piperidines and Mood-Disorders

Rimonabant, a cannabinoid receptor blocker, has recently been used in clinical practice for weight loss and weight maintenance. Our aim was to review the results of trials of the drug in relation to weight loss and maintenance, and its impact on cardio-metabolic risk factors.. Randomized controlled trials with rimonabant were selected, through a Medline search, using the terms: rimonabant, endocannabinoid antagonist and obesity. Reports of studies on large numbers of patients and covering the topics related to this review were included.. In all the trials, there was a considerable reduction in body weight in subjects taking 20 mg rimonabant daily varying from 2.6 to 6.3 kg (placebo-subtracted changes). Rimonabant was also associated with haemoglobin A(₁c) (HbA(₁c) ) reduction. In the Rimonabant in obesity (RIO)-diabetes study, diabetic patients taking metformin or sulphonylureas showed decrease in HbA(₁c) levels by 0.5-0.6 ± 0.8% when rimonabant was added, whereas in the Serenade trial patients with untreated diabetes showed a reduction in HbA(₁c) of 0.8% vs. 0.3% with placebo. Similar results were obtained in diabetic patients under insulin treatment. The lipidemic profile also improved in patients taking rimonabant 20 mg daily; levels of high density lipoprotein cholesterol (HDL-c) increased significantly while levels of triglycerides (TRG) decreased in all trials, and positive effects were also observed in patients with atherogenic or untreated dyslipidaemia. In all the RIO studies, prevalence of the metabolic syndrome decreased significantly. In addition, patients treated with 20 mg rimonabant daily exhibited increase in adiponectin. The metabolic changes observed were partly independent of the weight loss and could be attributed to independent peripheral effect of rimonabant. All these beneficial metabolic effects of rimonabant could lead to progress in the prevention of cardiovascular disease. However, in all the trials the incidence of adverse events leading to discontinuation was greater in the rimonabant treated patients than placebo, mainly because of psychiatric disorders (depression and anxiety), nausea and dizziness.. Rimonabant is effective in reducing weight in the obese but may lead to intolerable adverse effects most notably psychiatric effects, which make it unsuitable for routine use. However, the drug provides useful proof of principle for this approach to weight loss. Novel cannabinoid type 1 receptor blockers with selectivity for peripheral receptors, may achieve similar metabolic results with decreased prevalence of psychiatric adverse effects.

Topics: Anti-Obesity Agents; Humans; Molecular Targeted Therapy; Mood Disorders; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Rimonabant

The Positive and Negative Syndrome Scale (PANSS) total score is widely used to assess antipsychotic efficacy, however schizophrenia is a multi-dimensional disorder. We conducted a 5-factor analysis for evaluating the efficacy of iloperidone vs. placebo across these different domains in the treatment of schizophrenia.. The 5-factor model was determined from pooled data from 7 clinical trials (4 placebo- and active-controlled and 3 non-inferiority active-comparator trials of iloperidone) in schizophrenia (N=3580).Five factors were derived (excitement/hostility [P4,P7,G8,G14], depression/anxiety [G1,G2,G3,G4,G6], cognition [P2,N5,N7,G5,G10,G11,G12,G13,G15], positive [P1,P3,P5,P6,G9], and negative [N1,N2,N3,N4,N6,G7,G16]) from a factor analysis on the covariance matrix of 30 baseline PANSS items using a varimax rotation; factors retained had eigenvalues of ≥ 0.5. These newly derived 5 factors differ only slightly from other 5-factor analyses published by others using different datasets. The analysis of covariance model was then applied to assess these efficacy outcomes from the 4-6 week double-blind placebo and active controlled clinical trials of iloperidone.. Based on the placebo-controlled trials, iloperidone improvements from baseline (least squared mean change ± standard error) were as follows: excitement/hostility, 0.4 ± 0.21 for 10-16 mg, 0.6 ± 0.43 for 20-24 mg vs. -1.0 ± 0.23 for placebo; P<0.001 for both iloperidone doses vs. placebo; depression/anxiety, 1.9 ± 0.21 for 10-16 mg, 1.9 ± 0.41 for 20-24 mg vs. 1.1 ± 0.22 for placebo; P<0.05 for 10-16 mg dose vs. placebo; cognition, 2.8 ± 0.35 for 10-16 mg, 3.9 ± 0.69 for 20-24 mg vs. 1.6 ± 0.38 for placebo; P<0.05 for both iloperidone doses vs. placebo; positive, 3.7 ± 0.26 for 10-16 mg, 4.1 ± 0.53 for 20-24 mg vs. 2.7 ± 0.29 for placebo; P<0.05 for both iloperidone doses vs. placebo; and negative, 2.2 ± 0.29 for 10-16 mg, 2.5 ± 0.58 for 20-24 mg vs. 1.3 ± 0.32 for placebo; P<0.05 for 10-16 mg vs. placebo. Active controls validated iloperidone efficacy.. Iloperidone demonstrated positive treatment effects on these newly derived PANSS factors. The 10-16 mg and 20-24 mg dose groups had similar efficacy on the PANSS factors, with the exception of the depression/anxiety and negative factors, on which the 10-16 mg dose group showed statistical separation from placebo and the 20-24 mg dose group did not. At 6 weeks, the lack of separation from placebo for the higher dose group may have been due to the much smaller sample size in that group.

Topics: Adolescent; Adult; Age Factors; Aged; Antipsychotic Agents; Cognition Disorders; Dose-Response Relationship, Drug; Double-Blind Method; Factor Analysis, Statistical; Female; Follow-Up Studies; Humans; Isoxazoles; Male; Middle Aged; Mood Disorders; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Treatment Outcome; Young Adult

Patients with social phobia often describe personality traits characterized by avoidant social behavior and more general depressive-anxious features. There is only sparse knowledge about the effects of drug treatment on these traits.. Fifty-seven patients with social phobia completed a 12-week double-blind, placebo-controlled trial with the reversible and selective monoamine oxidase A inhibitor brofaromine 150 mg/day. The Clinical Global Impressions-Improvement scale, Liebowitz Social Anxiety Scale, a questionnaire with 140 items regarding personality traits, and ratings on the presence or absence of diagnostic criteria for the DSM-III-R avoidant and dependent personality disorders were used for assessments at baseline and endpoint. Comparisons were made with a group of 58 healthy controls.. Before treatment, there were no significant differences between the brofaromine and placebo groups in their ratings on situationally bound social anxiety or on personality traits that differed significantly from those of the controls. At endpoint, a marked normalization was noted in the brofaromine group. The changes that had occurred differed significantly from those in the placebo group. The normalization of traits seemed more marked than the normalization of anxiety in more specific social phobic situations. The number of brofaromine patients who fulfilled the criteria for avoidant personality disorder had diminished from 15 (60%) to 5 (20%).. The results support the conclusion that the maladaptive personality traits characteristic of social phobia are at least as responsive to the monoamine oxidase inhibitor brofaromine as are the more circumscribed social anxiety responses.

Topics: Adult; Comorbidity; Double-Blind Method; Female; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Mood Disorders; Personality Disorders; Phobic Disorders; Piperidines; Placebos; Self Concept; Treatment Outcome

The biochemical targets for antidepressants are relatively well established, but we lack a clear understanding of how actions at these proteins translate to clinical benefits. This study used a novel rodent assay to investigate how different antidepressant drugs act to modify affective biases that have been implicated in depression. In this bowl-digging task, rats encounter two equal value learning experiences on separate days (one during an affective manipulation and the other during control conditions). This induces an affective bias that is quantified using a preference test in which both digging substrates are presented together and the individual rats' choices recorded. The assay can be used to measure affective biases associated with learning (when the treatment is given at the time of the experience) or examine the modification of previously acquired biases (when the treatment is administered before the preference test). The rapid-onset antidepressant ketamine, but not the delayed-onset antidepressant, venlafaxine, attenuated the previously acquired FG7142-induced negative bias following systemic administration. Venlafaxine but not ketamine induced a positive bias when administered before learning. We then used local drug infusions and excitotoxic lesions to localize the effects of ketamine to the medial prefrontal cortex and venlafaxine to the amygdala. Using a modified protocol we also showed that positive and negative biases amplified further when the numbers of substrate-reinforcer associations are increased. We propose that this pattern of results could explain the delayed onset of action of venlafaxine and the rapid onset of action but lack of long-term efficacy seen with ketamine.

Topics: Animals; Antidepressive Agents; Association Learning; Brain; Cannabinoid Receptor Antagonists; Carbolines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; GABA Antagonists; Ketamine; Male; Mood Disorders; Piperidines; Pyrazoles; Rats; Reaction Time; Reinforcement, Psychology; Rimonabant; Stress, Psychological; Venlafaxine Hydrochloride

[(3)H]4-DAMP is a radioligand that has been used to quantify levels of the muscarinic receptor CHRM3 protein in situ. However, in addition to high affinity binding to CHRM3, [(3)H]4-DAMP binds with low affinity to CHRM1 confounding the potential to discriminate between changes in these two muscarinic receptors. We have developed a [(3)H]4-DAMP binding assay, optimised for measuring CHRM3 protein levels in the cortex, with minimal selectivity towards CHRM1. The selectivity of our assay towards CHRM3 was confirmed using recombinant receptor-expressing, cell lysate preparations. [(3)H]4-DAMP binding levels were similar between wildtype and CHRM1 knockout mice, confirming that the amount of [(3)H]4-DAMP binding to CHRM1 was negligible. We used this assay to measure CHRM3 protein levels in the frontal pole, obtained post-mortem from subjects with bipolar disorder (n = 15), major depressive disorder (n = 15) and matched controls (n = 20) and showed that [(3)H]4-DAMP binding was not altered in either bipolar disorder or major depressive disorder. Western blotting confirmed that CHRM3 protein levels were unchanged in these subjects.

Topics: Adult; Aged; Animals; Cerebral Cortex; Dose-Response Relationship, Drug; Humans; Mice; Mice, Knockout; Middle Aged; Mood Disorders; Muscarinic Antagonists; Piperidines; Pirenzepine; Protein Binding; Radioligand Assay; Radionuclide Imaging; Receptor, Muscarinic M1; Receptor, Muscarinic M3; Receptors, Muscarinic; Tritium

Endocannabinoid and serotonin systems are implicated in mechanisms underlying depression-like symptoms. Involvement of serotonin in mood disorders occurring after smoking cessation has been observed. We studied the interactions between endocannabinoid and serotonergic systems in mood and behavioral disorders caused by nicotine cessation. The effects of the endocannabinoid transport inhibitor AM404 and the cannabinoid receptor 1 antagonist AM251 in a nicotine-dependent rodent model were investigated.. Dependence was induced by subcutaneous injections of nicotine (2 mg/kg, 4 injections daily) for 15 consecutive days in mice. Animals treated with AM404 or AM251 were tested for locomotor activity and abstinence signs 24 hr after nicotine withdrawal and in forced swimming test (FST) at different times: immediately after last nicotine injection (t = 0) and 15 and 30 days after nicotine withdrawal. In nicotine-dependent mice treated with AM404 or AM251, expression of diencephalic serotonin receptor 1(A) (5-HT1(A)) was also measured. Effects of AM404, AM251, and WAY 100635 (5-HT(1A) receptor antagonist) in mice subjected to FST were evaluated.. A decrease in diencephalic 5-HT(1A) levels was observed in mice previously injected with nicotine. In the same animals, AM251 caused (0.5-2 mg/kg) a significant decrease of abstinence signs and AM404 (0.5-2 mg/kg) provoked a significant dose-dependent reduction in immobility time in the FST. Either AM251 or WAY 100635 antagonized anti-immobility effects of AM404.. Data indicate the existence of a link between serotonergic and endocannabinoid systems in the mechanisms underlying mood disorders caused by nicotine abstinence and suggest that these interactions are potential targets for pharmacological aid in smoking cessation.

Topics: Animals; Arachidonic Acids; Behavior, Animal; Cannabinoid Receptor Modulators; Disease Models, Animal; Drug Interactions; Endocannabinoids; Male; Mice; Mood Disorders; Motor Activity; Nicotine; Piperazines; Piperidines; Pyrazoles; Pyridines; Random Allocation; Receptor, Cannabinoid, CB1; Receptor, Serotonin, 5-HT1A; Serotonin; Serotonin 5-HT1 Receptor Antagonists; Serotonin Antagonists; Smoking Cessation; Substance Withdrawal Syndrome

Pharmacological blockade of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), produces CB(1) receptor (CB(1)R)-mediated analgesic, anxiolytic-like and antidepressant-like effects in murids. Using behavioral and electrophysiological approaches, we have characterized the emotional phenotype and serotonergic (5-HT) activity of mice lacking the FAAH gene in comparison to their wild type counterparts, and their response to a challenge of the CB(1)R antagonist, rimonabant. FAAH null-mutant (FAAH(-/-)) mice exhibited reduced immobility in the forced swim and tail suspension tests, predictive of antidepressant activity, which was attenuated by rimonabant. FAAH(-/-) mice showed an increase in the duration of open arm visits in the elevated plus maze, and a decrease in thigmotaxis and an increase in exploratory rearing displayed in the open field, indicating anxiolytic-like effects that were reversed by rimonabant. Rimonabant also prolonged the initiation of feeding in the novelty-suppressed feeding test. Electrophysiological recordings revealed a marked 34.68% increase in dorsal raphe 5-HT neural firing that was reversed by rimonabant in a subset of neurons exhibiting high firing rates (33.15% mean decrease). The response of the prefrontocortical pyramidal cells to the 5-HT(2A/2C) agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((+/-)-DOI) revealed desensitized 5-HT(2A/2C) receptors, likely linked to the observed anxiolytic-like behaviors. The hippocampal pyramidal response to the 5-HT(1A) antagonist, WAY-100635, indicates enhanced tonus on the hippocampal 5-HT(1A) heteroreceptors, a hallmark of antidepressant-like action. Together, these results suggest that FAAH genetic deletion enhances anxiolytic-like and antidepressant-like effects, paralleled by altered 5-HT transmission and postsynaptic 5-HT(1A) and 5-HT(2A/2C) receptor function.

Topics: Action Potentials; Amidohydrolases; Animals; Behavior, Animal; Benzamides; Brain; Cannabinoid Receptor Antagonists; Carbamates; Enzyme Inhibitors; Exploratory Behavior; Hindlimb Suspension; Hippocampus; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Mood Disorders; Piperidines; Prefrontal Cortex; Pyrazoles; Raphe Nuclei; Rimonabant; Serotonin; Serotonin Agents; Swimming

The effect of piperine, the main alkaloid from piper nigrum, on the central nervous system is not clearly known until now. In the present study, male Wistar rats were administered piperine at various doses ranging from 5, 10 and 20mg/kg BW once daily for 4 weeks and the animals were determined the neuropharmacological activity after single, 1, 2, 3 and 4 weeks of treatment. The results showed that piperine at all dosage range used in this study possessed anti-depression like activity and cognitive enhancing effect at all treatment duration. Therefore, piperine may be served as the potential functional food to improve brain function. However, further investigations about precise underlying mechanism are still required.

Topics: Alkaloids; Animals; Antidepressive Agents; Anxiety; Behavior, Animal; Benzodioxoles; Cognition Disorders; Food Analysis; Male; Maze Learning; Mood Disorders; Motor Activity; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Swimming

Hypersexuality in Alzheimer's disease (AD) has been rarely investigated. Hypersexual behaviours should be classified as a sexual obsession and included in the "obsessive-compulsive disorder-like" spectrum. Hypersexuality has no proven treatment, although reports have described reductions of this behaviour using antiandrogen treatment, H2-receptor antagonists and antipsychotic drugs. Serotonin reuptake blockers seem to be effective in the treatment of sexual obsessions or compulsions and less on paraphilic disturbances. We present the case of a 54-year-old male patient with Alzheimer's disease with compulsive sexual behaviour as reported by his wife. A 18-FDG PET scan evidenced prevalent hypometabolism of the right hemisphere, congruent with neuropsychological evaluation. Donepezil, 10 mg per day, produced cognitive improvement but no effects on sexual behaviour. Therapy with SSRI was subsequently started (citalopram): after 60 days, the patient showed improvement in both the compulsive pursuit of sex acts and the level of frustration when refused.

Topics: Alzheimer Disease; Brain; Citalopram; Cognition Disorders; Disease Progression; Donepezil; Fluorodeoxyglucose F18; Humans; Indans; Male; Memory Disorders; Middle Aged; Mood Disorders; Nootropic Agents; Obsessive-Compulsive Disorder; Piperidines; Positron-Emission Tomography; Selective Serotonin Reuptake Inhibitors; Serotonin; Sexual Behavior; Sexual Dysfunctions, Psychological; Treatment Outcome

The present study was made to investigate the role of tachykinin NK2 receptors in the expression of stress-related behaviors in animals. Under basal conditions, intraperitoneal (i.p.) administration of the selective tachykinin NK2 receptor antagonist, saredutant (1 and 3 mg/kg) or diazepam (1 mg/kg) exerted anxiolytic-like effects in rodents, as they reduced grooming score of Wistar male rats tested in the novelty-induced grooming sampling test (NGT) and increased percentage of time and entries in open arms of Swiss male mice tested in the elevated plus maze (EPM) test. After previous exposure to stress-related conditions, as induced by a 2-min forced swim made 5 min prior to the EPM test, saredutant but not diazepam, exhibited anxiolytic-like effects in mice. To study the antidepressant-like activity of tachykinin NK2 receptor antagonist under basal conditions, different groups of rats were injected i.p. with saredutant (2.5, 5 and 10 mg/kg) or the tricyclic antidepressant, clomipramine (50 mg/kg) and tested in the forced swim test (FST), a widely used antidepressant-responsive test. The influence of stress-related conditions was studied in rats subjected to electric foot-shocks (1 mA, 1 s) 24, 5 and 1 h prior to FST, after drugs injection. In the FST, clomipramine decreased the immobility time only under basal conditions, but not after application of acute foot-shocks. To the contrary, saredutant-treated rats also exhibited more active behavior in FST after previous exposure to stressors. These results give further support to the hypothesis that tachykinin NK2 receptors may be a therapeutic target for pharmacological treatment of stress-related diseases, such as anxiety and depression.

Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents, Tricyclic; Anxiety; Behavior, Animal; Benzamides; Clomipramine; Depressive Disorder; Diazepam; Electroshock; Grooming; Male; Mice; Mood Disorders; Motor Activity; Piperidines; Rats; Rats, Wistar; Receptors, Neurokinin-2; Stress, Psychological; Swimming

The delay in onset and treatment resistance of subpopulations of depressed patients to conventional serotonin reuptake inhibitors has lead to new drug development strategies to produce agents with improved antidepressant efficacy.. We report the in vivo characterization of the novel 5-HT(1A/1B) autoreceptor antagonist/5-HT transporter inhibitor (6-[(1-{2-[(2-methyl-5-quinolinyl)oxy]ethyl}-4-piperidinyl)methyl]-2H-1,4-benzoxazin-3(4H)-one), SB-649915-B.. Ex vivo binding was used to ascertain 5-HT(1A) receptor and serotonin transporter occupancy. 8-OH-DPAT-induced hyperlocomotion and SKF-99101-induced elevation of seizure threshold were used as markers of central blockade of 5-HT(1A) and 5-HT(1B) receptors, respectively. In vivo electrophysiology in the rat dorsal raphe and microdialysis in freely moving guinea pigs and rats were used to evaluate the functional outcome of SB-649915-B.. SB-649915-B (1-10 mg/kg p.o.) produced a dose-related inhibition of 5-HT(1A) receptor radioligand binding and inhibited ex vivo [(3)H]5-HT uptake in both guinea pig and rat cortex. SB-649915-B (0.1-10 mg/kg p.o.) reversed both 8-OH-DPAT-induced hyperlocomotor activity and SKF-99101-induced elevation of seizure threshold in the rat, demonstrating in vivo blockade of both 5-HT(1A) and 5-HT(1B) receptors, respectively. SB-649915-B (0.1-3 mg/kg i.v.) produced no change in raphe 5-HT neuronal cell firing per se but attenuated the inhibitory effect of 8-OH-DPAT. Acute administration of SB-649915-B resulted in increases (approximately two- to threefold) in extracellular 5-HT in the cortex of rats and the dentate gyrus and cortex of guinea pigs.. Based on these data, one may speculate that the 5-HT autoreceptor antagonist/5-HT transport inhibitor SB-649915-B will have therapeutic efficacy in the treatment of affective disorders with the potential for a faster onset of action compared to current selective serotonin reuptake inhibitors.

Topics: Animals; Benzoxazines; Dentate Gyrus; Dose-Response Relationship, Drug; Electrophysiology; Electroshock; Guinea Pigs; Locomotion; Male; Microdialysis; Mood Disorders; Neurons; Piperidines; Prefrontal Cortex; Quinolines; Radioligand Assay; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Seizures; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin 5-HT1 Receptor Antagonists; Serotonin Plasma Membrane Transport Proteins; Species Specificity

Topics: Appetite Depressants; Humans; Mood Disorders; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

The authors present a case of a patient with dementia with mood symptoms and multiple neurological manifestations of fragile X-associated tremor/ataxia syndrome (FXTAS). Despite a gradually deteriorating neurological course, he was managed for 2 years with combination therapy of donepezil and venlafaxine, which resulted in improvement and relative stabilization of his psychiatric status. Psychiatrists are hereby alerted to the description of a novel dementia syndrome that may respond to pharmacological intervention commonly used for other dementias.

Topics: Aged; Antidepressive Agents, Second-Generation; Ataxia; Atrophy; Brain; Cyclohexanols; Dementia; Dominance, Cerebral; Donepezil; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fragile X Mental Retardation Protein; Fragile X Syndrome; Genetic Carrier Screening; Humans; Image Processing, Computer-Assisted; Indans; Magnetic Resonance Imaging; Male; Mental Status Schedule; Mood Disorders; Neurologic Examination; Neuropsychological Tests; Nootropic Agents; Piperidines; Tremor; Trinucleotide Repeats; Venlafaxine Hydrochloride

Delirium is a common complication of dementia and may produce considerable morbidity. In addition to psychotic symptoms such as hallucinations and delusions, delirium may produce considerable agitation, which may be refractory to conventional medications such as antipsychotics and benzodiazepines. The main approach to delirium is to treat any underlying medical problem that could cause the delirium. However, delirium is not always reversible, and there is no specific treatment for persistent delirium. The authors present a case of delirium complicating a preexisting dementia that resolved rapidly following initiation of the cholinesterase inhibitor donepezil, suggesting that cholinergic dysfunction may have played a role in the etiology of this patient's delirium. Future research needs to be directed at the issue of cholinergic activity in delirium through monitoring of serum anticholinergic activity and its response to procholinergic therapy.

Topics: Aged; Alcohol Withdrawal Delirium; Cholinesterase Inhibitors; Cognition Disorders; Delirium; Dementia; Donepezil; Humans; Indans; Male; Mood Disorders; Piperidines; Treatment Outcome