Changes in sleep polygraphic variables and clinical state in depressed patients during treatment with citalopram

Drug-induced improvement of depression may be mediated by changes in sleep physiology. The aim of this study was to relate changes in sleep polygraphic variables to clinical state during treatment with citalopram, a highly specific serotonin uptake inhibitor. Sixteen patients took part. The study was single-blind and uncontrolled. A 1-week wash-out period was followed by 1 week of placebo administration, a medication period of 5 weeks, and a 1-week placebo period. For the entire group a significant decrease of rapid eye movement sleep (REMS) and a significant lengthening of REMS latency were observed initially as well as at the end of treatment. No changes in sleep continuity were found, but non-REMS stage 2 (percentage) was significantly increased. On the basis of clinical change, as expressed by the scores of the Hamilton Rating Scale for Depression, at the end of the citalopram treatment the patient group was split in two halves: eight less and eight more improved patients. The groups did not differ with respect to any sleep polygraphic varible.     

Protective effects of serotonin reuptake inhibitors, citalopram and clomipramine, against hippocampal CA1 neuronal damage following transient ischemia in the gerbil

To clarify the role of serotonin in cerebral ischemia, we examined the effects of selective serotonin reuptake inhibitors, citalopram and clomipramine, on ischemic neuronal damage in the gerbil. Pretreatment with citalopram (40 mg/kg i.p.) and clomipramine (20 mg/kg i.p.) protected against neuronal destruction of hippocampal CA1 pyramidal cells following 5 min of forebrain ischemia. Furthermore, microdialysis assays showed that a striking increase in extracellular excitatory amino acid levels during ischemia was significantly inhibited by pretreatment with citalopram and clomipramine. However, citalopram (40 mg/kg i.p.) did not alter the extracellular amino acid concentrations in normal gerbils. Thus, serotonin reuptake inhibitors have a protective effect against ischemic neuronal damage. Furthermore, the present result suggests that the protective effect is mediated through prevention of the accumulation of extracellular excitatory amino acids during and after ischemia.     

西酞普兰与氯丙咪嗪治疗颈椎间盘突出症术后抑郁焦虑症状的对照研究

目的比较西酞普兰与氯丙咪嗪治疗颈椎间盘突出症伴抑郁焦虑症状的疗效和不良反应。方法对200例颈椎间盘突出症伴抑郁焦虑症状患者分别以西酞普兰与氯丙咪嗪治疗,共治疗6周。采用汉密尔顿抑郁量表(HAMD)评定临床疗效,采用副反应量表(TESS)评定副反应。结果西酞普兰组有效率91%;氯丙咪嗪组有效率90%,2组疗效相当。但西酞普兰组起效时间平均(11.1±5.6)d,而氯丙咪嗪组平均(15.1±8.2)d,以西酞普兰组显著较快(P<0.01)。西酞普兰组不良反应发生率为13%,而氯丙咪嗪组发生率为50%,西酞普兰组不良反应发生率较低。结论西酞普兰治疗颈椎间盘突出症术后伴抑郁焦虑症状的疗效与氯丙咪嗪相当,副反应少,值得推广应用。     

Biochemical effects and drug levels in rats after long-term treatment with the specific 5-HT-uptake inhibitor,citalopram

The effects in rats of long-term administration of the potent, specific 5-HT uptake inhibitor citalopram have been investigated. Citalopram hydrobromide (MW=405) was given in the diet, 99 or 25 mol/kg daily, for 13 days or orally, 49 mol/kg twice a day, for 14 days. High plasma and brain levels of citalopram were found during the treatment period, whereas negligible amounts were found 24 h after withdrawal. The 5-HT uptake mechanism in blood platelets was completely blocked, since levels of whole blood 5-HT during and shortly (2 days) after treatment were decreased by 75–90%. The drug load after the two highest doses in terms of plasma drug levels was the same as in depressed patients treated with citalopram. Receptor binding technique ex vivo was applied to different brain parts to measure receptor parameters for several neurotransmitters. All data were evaluated by Eadie-Hoffstee analysis. No changes were seen in B _max and K _d for -receptors (³H-dihydroalprenolol) in frontal cortex, occipital+temporal cortex, whole cortex and limbic structures, 5-HT₂ receptors (³H-spiroperidol) in frontal and whole cortex, ₁-receptors (³H-prazosin) in rest of brain and DA D-2 receptors (³H-spiroperidol) in corpus striatum and limbic structures. The uptake mechanism for 5-HT as well as the inhibitory effect of citalopram on this uptake remained unaffected in brain synaptosomes derived from control and from citalopram (99 mol/kg)-treated rats. Thus long-term treatment with citalopram does not induce changes in neurotransmitter receptors as seen with most tricyclic as well as newer atypical antidepressants. Most striking is the lack of - and 5-HT₂ receptor down-regulation. Since citalopram clinically shows clear antidepressant activity, this down-regulation does not seem to be a prerequisite of antidepressant activity.     

Changes in rat dopamine- and serotonin function in vivo after prolonged administration of the specific 5-HT uptake inhibitor,citalopram

The effect of prolonged administration of the potent and specific 5-HT uptake inhibitor citalopram on behavioural measures of dopaminergic and serotonergic activity has been studied in rats. Administration of citalopram in the diet at a daily dose of 99 mol/kg led to supersensitivity to d-amphetamine-induced hypermotility and stereotypy and to subsensitivity to apomorphine-induced hypomotility 2 h after withdrawal. Forepaw clonus induced by 5-methoxy-N,N-dimethyltryptamine was decreased 2 h and 24 h after withdrawal and the number of head shakes induced by 1-5-HTP and citalopram were decreased 24 h after withdrawal. The d-amphetamine potentiation was still seen after 24 h, whereas the response had returned to normal 3 and 7 days after withdrawal. The content of amphetamine in three different brain regions was about 50% higher compared with controls 24 h after withdrawal of prolonged citalopram administration. At this time citalopram had been eliminated, and citalopram itself could not affect amphetamine metabolism. Other experiments indicated a linear relation between d-amphetamine brain concentration and motility level. Thus, a 50% increase in citalopram-treated rats cannot alone account for 3-fold increase in d-amphetamine-induced motility. Potentiation of d-amphetamine-induced hypermotility was also found after citalopram in a daily dietary dose of 25 mol/kg for 13 days and after oral bolus injection (49 mol/kg twice daily for 14 days). Acute citalopram injection had no effect in any of these models. The results suggest increased responsiveness of dopaminergic mechanisms mediating hypermotility, and decreased sensitivity of dopamine receptors mediating sedation (proposed autoreceptors). Sensitivity of 5-HT receptors was also decreased. The mechanisms by which citalopram induces d-amphetamine supersensitivity as well as subsensitivity to apomorphine and 5-HT agonists are presently unknown, since no changes in dopaminergic and serotonergic receptor binding have been found after an identical dose regimen.     

Up-regulation of β1-adrenergic receptors in rat brain after chronic citalopram and fluoxetine treatments

Quantitative receptor autoradiography was used to study the effects of the selective serotonin reuptake inhibitors citalopram and fluoxetine and the tricyclic antidepressant imipramine on the regulation of ₁-adrenergic receptors in the rat brain. Rats were treated with saline, citalopram (10 mg kg^–1), fluoxetine (10 mg kg^–1), or imipramine (15 mg kg^–1) SC once daily for 14 days. [¹²⁵I]Iodocyanopindolol binding to ₁-adrenergic receptors was found to increase significantly in the caudate-putamen and the somatosensory areas of the frontal cortex after both citalopram and fluoxetine treatments. Imipramine treatment elicited a marked decrease in ₁ binding in the outer laminae of the cingulate cortex, as well as in the motor and somatosensory areas of the frontal cortex. In a separate experiment, rats were treated with saline, citalopram (2.5, 10 and 20 mg kg^–1) or fluoxetine (2.5, 10 and 20 mg kg^–1) SC once daily for 14 days. The effects of citalopram and fluoxetine on ₁ receptors in the somatosensory cortex and caudate-putamen were replicated. These results demonstrate that chronic administration of selective serotonin reuptake inhibitors, in contrast to imipramine, can cause a regional up-regulation of ₁-adrenergic receptors in the rat brain.     

In vivo studies of effects of antidepressants on parotid salivary secretion in the rat

Tricyclic antidepressants (TCA) are well-known xerogenic drugs, while antidepressants such as selective serotonin reuptake inhibitors (SSRI) are considered less xerogenic. The antimuscarinic effect of the TCAs has been considered to be the principal mechanism causing a dry mouth. Although the muscarinic receptor is commonly targeted by xerogenic pharmaceuticals, the salivation reflex arc may be affected at other levels as well. We currently wondered whether or not antidepressants exert an inhibition of the salivary reflex not only at the glandular level but at a central level as well. In this study, the effects of a TCA (clomipramine), a SSRI (citalopram) and a serotonin-noradrenaline reuptake inhibitor (SNRI; venlafaxine) were examined on reflex- (0.5 M citric acid applied on the tongue) and methacholine-evoked salivary secretion. While all three compounds inhibited citric acid-evoked secretion (−40 to −60% at 5 mg/kg i.v. of the antidepressants), only clomipramine inhibited methacholine-evoked secretion (−30% at 5 mg/kg i.v.). On the contrary, both citalopram and venlafaxine increased the methacholine-evoked secretion (+44 to 49%). This was particularly obvious for the salivary protein output (>200%). In the presence of α- and β-adrenoceptor antagonists, the citalopram- and venlafaxine-induced increases were reduced. Thus, antidepressants irrespective of type may exert xerogenic effects by inhibiting the salivary reflex in the central nervous system. However, while TCAs may also hamper the secretory response by antimuscarinic effects, the SSRI and the SNRI groups of pharmaceuticals seem to lack this additional xerogenic mechanism indicating a better therapeutic profile and better opportunities for pharmacological treatment of drug-induced xerostomia.     

安非他酮与西酞普兰治疗老年期抑郁症对照研究

目的观察安非他酮缓释片治疗老年期抑郁症的临床疗效和安全性。方法进行6周的开放式前瞻性随机对照研究,将56名老年期障碍的患者随机分为两组,安非他酮组(26例)和西酞普兰组(30例),疗程6周,采用汉密尔顿抑郁量表(HAMD)和汉密尔顿焦虑量表(HAMA)及副反应量表(TESS)在治疗前和治疗后1、2、4、6周末评定药物疗效和副反应。结果采用t检验,两组HAMD和HAMA总分及各因子分从疗后2~6周均较治疗前显著降低(t=20.45,13.50,6.7,6.06;P均0.01),两组间无显著性差异;治疗结束时TESS评分安非他酮组与西酞普兰组无显著性差异(t=0.23,P0.05)。结论安非他酮缓释片治疗老年期抑郁症的疗效及药物不良反应均与西酞普兰相当,可作为治疗老年期抑郁症的一线药物使用。     

A fatal poisoning case of acetone cyanohydrin and citalopram

Acetone cyanohydrin (ACH) is a readily available source of cyanide and is widely used in basic and applied sciences. In toxicology, ACH is classified as extremely hazardous as it readily decomposes on contact with water, with the potential rapid release of highly toxic hydrogen cyanide (HCN). We report the case of a young woman found dead from the intentional ingestion of ACH and citalopram, an antidepressant of the selective serotonin reuptake inhibitor class. The autopsy findings included bright reddish-purple hypostasis and mild pulmonary edema. As ACH can decompose to acetone and HCN, we quantified the concentration of each compound and thiocyanate separately in various body fluids and organs and determined their whole-body distributions by using gas chromatography–mass spectrometry (GC–MS). We observed high concentrations of both acetone and cyanide in the blood (0.63 mg/mL and 17.99 mM, respectively) and gastric contents (9.76 mg/mL and 472.44 mM). The whole-body distributions of acetone and cyanide were similar (i.e., the concentration of each compound was the highest in the lung, followed by the heart, and then the liver). Our results suggest that not only the route of administration but also the dose taken could greatly affect the body distributions of cyanide in humans. In addition, as toxicological screening detected citalopram, which was not prescribed to the deceased, we performed a chiral analysis by using liquid chromatography–tandem mass spectrometry (LC–MS/MS). We determined that only (S)-citalopram was ingested antemortem; its concentration was 0.36 μg/mL, which is in the toxic range.     

Pharmacogenomic predictors of citalopram treatment outcome in major depressive disorder

Objectives. A significant proportion of patients with major depressive disorder (MDD) do not improve following treatment with first-line antidepressants and, currently, there are no objective indicators of predictors of antidepressant response. The aim of this study was to investigate pre-treatment peripheral gene expression differences between future remitters and non-responders to citalopram treatment and identify potential pharmacogenomic predictors of response. Methods. We conducted a gene expression study using Affymetrix HG-U133 Plus2 microarrays in peripheral blood samples from untreated individuals with MDD (N = 77), ascertained at a community outpatient clinic, prior to an 8-week treatment with citalopram. Gene expression differences were assessed between remitters and non-responders to treatment. Technical validation of significant probesets was carried out by qRT-PCR. Results. A total of 434 probesets displayed significant correlation to change in score and 33 probesests were differentially expressed between eventual remitters and non-responders. Probesets for SMAD 7 (SMA- and MAD-related protein 7) and SIGLECP3 (sialic acid-binding immunoglobulin-like lectin, pseudogene 3) were the most significant differentially expressed genes following FDR correction, and both were down-regulated in individuals who responded to treatment. Conclusions. These findings point to SMAD7 and SIGLECP3 as candidate predictive biomarkers of antidepressant response.