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Medical research on lexapro
J Mol Neurosci. 2008 Jul 1;
Reichenstein M, Rehavi M, Pinhasov A
Recent studies have suggested antidepressant involvement in synaptic plasticity, possibly mediated by neurotrophins and neuropeptides. Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide and neuromodulator. Since its discovery, PACAP has been extensively investigated with regard to its neurotrophic properties including regulation of brain-derived neurotrophic factor (BDNF) expression, a neurotrophin postulated to be involved in the mechanism of antidepressant action and etiology of affective disorders. Using real-time polymerase chain reaction (PCR) technique, we demonstrate in this paper a robust upregulation of BDNF messenger RNA (mRNA) expression in rat primary cortical neurons following a 6-hour incubation with PACAP, and subsequently elevated BDNF expression after prolonged treatment. Additional experiments were conducted to evaluate the effects of antidepressants on the expression of PACAP, its receptors and BDNF. In rat hippocampal neurons, prolonged (72-hour) treatment with selective serotonin reuptake inhibitors paroxetine and citalopram significantly up-regulated BDNF and PACAP expression and down-regulated PACAP receptor (PAC1 and VPAC2) expression; the tricyclic antidepressant imipramine had an opposite effect. These alterations in BDNF expression correlated negatively with PAC1 and VPAC2 expression, and positively with PACAP mRNA levels. Thus, our findings suggest the possible involvement of PACAP signaling in the neuronal plasticity induced by antidepressant treatment.
Psychopharmacology (Berl). 2008 Jun 30;
Lapiz-Bluhm MD, Soto-Piña AE, Hensler JG, Morilak DA
RATIONALE: Chronic stress perturbs modulatory brain neurotransmitter systems, including serotonin (5-HT), and is a risk factor for psychiatric disorders such as depression. Deficits in cognitive flexibility, reflecting prefrontal cortical dysfunction, are prominent in such disorders. Orbitofrontal cortex (OFC) has been implicated specifically in reversal learning, a form of cognitive flexibility modulated by 5-HT. OBJECTIVES: The objectives of the study were (1) to assess the effects of chronic intermittent cold (CIC) stress, a potent metabolic stressor, on performance of rats in an attentional set-shifting test (AST), and (2) to assess a possible role for serotonin in CIC-induced deficits and test the effects of acute serotonin reuptake blockade. MATERIALS AND METHODS: Male Sprague-Dawley rats were exposed to CIC stress (14 days x 6 h/day at 4 degrees C) before testing on the AST. In subsequent experiments, brain 5-HT was depleted in naïve rats with para-chlorophenylalanine or 5-HT release was increased acutely in CIC-stressed rats with citalopram (5 mg/kg, s.c.) given 30 min prior to the first reversal task. Microdialysis was used to assess CIC-induced changes in 5-HT release in OFC during testing. RESULTS: CIC-stressed rats exhibited a selective impairment on the first reversal task in the AST. 5-HT depletion induced a similarly selective deficit in reversal learning. The CIC-induced impairment in reversal learning was attenuated by acute 5-HT reuptake blockade. 5-HT release was reduced in OFC of CIC-stressed rats during behavioral testing. CONCLUSIONS: The CIC stress-induced impairment of cognitive flexibility may involve dysregulation of 5-HT modulatory function in OFC. Such deficits may thus model relevant symptoms of neuropsychiatric disorders that respond positively to SSRI treatment.
Gen Hosp Psychiatry. 2008 Jul-Aug; 30(4): 372-7
Levin TT, Cortes-Ladino A, Weiss M, Palomba ML
OBJECTIVE: To discuss two cases of life-threatening serotonin toxicity due to a drug interaction between citalopram and fluconazole and to review the pertinent literature. METHODS: A Medline search without date limitation was conducted using the terms serotonin syndrome, serotonin toxicity, fluconazole and citalopram. RESULTS AND DISCUSSION: Fluconazole inhibits CYP2C19. Citalopram is a substrate for 2C19 and inhibition of its metabolism may result in serotonin toxicity. Serotonin toxicity in oncology patients may not present with the classic constellation of signs typically described in the literature. Delirium may be the only presenting feature. Current level of evidence for treatment of serotonin toxicity is level 4 or 5 (case series and expert opinion). Nevertheless, there is a strong theoretical basis for treating serotonin toxicity in medical patients with a 5H(2A) blocker such as cyproheptadine. CONCLUSIONS: Consultation-liaison psychiatrists and oncologists should be aware of this preventable and underrecognized interaction. Citalopram should be stopped or substituted prior to the concurrent administration of fluconazole, and in the event of toxicity, treatment with cyproheptadine has a favorable risk-benefit ratio despite a lack of randomized controlled data to support its use.
Abnormal temporal difference reward-learning signals in major depression.
Brain. 2008 Jun 25;
Kumar P, Waiter G, Ahearn T, Milders M, Reid I, Steele JD
Anhedonia is a core symptom of major depressive disorder (MDD), long thought to be associated with reduced dopaminergic function. However, most antidepressants do not act directly on the dopamine system and all antidepressants have a delayed full therapeutic effect. Recently, it has been proposed that antidepressants fail to alter dopamine function in antidepressant unresponsive MDD. There is compelling evidence that dopamine neurons code a specific phasic (short duration) reward-learning signal, described by temporal difference (TD) theory. There is no current evidence for other neurons coding a TD reward-learning signal, although such evidence may be found in time. The neuronal substrates of the TD signal were not explored in this study. Phasic signals are believed to have quite different properties to tonic (long duration) signals. No studies have investigated phasic reward-learning signals in MDD. Therefore, adults with MDD receiving long-term antidepressant medication, and comparison controls both unmedicated and acutely medicated with the antidepressant citalopram, were scanned using fMRI during a reward-learning task. Three hypotheses were tested: first, patients with MDD have blunted TD reward-learning signals; second, controls given an antidepressant acutely have blunted TD reward-learning signals; third, the extent of alteration in TD signals in major depression correlates with illness severity ratings. The results supported the hypotheses. Patients with MDD had significantly reduced reward-learning signals in many non-brainstem regions: ventral striatum (VS), rostral and dorsal anterior cingulate, retrosplenial cortex (RC), midbrain and hippocampus. However, the TD signal was increased in the brainstem of patients. As predicted, acute antidepressant administration to controls was associated with a blunted TD signal, and the brainstem TD signal was not increased by acute citalopram administration. In a number of regions, the magnitude of the abnormal signals in MDD correlated with illness severity ratings. The findings highlight the importance of phasic reward-learning signals, and are consistent with the hypothesis that antidepressants fail to normalize reward-learning function in antidepressant-unresponsive MDD. Whilst there is evidence that some antidepressants acutely suppress dopamine function, the long-term action of virtually all antidepressants is enhanced dopamine agonist responsiveness. This distinction might help to elucidate the delayed action of antidepressants. Finally, analogous to recent work in schizophrenia, the finding of abnormal phasic reward-learning signals in MDD implies that an integrated understanding of symptoms and treatment mechanisms is possible, spanning physiology, phenomenology and pharmacology.
Eur J Pharmacol. 2008 May 23;
Takahashi E, Katayama M, Niimi K, Itakura C
The main clinically used antidepressant drugs are selective monoamine reuptake inhibitors, including selective serotonin reuptake inhibitors (citalopram, sertraline), selective dopamine reuptake inhibitor (nomifensine) and selective noradrenaline reuptake inhibitor (reboxetine), but they have various side effects. Because cannabinoid CB(1) receptor antagonists (SR141716A, AM251) enhance monoamine release, they might be beneficial in the therapy of affective disorders. We hypothesized that the use of monoamine reuptake inhibitors in combination with cannabinoid CB(1) receptor antagonists would allow a lower dose of monoamine reuptake inhibitors to be used in the therapy of depression, thereby reducing or eliminating the side effects. To test this hypothesis, we examined the combination of SR141716A or AM251 with citalopram, sertraline, nomifensine or reboxetine at subthreshold doses to see whether these combinations would show an additive effect in the forced swimming test and the tail suspension test with mice. Subthreshold doses of cannabinoid CB(1) receptor antagonist and selective serotonin reuptake inhibitors, which separately had no effect on the immobility of mice in the tests, showed a clear effect when the drugs were administered at 40 and 30 min, respectively, before the tests, without any change of motor activity. Therefore, the use of subthreshold doses of these agents in combination might be useful to enhance mainly serotonergic neurotransmission, and to reduce or eliminate the side effects of citalopram and sertraline.
Citalopram Overdose: Late Presentation of Torsades De Pointes (TdP) With Cardiac Arrest.
J Med Toxicol. 2008 Jun; 4(2): 101-5
Tarabar AF, Hoffman RS, Nelson L
Introduction: Citalopram overdose may produce bradycardia, QT prolongation, and torsades de pointes (TdP). A cardiotoxic metabolite may be responsible for the delayed onset of cardiotoxicity. Although some authorities recommend a minimum of 24 hours of observation following citalopram overdose, a recent analysis suggested that dysrhythmias rarely occur beyond 13 hours post-ingestion. We present a case of citalopram overdose with a substantially delayed onset of cardiac toxicity. Case Report: A 36-year-old woman complained of shakiness, numbness in the arms, and palpitations that began approximately 32 hours after ingesting 50 (20-mg) tablets of citalopram. Her initial vital signs were: blood pressure, 84/44 mmHg; pulse, 102-150/minute; respirations, 17/min; temperature, 99.3 degrees F (37.3 degrees C). Her initial ECG showed sinus rhythm with a prolonged corrected QT interval (572 msec) with paroxysmal, self-limited runs of wide-complex tachycardia that appeared multifocal in nature. Approximately 20 minutes after presentation, she experienced self-terminating TdP, with transient hypotension and loss of consciousness. Her serum citalopram concentration (33 hours post-ingestion) was 477 ng/mL (therapeutic: 40-110 ng/mL); desmethylcitalopram concentration was 123.2 ng/mL (therapeutic: 14-40 ng/mL). She was treated with magnesium and lidocaine, and her corrected QT interval remained abnormal for 24 hours after presentation. Discussion: Citalopram overdose can produce life-threatening cardiac toxicity with a clinical onset that may be delayed beyond a routine observation period of 6 hours. Once the QT interval is prolonged, it seems prudent to prolong the observation period.
Pharmacol Biochem Behav. 2008 May 6;
Ulak G, Mutlu O, Akar FY, Komsuoğlu FI, Tanyeri P, Erden BF
Treatment-resistant depression has necessitated new therapeutic strategies in augmenting the therapeutic actions of currently existing antidepressant drugs. The aim of this study was to investigate the possibility of synergistic interaction between 1-(2-trifluoromethylphenyl)-imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor and conventional antidepressants of different classes in the forced swimming test (FST) in rats. TRIM decreased the immobility time at 50 mg/kg doses in the FST in rats. Treatment with a behaviourally subeffective dose of TRIM (20 mg/kg) augmented the behavioural effect of tricyclic antidepressant imipramine, selective serotonin re-uptake inhibitor (SSRI) citalopram and fluoxetine or selective serotonin reuptake enhancer tianeptine but failed to augment the antidepressant effect of reboxetine, a noradrenaline re-uptake inhibitor, in this test. Therefore inhibition of NOS augments the effects of antidepressants acting on serotonergic system in the FST. Neither TRIM (10-50 mg/kg) nor other drug treatments affected the locomotor activity of animals. These findings are in agreement with the view that antidepressant effects or augmentation of these effects in the FST may be explained with inhibition of NOS activity and this may be a new approach in offering greater therapeutic efficacy of antidepressants acting via serotonergic system.
Eur J Pharmacol. 2008 Apr 8;
Egashira N, Matsuda T, Koushi E, Higashihara F, Mishima K, Chidori S, Hasebe N, Iwasaki K, Nishimura R, Oishi R, Fujiwara M
In the present study, we investigated the effect of Delta(9)-tetrahydrocannabinol (THC), the principal psychoactive component of marijuana, on immobility time during the forced swim test. THC (2 and 6 mg/kg, i.p.) significantly prolonged the immobility time. In addition, THC at the same doses did not significantly affect locomotor activity in the open-field test. The selective cannabinoid CB(1) receptor antagonist rimonabant (3 mg/kg, i.p.) significantly reduced the enhancement of immobility by THC (6 mg/kg). Similarly, the selective serotonin (5-HT) reuptake inhibitor (SSRI) citalopram (10 mg/kg, i.p.) and 5-HT(1A/7) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.3 mg/kg, i.p.) significantly reduced this THC-induced effect. Moreover, the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide dihydrochloride (WAY100635, 1 mg/kg, i.p.) and the postsynaptic 5-HT(1A) receptor antagonist MM-77 (0.1 mg/kg, i.p.) reversed this reduction effect of 8-OH-DPAT (0.3 mg/kg). In contrast, the selective 5-HT(7) receptor antagonist (R)-3-[2-[2-(4-methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulfonyl]phenol hydrochloride (SB269970) had no effect on this reduction effect of 8-OH-DPAT. WAY100635 (1 mg/kg) also reversed the reduction effect of citalopram (10 mg/kg). These findings suggest that the 5-HT(1A) receptors are involved in THC-induced enhancement of immobility.
Effect of activated charcoal on citalopram-induced QT prolongation.
Ann Emerg Med. 2008 Jul; 52(1): 86-7; author reply 87-8
Greene SC, Brooks DE, Lovecchio F
Anhedonia and activity deficits in rats: impact of post-stroke depression.
J Psychopharmacol. 2008 Jun 18;
Wang SH, Zhang ZJ, Guo YJ, Zhou H, Teng GJ, Chen BA
Abstract Animal models may allow investigation into the aetiology and treatment of various human disorders. In the present study, a rat model for post-stroke depression (PSD) has been developed using middle cerebral artery occlusion (MCAO), followed by an 18-day chronic mild stress (CMS) paradigm in conjuncture with isolation rearing. The open-field test (OFT) and the sucrose consumption test were used to assess depression-like behaviour and the effects of the antidepressant citalopram. CMS induced behavioural changes in the ischemic animals, including decreased locomotor and rearing activity and reduced sucrose preference (compared with baseline, control and stroke groups respectively), all these behaviours were reversed by chronic administration of citalopram. During the recovery period for the PSD models, the open-field activity and preference for sweet sucrose solution decreased continually, opposed to rats subjected to stress only. Decreased locomotor and rearing represents activity deficits, whereas reduced sucrose preference may indicate desensitisation of the brain reward mechanism (anhedonia). Our findings suggest that anhedonia, one of the core symptoms in patients with PSD, and activity deficits can be found in the MCAO+CMS group of animals. Furthermore, citalopram can ameliorate the behavioural abnormalities observed in these animals. With high validity, good operability and repeatability, our findings suggest that the ischemic rat CMS model is an appropriate model for further PSD research.