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BMC Neuroscience Nov 2010The molecular and biological mechanisms by which many antidepressants function are based on the monoamine depletion hypothesis. However, the entire cascade of mechanisms...
BACKGROUND
The molecular and biological mechanisms by which many antidepressants function are based on the monoamine depletion hypothesis. However, the entire cascade of mechanisms responsible for the therapeutic effect of antidepressants has not yet been elucidated.
RESULTS
We used a genome-wide microarray system containing 30,000 clones to evaluate total RNA that had been isolated from the brains of treated rats to identify the genes involved in the therapeutic mechanisms of various antidepressants, a tricyclic antidepressant (imipramine). a selective serotonin reuptake inhibitor (fluoxetine), a monoamine oxidase inhibitor (phenelzine) and psychoactive herbal extracts of Nelumbinis Semen (NS). To confirm the differential expression of the identified genes, we analyzed the amount of mRNA that was isolated from the hippocampus of rats that had been treated with antidepressants by real-time RT-PCR using primers specific for selected genes of interest. These data demonstrate that antidepressants interfere with the expression of a large array of genes involved in signaling, survival and protein metabolism, suggesting that the therapeutic effect of these antidepressants is very complex. Surprisingly, unlike other antidepressants, we found that the standardized herbal medicine, Nelumbinis Semen, is free of factors that can induce neurodegenerative diseases such as caspase 8, α-synuclein, and amyloid precursor protein. In addition, the production of the inflammatory cytokine, IFNγ, was significantly decreased in rat hippocampus in response to treatment with antidepressants, while the inhibitory cytokine, TGFβ, was significantly enhanced.
CONCLUSIONS
These results suggest that antidepressants function by regulating neurotransmission as well as suppressing immunoreactivity in the central nervous system.
Topics: Animals; Antidepressive Agents; Antidepressive Agents, Tricyclic; Depressive Disorder; Gene Expression Profiling; Genome-Wide Association Study; Hippocampus; Male; Oligonucleotide Array Sequence Analysis; Rats; Rats, Sprague-Dawley
PubMed: 21118505
DOI: 10.1186/1471-2202-11-152 -
Journal of Clinical Sleep Medicine :... Aug 2010Prazosin is recommended for treatment of Posttraumatic Stress Disorder (PTSD)-associated nightmares. Level A. Image Rehearsal Therapy (IRT) is recommended for treatment...
Prazosin is recommended for treatment of Posttraumatic Stress Disorder (PTSD)-associated nightmares. Level A. Image Rehearsal Therapy (IRT) is recommended for treatment of nightmare disorder. Level A. Systematic Desensitization and Progressive Deep Muscle Relaxation training are suggested for treatment of idiopathic nightmares. Level B. Venlafaxine is not suggested for treatment of PTSD-associated nightmares. Level B. Clonidine may be considered for treatment of PTSD-associated nightmares. Level C. The following medications may be considered for treatment of PTSD-associated nightmares, but the data are low grade and sparse: trazodone, atypical antipsychotic medications, topiramate, low dose cortisol, fluvoxamine, triazolam and nitrazepam, phenelzine, gabapentin, cyproheptadine, and tricyclic antidepressants. Nefazodone is not recommended as first line therapy for nightmare disorder because of the increased risk of hepatotoxicity. Level C. The following behavioral therapies may be considered for treatment of PTSD-associated nightmares based on low-grade evidence: Exposure, Relaxation, and Rescripting Therapy (ERRT); Sleep Dynamic Therapy; Hypnosis; Eye-Movement Desensitization and Reprocessing (EMDR); and the Testimony Method. Level C. The following behavioral therapies may be considered for treatment of nightmare disorder based on low-grade evidence: Lucid Dreaming Therapy and Self-Exposure Therapy. Level C No recommendation is made regarding clonazepam and individual psychotherapy because of sparse data.
Topics: Adult; Clonidine; Cognitive Behavioral Therapy; Dreams; Evidence-Based Medicine; Eye Movement Desensitization Reprocessing; Humans; Hypnosis; Norepinephrine; Prazosin; Psychotropic Drugs; Randomized Controlled Trials as Topic; Relaxation Therapy; Stress Disorders, Post-Traumatic
PubMed: 20726290
DOI: No ID Found -
Journal of Medical Toxicology :... Dec 2010Phenelzine is an irreversible monoamine oxidase inhibitor (MAOI). Hypertensive reactions after ingestion of tyramine-rich foods such as cheese are well known. However, a...
INTRODUCTION
Phenelzine is an irreversible monoamine oxidase inhibitor (MAOI). Hypertensive reactions after ingestion of tyramine-rich foods such as cheese are well known. However, a review of the available medical literature found no previous reports of myocardial infarction resulting from the ingestion of cheese by a patient taking a MAOI.
CASE REPORT
A 34-year-old female taking phenelzine for depression developed severe chest pain 1 h after eating cheese. She was hypertensive and the electrocardiography showed ischemic changes in the antero-lateral chest leads. The chest pain and elevated blood pressure were relieved with intravenous morphine and nitroprusside. The initial serum troponin I level was normal, but serial repeat levels showed a rising trend with a peak at 4.89 ug/L (reference range <0.05 ug/L) 6 h after the initial blood draw, suggestive of a non-ST elevation myocardial infarction. The patient subsequently developed hypotension 4 h after another therapeutic dose of phenelzine was served to the patient 4 h after her admission to the ED. This was corrected with at least 2 L of intravenous normal saline boluses. Subsequent EKGs and Sestamibi scan showed no evidence of cardiac ischemia. She was discharged home after a hospital stay of 3 days.
DISCUSSION
We believe this to be the first reported case of myocardial infarction resulting from ingestion of cheese in a patient taking a MAOI. It might be expected that hypertensive crisis could lead to a myocardial infarction, but a review of the medical literature found no such cases reported.
Topics: Adult; Cheese; Chest Pain; Electrocardiography; Female; Food-Drug Interactions; Heart; Humans; Injections, Intravenous; Monoamine Oxidase Inhibitors; Morphine; Myocardial Infarction; Nitroprusside; Phenelzine; Treatment Outcome; Troponin I; Vasodilator Agents
PubMed: 20652662
DOI: 10.1007/s13181-010-0101-y -
The antidepressant phenelzine protects neurons and astrocytes against formaldehyde-induced toxicity.Journal of Neurochemistry Sep 2010Reactive aldehydes have been implicated in the etiology of several neurological and psychiatric disorders, and there is considerable interest in drugs to counteract the... (Comparative Study)
Comparative Study
Reactive aldehydes have been implicated in the etiology of several neurological and psychiatric disorders, and there is considerable interest in drugs to counteract the actions of these aldehydes. Increased formaldehyde (FA) and up-regulation of semicarbazide-sensitive amine oxidase, which forms FA from methylamine, have been implicated in disorders such as cerebrovascular disorders, alcohol abuse, diabetes and Alzheimer's disease. Phenelzine (PLZ), a monoamine oxidase inhibitor, is an antidepressant that has recently received attention for its neuroprotective/neurorescue properties. We investigated FA-induced toxicity and the effects of PLZ using rat primary cortical neurons and astrocytes and found that FA induced toxicity in neurons and astrocytes by multiple means. In astrocytes, FA decreased glutamate transporter expression, inhibiting glutamate uptake. PLZ reversed the decrease of glutamate uptake and the alteration of the second messengers, AKT and p38, induced by FA. PLZ alone affected the GLT-1 glutamate transporter in opposite directions in astrocytes and neurons. Thus, PLZ has multiple actions in neurons and astrocytes that may contribute to its neuroprotection.
Topics: Animals; Antidepressive Agents; Astrocytes; Cells, Cultured; Female; Formaldehyde; Neurons; Neuroprotective Agents; Phenelzine; Pregnancy; Rats; Rats, Sprague-Dawley
PubMed: 20557421
DOI: 10.1111/j.1471-4159.2010.06857.x -
The Cochrane Database of Systematic... Jun 2010Drugs are widely used in borderline personality disorder (BPD) treatment, chosen because of properties known from other psychiatric disorders ("off-label use"), mostly... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Drugs are widely used in borderline personality disorder (BPD) treatment, chosen because of properties known from other psychiatric disorders ("off-label use"), mostly targeting affective or impulsive symptom clusters.
OBJECTIVES
To assess the effects of drug treatment in BPD patients.
SEARCH STRATEGY
We searched bibliographic databases according to the Cochrane Developmental, Psychosocial and Learning Problems Group strategy up to September 2009, reference lists of articles, and contacted researchers in the field.
SELECTION CRITERIA
Randomised studies comparing drug versus placebo, or drug versus drug(s) in BPD patients. Outcomes included total BPD severity, distinct BPD symptom facets according to DSM-IV criteria, associated psychopathology not specific to BPD, attrition and adverse effects.
DATA COLLECTION AND ANALYSIS
Two authors selected trials, assessed quality and extracted data, independently.
MAIN RESULTS
Twenty-eight trials involving a total of 1742 trial participants were included. First-generation antipsychotics (flupenthixol decanoate, haloperidol, thiothixene); second-generation antipsychotics (aripirazole, olanzapine, ziprasidone), mood stabilisers (carbamazepine, valproate semisodium, lamotrigine, topiramate), antidepressants (amitriptyline, fluoxetine, fluvoxamine, phenelzine sulfate, mianserin), and dietary supplementation (omega-3 fatty acid) were tested. First-generation antipsychotics were subject to older trials, whereas recent studies focussed on second-generation antipsychotics and mood stabilisers. Data were sparse for individual comparisons, indicating marginal effects for first-generation antipsychotics and antidepressants.The findings were suggestive in supporting the use of second-generation antipsychotics, mood stabilisers, and omega-3 fatty acids, but require replication, since most effect estimates were based on single studies. The long-term use of these drugs has not been assessed.Adverse event data were scarce, except for olanzapine. There was a possible increase in self-harming behaviour, significant weight gain, sedation and changes in haemogram parameters with olanzapine. A significant decrease in body weight was observed with topiramate treatment. All drugs were well tolerated in terms of attrition.Direct drug comparisons comprised two first-generation antipsychotics (loxapine versus chlorpromazine), first-generation antipsychotic against antidepressant (haloperidol versus amitriptyline; haloperidol versus phenelzine sulfate), and second-generation antipsychotic against antidepressant (olanzapine versus fluoxetine). Data indicated better outcomes for phenelzine sulfate but no significant differences in the other comparisons, except olanzapine which showed more weight gain and sedation than fluoxetine. The only trial testing single versus combined drug treatment (olanzapine versus olanzapine plus fluoxetine; fluoxetine versus fluoxetine plus olanzapine) yielded no significant differences in outcomes.
AUTHORS' CONCLUSIONS
The available evidence indicates some beneficial effects with second-generation antipsychotics, mood stabilisers, and dietary supplementation by omega-3 fatty acids. However, these are mostly based on single study effect estimates. Antidepressants are not widely supported for BPD treatment, but may be helpful in the presence of comorbid conditions. Total BPD severity was not significantly influenced by any drug. No promising results are available for the core BPD symptoms of chronic feelings of emptiness, identity disturbance and abandonment. Conclusions have to be drawn carefully in the light of several limitations of the RCT evidence that constrain applicability to everyday clinical settings (among others, patients' characteristics and duration of interventions and observation periods).
Topics: Antidepressive Agents; Antipsychotic Agents; Borderline Personality Disorder; Fatty Acids, Omega-3; Humans; Randomized Controlled Trials as Topic
PubMed: 20556762
DOI: 10.1002/14651858.CD005653.pub2 -
Archives of General Psychiatry Mar 2010Medication and cognitive behavioral treatment are the best-established treatments for social anxiety disorder, yet many individuals remain symptomatic after treatment. (Comparative Study)
Comparative Study Randomized Controlled Trial
CONTEXT
Medication and cognitive behavioral treatment are the best-established treatments for social anxiety disorder, yet many individuals remain symptomatic after treatment.
OBJECTIVE
To determine whether combined medication and cognitive behavioral treatment is superior to either monotherapy or pill placebo.
DESIGN
Randomized, double-blind, placebo-controlled trial.
SETTING
Research clinics at Columbia University and Temple University.
PARTICIPANTS
One hundred twenty-eight individuals with a primary DSM-IV diagnosis of social anxiety disorder.
INTERVENTIONS
Cognitive behavioral group therapy (CBGT), phenelzine sulfate, pill placebo, and combined CBGT plus phenelzine.
MAIN OUTCOME MEASURES
Liebowitz Social Anxiety Scale and Clinical Global Impression (CGI) scale scores at weeks 12 and 24.
RESULTS
Linear mixed-effects models showed a specific order of effects, with steepest reductions in Liebowitz Social Anxiety Scale scores for the combined group, followed by the monotherapies, and the least reduction in the placebo group (Williams test = 4.97, P < .01). The CGI response rates in the intention-to-treat sample at week 12 were 9 of 27 (33.3%) (placebo), 16 of 34 (47.1%) (CBGT), 19 of 35 (54.3%) (phenelzine), and 23 of 32 (71.9%) (combined treatment) (chi(2)(1) = 8.76, P < .01). Corresponding remission rates (CGI = 1) were 2 of 27 (7.4%), 3 of 34 (8.8%), 8 of 35 (22.9%), and 15 of 32 (46.9%) (chi(2)(1) = 15.92, P < .01). At week 24, response rates were 9 of 27 (33.3%), 18 of 34 (52.9%), 17 of 35 (48.6%), and 25 of 32 (78.1%) (chi(2)(1) = 12.02, P = .001). Remission rates were 4 of 27 (14.8%), 8 of 34 (23.5%), 9 of 35 (25.7%), and 17 of 32 (53.1%) (chi(2)(1) = 10.72, P = .001).
CONCLUSION
Combined phenelzine and CBGT treatment is superior to either treatment alone and to placebo on dimensional measures and on rates of response and remission.
Topics: Adolescent; Adult; Aged; Cognitive Behavioral Therapy; Combined Modality Therapy; Diagnostic and Statistical Manual of Mental Disorders; Female; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Phenelzine; Phobic Disorders; Placebos; Psychiatric Status Rating Scales; Psychometrics; Psychotherapy, Group; Severity of Illness Index; Surveys and Questionnaires; Treatment Outcome
PubMed: 20194829
DOI: 10.1001/archgenpsychiatry.2010.11 -
Journal of Clinical Sleep Medicine :... Feb 2010Pharmacologically induced/exacerbated restless legs syndrome (RLS), periodic limb movements in sleep (PLMS), and REM behavior disorder/REM sleep without atonia (RSWA)... (Comparative Study)
Comparative Study Review
Pharmacologically induced/exacerbated restless legs syndrome, periodic limb movements of sleep, and REM behavior disorder/REM sleep without atonia: literature review, qualitative scoring, and comparative analysis.
BACKGROUND
Pharmacologically induced/exacerbated restless legs syndrome (RLS), periodic limb movements in sleep (PLMS), and REM behavior disorder/REM sleep without atonia (RSWA) are increasingly recognized in clinical sleep medicine. A scoring system to evaluate the literature was created and implemented. The aim was to identify the evidence with the least amount of confound, allowing for more reliable determinations of iatrogenic etiology.
METHODS
Points were provided for the following criteria: manuscript type (abstract, peer-reviewed paper); population size studied (large retrospective study, small case series, case report); explicitly stated dosage timing; identification of peak symptoms related to time of medication administration (i.e., medication was ingested in the evening or at bedtime); initiation of a treatment plan; symptoms subsided or ceased with decreased dosage or drug discontinuation (for RLS articles only); negative personal history for RLS prior to use of the medication; exclusion of tobacco/alcohol/excessive caffeine use; exclusion of sleep disordered breathing by polysomnography (PSG); and PSG documentation of presence or absence of PLMS. For RLS and PLMS articles were also given points for the following criteria: each 2003 National Institutes of Health (NIH) RLS criteria met; exclusion of low serum ferritin; and exclusion of peripheral neuropathy by neurological examination.
RESULTS
Thirty-two articles on drug-induced RLS, 6 articles on drug-induced PLMS, and 15 articles on drug-induced RBD/ RSWA were analyzed.
CONCLUSION
Based on scores < or = 10 and trials of medication reduction/cessation, the strongest evidence available for drug induced RLS are for the following drugs: escitalopram; fluoxetine; L-dopa/carbidopa and pergolide; L-thyroxine; mianserin; mirtazapine; olanzapine; and tramadol. Since none of the PLMS articles assessed PLMI in trials of medication reduction/cessation, the strongest evidence based on scores > or = 10 are for the following drugs: bupropion, citalopram, fluoxetine, paroxetine, sertraline, and venlafaxine. Based on scores > or = 10 and/or trials of medication cessation, the strongest evidence for drug induced RBD/ RSWA is for the following drugs: clomipramine, selegiline, and phenelzine.
Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Nocturnal Myoclonus Syndrome; REM Sleep Behavior Disorder; Restless Legs Syndrome
PubMed: 20191944
DOI: No ID Found -
Journal of the American Chemical Society Mar 2010LSD1 is a flavin-dependent histone demethylase that oxidatively removes methyl groups from Lys-4 of histone H3. LSD1 belongs to the amine oxidase enzyme superfamily... (Comparative Study)
Comparative Study
LSD1 is a flavin-dependent histone demethylase that oxidatively removes methyl groups from Lys-4 of histone H3. LSD1 belongs to the amine oxidase enzyme superfamily which utilize molecular oxygen to transform amines to imines that are hydrolytically cleaved to formaldehyde. In prior studies, it has been shown that monoamine oxidase inhibitory scaffolds such as propargylamines and cyclopropylamines can serve as mechanism-based inactivators of LSD1. Propargylamine-histone H3 peptide analogues are potent LSD1 inhibitors, whereas small molecule antidepressant MAO acetylenic inhibitors like pargyline do not inhibit LSD1. In contrast, the small molecule MAO cyclopropylamine inhibitor tranylcypromine is a time-dependent LSD1 inhibitor but exo-cyclopropylamine-peptide substrate analogue is not. To provide further insight into small molecule versus peptide relationships in LSD1 inhibition, herein we further our analysis of warheads in peptide scaffolds to include the chlorovinyl, endo-cyclopropylamine, and hydrazine-functionalities as LSD1 inactivators. We find that chlorovinyl-H3 is a mechanism-based LSD1 inactivator whereas endo-cyclopropylamine-H3 does not show time-dependent inactivation. The hydrazine-H3 was shown to be the most potent LSD1 suicide inhibitor yet reported, more than 20-fold more efficient in inhibiting demethylation than propargylamine-H3 derivatives. We re-explored MAO antidepressant agent phenelzine (phenethylhydrazine), previously reported to be a weak LSD1 inhibitor, and found that it is far more potent than previously appreciated. We show that phenelzine can block histone H3K4Me demethylation in cells, validating it as a pharmacologic tool and potential lead structure for anticancer therapy.
Topics: Animals; Cells, Cultured; Enzyme Inhibitors; Histone Demethylases; Histones; Hydrazines; Pargyline; Peptides; Propylamines; Rats; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Structure-Activity Relationship
PubMed: 20148560
DOI: 10.1021/ja909996p -
BMJ Clinical Evidence Feb 2010Post-traumatic stress disorder (PTSD) may affect 10% of women and 5% of men at some stage, and symptoms may persist for several years. Risk factors include major trauma,... (Review)
Review
INTRODUCTION
Post-traumatic stress disorder (PTSD) may affect 10% of women and 5% of men at some stage, and symptoms may persist for several years. Risk factors include major trauma, lack of social support, peritraumatic dissociation, and previous psychiatric history or personality factors.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent PTSD? What are the effects of interventions to treat PTSD? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 46 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review we present information relating to the effectiveness and safety of the following interventions: affect management; antiepileptic drugs; antihypertensive drugs; benzodiazepines; brofaromine; CBT; drama therapy; eye movement desensitisation and reprocessing; fluoxetine; group therapy; hydrocortisone; hypnotherapy; inpatient treatment programmes; Internet-based psychotherapy; mirtazapine; multiple-session CBT; multiple-session collaborative trauma support; multiple-session education; nefazodone; olanzapine; paroxetine; phenelzine; psychodynamic psychotherapy; risperidone; SSRIs (versus other antidepressants); sertraline; single-session group debriefing; single-session individual debriefing; supportive psychotherapy; supportive counselling; temazepam; tricyclic antidepressants; and venlafaxine.
Topics: Antidepressive Agents; Fluoxetine; Humans; Psychotherapy, Psychodynamic; Sertraline; Stress Disorders, Post-Traumatic
PubMed: 21718580
DOI: No ID Found -
The American Journal of Pathology Oct 2009Reactive oxygen species (ROS) production is an antimicrobial response to pathogenic challenge that may, in the case of persistent infection, have deleterious effects on...
Reactive oxygen species (ROS) production is an antimicrobial response to pathogenic challenge that may, in the case of persistent infection, have deleterious effects on the tissue of origin. A rat periodontal disease model was used to study ROS-induced chronic epithelial inflammation and bone loss. Lipopolysaccharide (LPS) was applied for 8 weeks into the gingival sulcus, and histological analysis confirmed the onset of chronic disease. Junctional epithelium was collected from healthy and diseased animals using laser-capture microdissection, and expression microarray analysis was performed. Of 19,730 genes changed in disease, 42 were up-regulated >/=4-fold. Three of the top 10 LPS-induced genes, monoamine oxidase B (MAO/B) and flavin-containing monooxygenase 1 and 2, are implicated in ROS signaling. LPS-associated induction of the ROS mediator H(2)O(2), as well as MAO/B and tumor necrosis factor (TNF)-alpha levels were validated in the rat histological sections and a porcine junctional epithelial cell culture model. Topical MAO inhibitors significantly counteracted LPS-associated elevation of H(2)O(2) production and TNF-alpha expression in vivo and in vitro, inhibited disease-associated apical migration and proliferation of junctional epithelium and inhibited induced systemic H(2)O(2) levels and alveolar bone loss in vivo. These results suggest that LPS induces chronic wounds via elevated MAO/B-mediated increases in H(2)O(2) and TNF-alpha activity by epithelial cells and is further associated with more distant effects on systemic oxidative stress and alveolar bone loss.
Topics: Alveolar Bone Loss; Animals; Chronic Disease; Disease Models, Animal; Epithelial Cells; Hydrogen Peroxide; Lipopolysaccharides; Male; Microdissection; Monoamine Oxidase; Oligonucleotide Array Sequence Analysis; Phenelzine; Principal Component Analysis; RNA, Complementary; Rats; Rats, Wistar; Reproducibility of Results; Tumor Necrosis Factor-alpha; Wound Healing
PubMed: 19779138
DOI: 10.2353/ajpath.2009.090108