induced low levels of contralateral rotation in rats with unilateral substantia nigra 6-hydroxydopamine lesions (10 mg/kg i.p.), a behavioral profile similar to that of the D(2) partial agonist aripiprazole. In a rat model predictive of antipsychotic-like activity, WS-50030 and aripiprazole reduced conditioned avoidance responding by 42 and 55% at 10 mg/kg, respectively. Despite aripiprazole's reported lack of effect on serotonin transporters, long-term treatment with aripiprazole or WS-50030 reversed olfactory bulbectomy-induced hyperactivity at doses that did not reduce activity in sham-operated rats, indicating antidepressant-like activity for both compounds. Despite possessing serotonin reuptake inhibitory activity in addition to D(2) receptor partial agonism, WS-50030 displays activity in preclinical models predictive of antipsychotic- and antidepressant efficacy similar to aripiprazole, suggesting potential efficacy of WS-50030 versus positive and negative symptoms of schizophrenia, comorbid mood symptoms, bipolar disorder, major depressive disorder, and treatment-resistant depression. Furthermore, WS-50030 provides a tool to further explore how combining these mechanisms might differentiate from other antipsychotics or antidepressants.

Preclinical characterization of BRL 44408: antidepressant- and analgesic-like activity through selective alpha2A-adrenoceptor antagonism.

Biogenic amines such as norepinephrine, dopamine, and serotonin play a well-described role in the treatment of mood disorders and some types of pain. As alpha2A-adrenoceptors regulate the release of these neurotransmitters, we examined the therapeutic potential of BRL 44408, a potent (Ki=8.5 nM) and selective (>50-fold) alpha2A-adrenoceptor antagonist (K(B)=7.9 nM). In rats, BRL 44408 penetrated the central nervous system resulting in peak brain and plasma concentrations of 586 ng/g and 1124 ng/ml, respectively. In a pharmacodynamic assay, pretreatment with BRL 44408 to rats responding under a fixed-ratio 30 operant response paradigm resulted in a rightward shift of the clonidine dose-response curve, an effect indicative of alpha2-adrenoceptor antagonism in vivo. Consistent with presynaptic autoreceptor antagonism and tonic regulation of neurotransmitter release, acute administration of BRL 44408 elevated extracellular concentrations of norepinephrine and dopamine, but not serotonin, in the medial prefrontal cortex. Additionally, BRL 44408, probably by inhibiting alpha2A heteroceptors, produced a significant increase in cortical levels of acetylcholine. In the forced swim test and schedule-induced polydipsia assay, BRL 44408 produced an antidepressant-like response by dose-dependently decreasing immobility time and adjunctive water intake, respectively, while in a model of visceral pain, BRL 44408 exhibited analgesic activity by decreasing para-phenylquinone (PPQ)-induced abdominal stretching. Finally, BRL 44408 did not produce deficits in overall motor coordination nor alter general locomotor activity. This preclinical characterization of the neurochemical and behavioural profile of BRL 44408 suggests that selective antagonism of alpha2A-adrenoceptors may represent an effective treatment strategy for mood disorders and visceral pain.

Acid sensing ion channel (ASIC) inhibitors exhibit anxiolytic-like activity in preclinical pharmacological models.

RATIONALE: Acid sensing ion channels (ASICs) are proton-gated ion channels located in the central and peripheral nervous systems. Of particular interest is ASIC1a, which is located in areas associated with fear and anxiety behaviors. Recent reports suggest a role for ASIC1a in preclinical models of fear conditioning and anxiety. OBJECTIVES: The present experiments evaluated various ASIC inhibitors in preclinical models of autonomic and behavioral parameters of anxiety. In addition, neurochemical studies evaluated the effects of an ASIC inhibitor (A-317567) on neurotransmitter levels in the amygdala. RESULTS: In electrophysiological studies using hippocampal primary neuronal cultures, three ASIC inhibitors (PcTX-1, A-317567, and amiloride) produced concentration-dependent inhibition of acid-evoked currents. In the stress-induced hyperthermia model, acute administration of psalmotoxin 1 (PcTX-1; 10-56 ng, i.c.v.), A-317567 (0.1-1.0 mg/kg, i.p.), and amiloride (10-100 mg/kg, i.p.) prevented stress-induced elevations in core body temperature. In the four-plate test, acute treatment with PcTX-1 (10-56 ng, i.c.v.) and A-317567 (0.01-0.1 mg/kg, i.p.), but not amiloride (3-100 mg/kg, i.p.), produced dose-dependent and significant increases in the number of punished crossings relative to vehicle-treated animals. Additionally, PcTX-1 (56-178 ng, i.c.v.), A-317567 (0.1-10 mg/kg, i.p.), and amiloride (10-100 mg/kg, i.p.) lacked significant anxiolytic-like activity in the elevated zero maze. In neurochemical studies, an infusion of A-317567 (100 microM) into the amygdala significantly elevated the extracellular levels of GABA, but not glutamate, in this brain region. CONCLUSIONS: These findings demonstrate that ASIC inhibition produces anxiolytic-like effects in some behavioral models and indicate a potential role for GABAergic mechanisms to underlie these anxiolytic-like effects.

Metabolite identification in rat brain microdialysates by direct infusion nanoelectrospray ionization after desalting on a ZipTip and LTQ/Orbitrap mass spectrometry.

Analyzing brain microdialysate samples by mass spectrometry is challenging due to the high salt content of the artificial cerebral spinal fluid (aCSF), low analyte concentrations and small sample volumes collected. A drug and its major metabolites can be examined in brain microdialysates by targeted approaches such as selected reaction monitoring (SRM) which provides selectivity and high sensitivity. However, this approach is not well suited for metabolite profiling in the brain which aims to determine biotransformation pathways. Identifying minor metabolites, or metabolites that arise from brain metabolism, remains a challenge and, for a drug in early discovery, identification of metabolites present in the brain can provide useful information for understanding the pharmacological activity and potential toxicological liabilities of the drug. A method is described here for rapid metabolite profiling in brain microdialysates that involves sample clean-up using C18 ZipTips to remove salts followed by direct infusion nanoelectrospray with an LTQ/Orbitrap mass spectrometer using real-time internal recalibration. Full scan mass spectra acquired at high resolving power (100 K at m/z 400) were examined manually and with mass defect filtering. Metabolite identification was aided by sub-parts-per-million mass accuracy and structural characterization was accomplished by tandem mass spectrometry (MS/MS) experiments in the Orbitrap or LTQ depending on the abundance of the metabolite. Using this approach, brain microdialysate samples from rats dosed with one of four CNS drugs (imipramine, reboxetine, citalopram or trazodone) were examined for metabolites. For each drug investigated, metabolites, some of which not previously reported in rat brain, were identified and characterized.

Novel 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines are potent 5-HT(6) agonists.

A series of 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 10a-z was prepared as novel 5-HT(6) ligands. The best compounds were high affinity, full agonists at 5-HT(6) receptors. Several agonists demonstrated good selectivity over other serotonergic and dopaminergic receptors. Acute administration of selective agonist 10e significantly increased extracellular GABA concentrations in rat frontal cortex. This compound also reduced adjunctive drinking behavior in the rat schedule-induced polydipsia assay, possibly predictive of efficacy in obsessive compulsive disorder and other anxiety related disorders.

Tygerberg Research Ubuntu-Inspired Community Engagement Model: Integrating Community Engagement into Genomic Biobanking.

Introduction: Community engagement (CE) is an ethical imperative in research, but the knowledge base for what constitutes effective and ethically sound CE is limited. Ubuntu, as a component of responsive communitarianism where communal welfare is valued together with individual autonomy, is useful in furthering our understanding of effective CE and how it could best be achieved. Similarly, a relative solidarity model serves as a compromise between extreme individualism and extreme communalism and is more appropriate in a heterogenous African context. Approaching CE from an Ubuntu philosophical perspective in southern Africa is particularly important in genomic biobanking, given the implications for individuals, families, and communities. Discussion: CE is often implemented in a tokenistic manner as an ancillary component of research. Understanding consent information is challenging where genomic biobanking is concerned due to scientific complexity. We started a process of CE around genomic biobanking and conducted empirical research in an attempt to develop a model to promote effective and ethically sound CE, using relative solidarity to create a nuanced application of Ubuntu. The TRUCE model is an eight-step model that uses social mapping to identify potential communities, establishes the scope of CE, and requires that communities are approached early. Co-creation strategies for CE are encouraged and co-ownership of knowledge production is emphasized. Recruiting and engaging communities at each stage of research is necessary. Evaluation and adaptation of CE strategies are included. Discussion and dissemination of results after the research is completed are encouraged. Conclusions: There is a significant gap between the theory of CE and its authentic application to research in Africa. This Ubuntu-inspired model facilitates bridging that gap and is particularly suited to genomic biobanking. The CE model enhances and complements the consent process and should be integrated into research as a funding and regulatory requirement where applicable.

Amiloride is neuroprotective in an MPTP model of Parkinson's disease.

The diuretic amiloride has recently proven neuroprotective in models of cerebral ischemia, a property attributable to the drug's inhibition of central acid-sensing ion channels (ASICs). Given that Parkinson's disease (PD), like ischemia, is associated with cerebral lactic acidosis, we tested amiloride in the MPTP-treated mouse, a model of PD also manifesting lactic acidosis. Amiloride was found to protect substantia nigra (SNc) neurons from MPTP-induced degeneration, as determined by attenuated reductions in striatal tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunohistochemistry, as well as smaller declines in striatal DAT radioligand binding and dopamine levels. More significantly, amiloride also preserved dopaminergic cell bodies in the SNc. Administration of psalmotoxin venom (PcTX), an ASIC1a blocker, resulted in a much more modest effect, attenuating only the deficits in striatal DAT binding and dopamine. These findings represent the first experimental evidence of a potential role for ASICs in the pathogenesis of Parkinson's disease.

Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466.

One of the most recently identified serotonin (5-hydroxytryptamine (5-HT)) receptor subtypes is the 5-HT6 receptor. Although in-depth localization studies reveal an exclusive distribution of 5-HT6 mRNA in the central nervous system, the precise biological role of this receptor still remains unknown. In the present series of experiments, we report the pharmacological and neurochemical characterization of two novel and selective 5-HT6 receptor agonists. WAY-181187 and WAY-208466 possess high affinity binding (2.2 and 4.8 nM, respectively) at the human 5-HT6 receptor and profile as full receptor agonists (WAY-181187: EC50=6.6 nM, Emax=93%; WAY-208466: EC50=7.3 nM; Emax=100%). In the rat frontal cortex, acute administration of WAY-181187 (3-30 mg/kg, subcutaneous (s.c.)) significantly increased extracellular GABA concentrations without altering the levels of glutamate or norepinephrine. Additionally, WAY-181187 (30 mg/kg, s.c.) produced modest yet significant decreases in cortical dopamine and 5-HT levels. Subsequent studies showed that the neurochemical effects of WAY-181187 in the frontal cortex could be blocked by pretreatment with the 5-HT6 antagonist, SB-271046 (10 mg/kg, s.c.), implicating 5-HT6 receptor mechanisms in mediating these responses. Moreover, the effects of WAY-181187 on catecholamines were attenuated by an intracortical infusion of the GABA A receptor antagonist, bicuculline (10 microM), confirming a local relationship between 5-HT6 receptors and GABAergic systems in the frontal cortex. In the dorsal hippocampus, striatum, and amygdala, WAY-181187 (10-30 mg/kg, s.c.) elicited robust elevations in extracellular levels of GABA without producing similar effects on concentrations of norepinephrine, serotonin, dopamine, or glutamate. In contrast to these brain regions, WAY-181187 had no effect on the extracellular levels of GABA in the nucleus accumbens or thalamus. Additional studies showed that WAY-208466 (10 mg/kg, s.c.) preferentially elevated cortical GABA levels following both acute and chronic (14 day) administration, indicating that neurochemical tolerance does not develop following repeated 5-HT6 receptor stimulation. In hippocampal slice preparations (in vitro), 5-HT(6) receptor agonism attenuated stimulated glutamate levels elicited by sodium azide and high KCl treatment. Furthermore, in the rat schedule-induced polydipsia model of obsessive compulsive disorder (OCD), acute administration of WAY-181187 (56-178 mg/kg, po) decreased adjunctive drinking behavior in a dose-dependent manner. In summary, WAY-181187 and WAY-208466 are novel, selective, and potent 5-HT6 receptor agonists displaying a unique neurochemical signature in vivo. Moreover, these data highlight a previously undescribed role for 5-HT6 receptors to modulate basal GABA and stimulated glutamate transmission, as well as reveal a potential therapeutic role for this receptor in the treatment of some types of anxiety-related disorders (eg OCD).

Differentiating antidepressants of the future: efficacy and safety.

There have been significant advances in the treatment of depression since the serendipitous discovery that modulating monoaminergic neurotransmission may be a pathological underpinning of the disease. Despite these advances, particularly over the last 15years with the introduction of selective serotonin and/or norepinephrine reuptake inhibitors (SNRI), there still remain multiple unmet clinical needs that would represent substantial improvements to current treatment regimens. In terms of efficacy there have been improvements in the percentage of patients achieving remission but this can still be dramatically improved and, in fact, issues still remain with relapse. Furthermore, advances are still required in terms of improving the onset of efficacy as well as addressing the large proportion of patients who remain treatment resistant. While this is not well understood, collective research in the area suggests the disease is heterogeneous in terms of the multiple parameters related to etiology, pathology and response to pharmacological agents. In addition to efficacy further therapeutic advances will also need to address such issues as cognitive impairment, pain, sexual dysfunction, nausea and emesis, weight gain and potential cardiovascular effects. With these unmet needs in mind, the next generation of antidepressants will need to differentiate themselves from the current array of therapeutics for depression. There are multiple strategies for addressing unmet needs that are currently being investigated. These range from combination monoaminergic approaches to subtype selective agents to novel targets that include mechanisms to modulate neuropeptides and excitatory amino acids (EAA). This review will discuss the many facets of differentiation and potential strategies for the development of novel antidepressants.

ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: a novel metabotropic glutamate receptor 5-selective positive allosteric modulator with preclinical antipsychotic-like and procognitive activities.

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) enhance N-methyl-d-aspartate receptor function and may represent a novel approach for the treatment of schizophrenia. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone], a recently identified potent and selective mGlu5 PAM, increased (9-fold) the response to threshold concentration of glutamate (50 nM) in fluorometric Ca(2+) assays (EC(50) = 170 nM) in human embryonic kidney 293 cells expressing rat mGlu5. In the same system, ADX47273 dose-dependently shifted mGlu5 receptor glutamate response curve to the left (9-fold at 1 microM) and competed for binding of [(3)H]2-methyl-6-(phenylethynyl)pyridine (K(i) = 4.3 microM), but not [(3)H]quisqualate. In vivo, ADX47273 increased extracellular signal-regulated kinase and cAMP-responsive element-binding protein phosphorylation in hippocampus and prefrontal cortex, both of which are critical for glutamate-mediated signal transduction mechanisms. In models sensitive to antipsychotic drug treatment, ADX47273 reduced rat-conditioned avoidance responding [minimal effective dose (MED) = 30 mg/kg i.p.] and decreased mouse apomorphine-induced climbing (MED = 100 mg/kg i.p.), with little effect on stereotypy or catalepsy. Furthermore, ADX47273 blocked phencyclidine, apomorphine, and amphetamine-induced locomotor activities (MED = 100 mg/kg i.p.) in mice and decreased extracellular levels of dopamine in the nucleus accumbens, but not in the striatum, in rats. In cognition models, ADX47273 increased novel object recognition (MED = 1 mg/kg i.p.) and reduced impulsivity in the five-choice serial reaction time test (MED = 10 mg/kg i.p.) in rats. Taken together, these effects are consistent with the hypothesis that allosteric potentiation of mGlu5 may provide a novel approach for development of antipsychotic and procognitive agents.

Pharmacology of neuropeptide S in mice: therapeutic relevance to anxiety disorders.

RATIONALE: Neuropeptide S (NPS) and its receptor (NPSR) comprise a recently deorphaned G protein-coupled receptor system. Recent reports implicate NPS in the mediation of anxiolytic-like activity in rodents. OBJECTIVES: To extend the characterization of NPS, the present studies examined the in vitro pharmacology of mouse NPSR and the in vivo pharmacology of NPS in three preclinical mouse models predictive of anxiolytic action: the four-plate test (FPT), elevated zero maze (EZM), and stress-induced hyperthermia (SIH). The ability of NPS to produce antidepressant-like effects in the tail suspension test (TST) was also investigated. RESULTS: In vitro, mouse NPS 1-20 (mNPS 1-20) and the C-terminal glutamine-truncated mouse NPS 1-19 bound mNPSR with high affinity (Ki = 0.203 +/- 0.060, 0.635 +/- 0.141 nM, respectively) and potently activated intracellular calcium release (EC50 = 3.73 +/- 1.08, 4.10 +/- 1.25 nM). NPS produced effects in vivo consistent with anxiolytic-like activity. In FPT, NPS increased punished crossings (minimal effective dose [MED]: mNPS 1-20 = 0.2 microg, mNPS(1-19) = 0.02 microg), similar to the reference anxiolytic, alprazolam (MED 0.5 microg). NPS increased the percentage of time spent in the open quadrants of EZM (MED: mNPS 1-20 = 0.1 microg, mNPS 1-19 = 1.0 microg), like the reference anxiolytic, chlordiazepoxide (MED 56 microg). In SIH, NPS attenuated stress-induced increases in body temperature similar to alprazolam but with a large potency difference between the NPS peptides (MED: mNPS 1-20 = 2.0 microg, mNPS 1-19 = 0.0002 microg) and mNPS 1-20 increased baseline temperature. Unlike fluoxetine, NPS did not effect immobility time in TST, indicating a lack of antidepressant-like activity. CONCLUSIONS: These data provide an important confirmation and expansion of the anxiolytic-like effects of NPS and implicate the NPS system as a novel target for anxiolytic drug discovery.

Inhibition of uptake 2 (or extraneuronal monoamine transporter) by normetanephrine potentiates the neurochemical effects of venlafaxine.

Two distinct norepinephrine (NE) transporter mechanisms (uptake 1 and uptake 2) regulate extracellular NE concentrations. An association has been observed between the gradual improvement in patients treated with antidepressants that inhibit the NE transporter (NET/uptake 1) and increases in urinary normetanephrine, the O-methylated NE metabolite and potent inhibitor of uptake 2. These observations led to the hypothesis that increased levels of normetanephrine, and consequently inhibition of uptake 2, may partly be responsible for the clinical efficacy of some antidepressants. To investigate this hypothesis, we employed microdialysis techniques in the rat frontal cortex to monitor extracellular changes in normetanephrine following chronic administration of the clinically effective antidepressant, venlafaxine (a serotonin (5-HT) and NE reuptake inhibitor). We evaluated the neurochemical effects of inhibiting uptake 2 alone, or in conjunction with venlafaxine, on extracellular levels of NE and 5-HT. Chronic venlafaxine administration (14 days, 10 mg/kg, s.c.) elicited significant increases in cortical NE and 5-HT while producing a non-significant trend to increase cortical levels of normetanephrine. Additional studies revealed that combining normetanephrine with venlafaxine (10 mg/kg, i.p.), at a dose of normetanephrine (10 mg/kg, i.p.) that did not produce changes in extracellular levels of NE on its own, potentiated antidepressant-induced increases in extracellular NE. We also report mouse behavioral data involving the tail suspension test that complement the neurochemical observations. These preclinical findings, taken together, suggest that inhibiting both uptake 1 and uptake 2 via venlafaxine and normetanephrine, respectively, elicits a greater increase in cortical levels of NE than inhibiting either transporter alone.

Do selective serotonin reuptake inhibitors acutely increase frontal cortex levels of serotonin?

Selective serotonin uptake inhibitors (SSRIs) exert their effects by inhibiting serotonin (5-HT) re-uptake. Although blockade occurs almost immediately, the neurochemical effects on 5-HT, as measured by in vivo microdialysis, have been a matter of considerable debate. In particular, literature reports yield conflicting neurochemical results in the rat frontal cortex. Thus, while some groups consistently find increases in extracellular 5-HT levels following acute SSRI administration, others reproducibly report an absence of these acute serotonergic effects. In an attempt to unravel this apparent discrepancy, we combined published literature with in-house microdialysis experiments. When we plotted the lateral stereotaxic coordinate of the dialysis probe against published reports on the acute effects of fluoxetine a clear correlation was revealed. Whereas pronounced increases in SSRI-induced 5-HT were observed when the dialysis probe was placed 0 to 1 mm from the midline, effects diminished when the lateral probe placement was greater than 3 mm from the midline. In-house microdialysis studies corroborated these reports. Overall, these results illustrate - for the first time - that the midline stereotaxic coordinate is critical for interpreting the acute serotonergic effects of SSRIs within the frontal cortex. Moreover, the common observation that the clinical efficacy of SSRIs is not evident following acute administration complements preclinical microdialysis results in the lateral frontal cortex. The significance of this observation, along with potential explanations for the disparate neurochemical findings in the medial versus lateral cortices, will be discussed.

Antipsychotics for aggression in adults: A meta-analysis.

Aggressive behavior complicates the presentation of many psychiatric illnesses, and is associated with significant morbidity. Antipsychotic medications are used to treat this symptom dimension across multiple diagnoses. In this meta-analysis we sought to identify the effect size of antipsychotic medications for the treatment of reactive-impulsive aggression in adults, and identify differences across underlying diagnosis and specific agent. A search was conducted of four databases, MEDLINE, PsychINFO, Embase and the Cochrane Library to end date of August 10, 2016. The search terms included "aggression", "irritable mood", "anger", "hostility" and "antipsychotic agents" or "dopamine antagonists". 505 results were found, of which 47 were reviewed in detail and 21 ultimately included in the analysis. Antipsychotics were broadly effective for the treatment of aggression, but with effect sizes similar to those for non-pharmacologic interventions (standard mean difference=0.29, 95% confidence interval 0.22-0.36, z=8.5, p<0.001). There was no evidence for differences according to choice of agent (χ2=2.7, df=6, p=0.85), or conclusive evidence as to the importance of the underlying diagnosis (χ2=3.2, df=3, p=0.36). A small but significant dose effect was identified (ß=0.0002, 95% CI 0.0001-0.0004, p=0.038). Although antipsychotics appear to be effective for treatment of aggression, their small effect sizes in the context of their significant side-effects should be taken into account when making clinical decisions about their use.

Meta-analysis: Risk of dry mouth with second generation antidepressants.

OBJECTIVE: The goal of this meta-analysis was to quantify the risk of dry mouth associated with commonly prescribed antidepressant agents and examine the potential implications of medication class, dose, and pharmacodynamics and dose on risk of treatment-induced dry mouth. DATA SOURCES AND STUDY SELECTION: A PubMed search was conducted to identify double-blind, randomized, placebo-controlled trials examining the efficacy and tolerability of second generation antidepressant medications for adults with depressive disorders, anxiety disorders, and OCD. DATA EXTRACTION: A random-effects meta-analysis was used to quantify the pooled risk ratio of treatment-emergent dry mouth with second generation antidepressants compared to placebo. Stratified subgroup analysis and meta-regression was utilized to further examine the effects antidepressant agent, class, dosage, indication, and receptor affinity profile on the measured risk of dry mouth. RESULTS: 99 trials involving 20,868 adults. SNRIs (Relative Risk (RR)=2.24, 95% Confidence Interval (CI): 1.95-2.58, z=11.2, p<0.001) were associated with a significantly greater risk of dry mouth (test for subgroup differences χ2=7.6, df=1; p=0.006) compared to placebo than SSRIs (RR=1.65, 95% CI: 1.39-1.95, z=5.8, p<0.001). There was a significant difference found in the risk of dry mouth between diagnostic indications within the SNRI class (test for subgroup differences χ2=9.63, df=1; p=0.002). Anxiety diagnoses (RR=2.78, 95% CI: 2.29-3.38, z=10.32, p<0.001) were associated with a greater risk of dry mouth compared to depression (RR=1.80, 95% CI: 1.48-2.18, z=5.85, p<0.001). Decreased affinity for Alpha-1 (PE=0.18, 95% CI: 0.07-0.28, z=3.26, p=0.001) and Alpha-2 (PE=0.49, 95% CI: 0.22-0.75, z=3.64, p<0.001) receptors and SERT (PE=0.07, 95% CI: 0.01-0.14, z=2.10, p<0.05) was significantly associated with increased risk of dry mouth. CONCLUSIONS: The current meta-analysis suggests that SSRIs, SNRIs, and atypical antidepressants are all associated with varying degrees of increased risk of dry mouth. SNRIs were associated with a significantly greater risk of dry mouth compared to SSRIs.