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General anesthesia with Nembutal (40 mg/kg) dramatically decreased the power of all waves of HRV spectrum in rats, especially in LF and VLF frequency bands, but the HR and respiration rate were little changed. At this, individual spectral peaks in HF range were observed at the same frequencies (1.3-1.5 Hz), which are characteristic of the wakeful state. Preliminary stimulation of noradrenergic system with maprotiline (10 mg/kg) increased the power of HF waves and elevated the respiratory rate in narcotized rats in comparison with the control values, although it did not shift the spectral peak at 1.5 Hz in frequency axis. Preliminary stimulation of cholinergic system with galantamine (2 mg/kg) somewhat decreased the power of HF waves and respiratory rate in narcotized rats (in comparison with the control values); additionally, it shifted HF peak to 1.1-1.4 Hz. Activation of serotonergic system with 5-hydroxytryptophan (50 mg/kg) and fluoxetine (3 mg/kg) decreased the HR, the power of HF waves, and respiratory rate in narcotized rats. It also shifted the spectral peak of HF waves to 0.9-0.95 Hz. Preliminary stimulation of dopaminergic system with L-DOPA (20 ml/kg) and amantadine (20 ml/kg) increased the power of VLF waves in narcotized rats in comparison with the control values. Numerous peaks appeared in HF (1.1-1.2 Hz) and VLF frequency bands. Generally, preliminary stimulation of serotonergic or dopaminergic systems markedly affects the neural activity under following general anesthesia: first aggravates the effect of anesthesia on vital centers in CNS, whereas second weakens the effect of anesthesia at the suprasegmental level of neural control.

To reveal the effect and mechanism of Jiaotai Pill (交泰丸, JTP) on insomniac rats. The insomniac model was established by intraperitoneal injection of p-chlorophenylalanine (PCPA). In behavioral experiments, rats were divided into control, insomniac model, JTP [3.3 g/(kg•d)], and diazepam [4 mg/(kg•d)] groups. The treatment effect of JTP was evaluated by weight measurement (increasement of body weight), open field test (number of crossings) and forced swimming test (immobility time). A high performance liquid chromatography-electrochemical detection (HPLC-ECD) method was built to determine the concentration of monoamine transmitters in hypothalamus and peripheral organs from normal, model, JTP, citalopram [30 mg/(kg•d)], maprotiline [40 mg/(kg•d)] and bupropion [40 mg/(kg•d)] groups. Expressions of serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET) were analyzed by quantitative polymerase chain reaction (qPCR) and Western blot in normal, model and JTP groups. A high performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI-MS/MS) method was established to determine the pharmacokinetics, urine cumulative excretion of metformin in vivo, and tissue slice uptake in vitro, which were applied to assess the activity of organic cation transporters (OCTs) in hypothalamus and peripheral organs. Compared with the insomniac model group, the body weight and spontaneous locomotor were increased, and the immobility time was decreased after treatment with JTP (P

Introduction. Tension headache (TH) is the most frequent type of headache. The overall amounts of patients’ disadaptation and social and economic damage caused by TH are more significant than ones caused by migraine. TH diagnostics and treatment are a challenge in outpatient conditions. Aim. To analyze in detail pathogenic mechanisms and chronification factors, and to generalize therapeutic approaches to TH treatment. Materials and methods. Materials from Russian and foreign publications for the last 20 years (PubMed, eLIBRARY and others) as well as clinical guidelines on TH diagnostics and treatment were systematized. Results. According to the results of a population study conducted in Russia in 2009–2011, TH prevalence rate was 30.8% over one year. TH is subdivided into infrequent, frequent and chronic headache. Apart from that, episodic and chronic TH with and without “tension” of pericranial muscles determined by palpation are distinguished. The studies conducted in recent years confirmed neurobiological genesis of TH. Peripheral as well as central mechanisms are involved in its genesis. The main risk factors of TH development include inability of psychological and muscular relaxation and insufficient nocturnal sleep. Emotional stress and pose strain are the most frequent predisposing factors. We thoroughly analyzed data of randomized controlled studies of rapid relief of TH symptoms and identified the most frequently used medications among which ketoprofen (Ketonal®) occupies an important place. Chronic or frequent episodic TH is indication for TH prevention therapy prescription. Antidepressants such as amitriptyline are considered the first choice medications for chronic TH treatment, mirtazapine and venlafaxine are of lower effectiveness. The third choice therapy includes other tricyclic and tetracyclic antidepressants, clomipramine, maprotiline, and mianserine. Effectiveness of muscle relaxant tizanidine use, dosage and duration of its use in TH treatment, possibilities of monotherapy and combination with antidepressants are discussed. Among non-pharmacological treatment methods biofeedback and cognitive behavior therapy are considered the most effective ones. Conclusion. Combination therapy, including non-pharmacological treatment methods along with pharmacotherapy, remains the most effective method of TH treatment.

Few studies have examined the relationship between the use of antidepressants and the onset of hyperglycemia and diabetes mellitus in Japan. We herein explored the possibility of this relationship using the Japanese Adverse Drug Event Report database (JADER). The present study included 20 individual antidepressants, consisting of 6 subclasses, which have been approved for use in Japan. We used Standardized MedDRA Queries 20000041 to extract patients who developed hyperglycemia/new onset diabetes mellitus (NODM) in JADER between April 2004 and September 2016. We calculated reporting odds ratios (RORs) with 95% confidence intervals (CI). We also calculated odds ratios defined as the ratio of odds of hyperglycemia/NODM to all other adverse drug events (ADEs) by the age cut-off group or sex in the cases of antidepressants. The lower limit of 95%CI of RORs for 13 antidepressants (imipramine, clomipramine, nortriptyline, amitriptyline, amoxapine, maprotiline, mianserin, sertraline, paroxetine, escitalopram, duloxetine, mirtazapine, and trazodone), which included all subclasses, exceeded 1. Younger age group was associated with hyperglycemia/NODM for 5 antidepressants (imipramine, amitriptyline, maprotiline, duloxetine, and trazodone), and female was associated with the ADEs for trazodone, although these results should be interpreted cautiously. Healthcare personnel need to be aware that the use of antidepressants may lead to hyperglycemia/NODM.

The prefrontal cortex is essential for executive functions such as decision-making and planning. There is also accumulating evidence that it is important for the modulation of pain. In this study, we investigated a possible role of prefrontal cortical calcium-independent phospholipase A2 (iPLA2) in antinociception induced by the norepinephrine reuptake inhibitor (NRI) and tetracyclic (tricyclic) antidepressant, maprotiline. Intraperitoneal injections of maprotiline increased iPLA2 mRNA and protein expression in the prefrontal cortex. This treatment also reduced grooming responses to von-Frey hair stimulation of the face after facial carrageenan injection, indicating decreased sensitivity to pain. The antinociceptive effect of maprotiline was abrogated by iPLA2 antisense oligonucleotide injection to the prefrontal cortex, indicating a role of this enzyme in antinociception. In contrast, injection of iPLA2 antisense oligonucleotide to the somatosensory cortex did not reduce the antinociceptive effect of maprotiline. Lipidomic analysis of the prefrontal cortex showed decrease in phosphatidylcholine species, but increase in lysophosphatidylcholine species, indicating increased PLA2 activity, and release of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) after maprotiline treatment. Differences in sphingomyelin/ceramide were also detected. These changes were not observed in maprotiline-treated mice that received iPLA2 antisense oligonucleotide to the prefrontal cortex. Metabolites of DHA and EPA may help to strengthen a known supraspinal antinociceptive pathway from the prefrontal cortex to the periaqueductal gray. Together, results indicate a role of prefrontal cortical iPLA2 and its enzymatic products in the antinociceptive effect of maprotiline.

Cutaneous adverse drug reactions (CADRs) in patients with psychotropic drugs are common. Large studies on the relevant drugs and other risk factors are still scarce. 594 cases of severe CADRs ("cases") were compared with 8085 cases of other adverse drug reactions ("non-cases") documented in a pharmacovigilance program in psychiatry (AMSP) from 1993 to 2014. Logistic regression was carried out to determine risk factors and between-drug differences. CADRs were relatively more prevalent in patients treated with clomipramine, maprotiline, carbamazepine, lamotrigine, acamprosate, clomethiazole and disulfiram as well as with antidepressants and anticonvulsants as drug classes (p

Antidepressant drugs may have proconvulsant effects. Psychiatric comorbidity in epilepsy is common. Prescribers might be reluctant to initiate treatment with antidepressants in fear of seizure aggravation. The purpose of this review was to focus upon the current evidence for proconvulsant effects of antidepressants and possible clinical implications. Most antidepressants are regarded as safe and may be used in patients with epilepsy, such as the newer serotonin and/or noradrenaline reuptake inhibitors. Four older drugs should, however, be avoided or used with caution; amoxapine, bupropion, clomipramine and maprotiline. Proconvulsant effects are concentration-related. Optimization of drug treatment includes considerations of pharmacokinetic variability to avoid high serum concentrations of the most proconvulsant antidepressants. The risk of seizures is regarded as small and should, therefore, not hamper the pharmacological treatment of depression in people with epilepsy.

Background Sleep is one of the most essential processes required to maintain a healthy human life, and patients experiencing psychiatric illness often experience an inability to sleep. The aim of this study is to test the hypothesis that antidepressant compounds with strong binding affinities for the serotonin 5-HT2C receptor, histamine H1 receptors, or norepinephrine transporter (NET) will be associated with the highest odds of somnolence. Methods Post-marketing cases of patient adverse drug reactions were obtained from the United States Food and Drug Administration Adverse Events Reporting System (FAERS) during the reporting window of January 2004 to September 2019. Disproportionality analyses of antidepressants reporting somnolence were calculated using the case/non-case method. The reporting odds-ratios (ROR) and corresponding 95% confidence interval (95% CI) were computed and all computations and graphing conducted in R. Results There were a total of 69,196 reported cases of somnolence out of a total of 7,366,864 cases reported from January 2004 to September 2019. Among the 30 antidepressants assessed, amoxapine (n = 16) reporting odds-ratio (ROR) = 7.1 (95% confidence interval [CI] [4.3–11.7]), atomoxetine (n = 1,079) ROR = 6.6 (95% CI [6.2–7.1]), a compound generally approved for attention deficit hyperactivity disorder (ADHD), and maprotiline (n = 18) ROR = 6.3 (95% CI, 3.9–10.1) were the top three compounds ranked with the highest reporting odds of somnolence. In contrast, vortioxetine (n = 52) ROR = 1.3 (95% CI [1.0–1.8]), milnacipran (n = 58) ROR = 2.1 (95% CI [1.7–2.8]), and bupropion (n = 1,048) ROR = 2.2 (95% CI [2.1–2.4]) are least significantly associated with somnolence. Moreover, levomilnacipran (n = 1) ROR = 0.4 (95% CI [0.1–2.9]) was not associated with somnolence. Conclusion Among the thirty tested antidepressants, consistent with the original hypothesis, amoxepine has strongest 5-HT2C receptor binding affinity and has the highest reporting odds of somnolence. Atomoxetine, ranked second in reporting odds of somnolence overall, binds to the NET with with the strongest binding affinity among the thirty compounds. Mirtazapine, a tetracyclic antidepressant, was ranked 11th in reporting odds of somnolence and had the strongest H1 receptor binding affinity. This study provides an informative ranking of somnolence among thirty antidepressant compounds with an already wide array of clinical indications as well as provides insight into potential drug repurposing in psychopharmacology.

OBJECTIVE To evaluate the efficacy and tolerability of dose increase compared to dose continuation of the initially prescribed antidepressant in antidepressant treatment failure (ATF). DATA SOURCES We searched CENTRAL, PubMed, Embase, and PsycINFO using generic terms for depression, dose increase, and randomized controlled trials (RCTs), without date or language restrictions. STUDY SELECTION Of 1,780 studies screened, 9 studies reporting on 1,273 patients were included for meta-analysis (PROSPERO Registration: CRD42017058389). Studies met the following predetermined inclusion criteria: randomized controlled trial, patients diagnosed with unipolar depression according to a standardized diagnostic instrument, ATF after a standard antidepressant trial (duration of ≥ 3 weeks at a standard dose), dose increase regimen, and control group of dose continuation. DATA EXTRACTION Two authors extracted data independently according to the Cochrane Handbook for Systematic Reviews. Analyses are based on random effects models. RESULTS All studies reported on selective serotonin reuptake inhibitors (SSRIs); 1 study also reported on maprotiline. Meta-analyses resulted in a statistically nonsignificant summary effect size of 0.053 standardized mean difference (95% CI, -0.143 to 0.248) in favor of antidepressant dose increase. Subgroup and sensitivity analyses and secondary outcome analyses resulted in similar effect estimates and supported the robustness of the results. CONCLUSIONS With clinically and statistically nonsignificant effect estimates, there is evidence from RCTs against increasing the dose of SSRIs (with the possible exception of citalopram) in adult patients with major depression and ATF. Dose increase with other antidepressants (eg, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors) and in other patient groups (minor depression, children and adolescents) or after long periods of first-line antidepressant therapy (ie, 8 weeks) have not been or not been sufficiently studied and, at this time, cannot be recommended in clinical practice.

What is known and objectives: Multiple adverse drug reactions (ADRs) are expected, and thus should be prevented in the elderly comorbid patient on polypharmacy. Rosuvastatin is commonly prescribed for the treatment and prevention of atherosclerotic diseases, and in rare cases, is associated with rhabdomyolysis. Maprotiline is a tetracyclic antidepressant, infrequently used in the United States, but seemingly more broadly in European countries. Acute colonic pseudo-obstruction (Ogilvie's syndrome) caused by maprotiline has thus far, to our knowledge, not yet been described in the literature. Case summary We present a unique case of synchronous rhabdomyolysis and Ogilvie's syndrome in an 80-year-old lung cancer survivor following a recent ischemic stroke for which she was prescribed clopidogrel and rosuvastatin for secondary prevention, and maprotiline for post-stroke, new-onset insomnia and anxiety. The ADRs resolved on removal of the offending agents and initiation of conservative treatment. Retrospective pharmacogenetic testing of the patient's drug-metabolizing enzymes and transporters was performed to guide further management and prevent future potential drug interactions and ADRs. What is novel and conclusions: This is an interesting, albeit unfortunate, complex case that depicts the risk of rare adverse effects to medications and their potential relationship to pharmacogenetics. The impact of anticholinergic side effects of antidepressants on gastrointestinal motility, risk of myopathies with statins, increased susceptibility to ADRs caused by drug-drug interactions, and the utility of pharmacogenomic testing are discussed. The question whether commercially available pharmacogenomic tools are relevant for everyday use to direct patient care and reduce harmful drug-drug interactions is addressed and warrants further research. .

Calcium-independent phospholipase A2 (iPLA2) is an 85-kDa enzyme that releases docosahexaenoic acid (DHA) from glycerophospholipids. DHA can be metabolized to resolvins and neuroprotectins that have anti-inflammatory properties and effects on neural plasticity. Recent studies show an important role of prefrontal cortical iPLA2 in hippocampo-prefrontal cortical LTP and antidepressant-like effect of the norepinephrine reuptake inhibitor (NRI) antidepressant, maprotiline. In this study, we elucidated the cellular mechanisms through which stimulation of adrenergic receptors could lead to increased iPLA2 expression. Treatment of SH-SY5Y neuroblastoma cells with maprotiline, another tricyclic antidepressant with noradrenaline reuptake inhibiting properties, nortriptyline, and the adrenergic receptor agonist, phenylephrine, resulted in increased iPLA2β mRNA expression. This increase was blocked by inhibitors to alpha-1 adrenergic receptor, mitogen-activated protein (MAP) kinase or extracellular signal-regulated kinase (ERK) 1/2, and sterol regulatory element-binding protein (SREBP). Maprotiline and phenylephrine induced binding of SREBP-2 to sterol regulatory element (SRE) region on the iPLA2 promoter, as determined by electrophoretic mobility shift assay (EMSA). Together, results indicate that stimulation of adrenoreceptors causes increased iPLA2 expression via MAP kinase/ERK 1/2 and SREBP, and suggest a possible mechanism for effect of CNS noradrenaline on neural plasticity and crosstalk between sterol and glycerophospholipid mediators, that may play a role in physiological or pathophysiological processes in the brain and other organs.

The effects of intraperitoneal DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, a noradrenergic neurotoxin) and maprotiline (an inhibitor of norepinephrine reuptake in synapses) on spectral components of heart rhythm variability were examined in outbred male and female rats treated with these agents in daily doses of 10 mg/kg for 3 days. At rest, DSP-4 elevated LF and VLF spectral components in male and female rats. Maprotiline elevated LF and VLF components in males at rest, increased HR and reduced all spectral components in resting females. Stress against the background of DSP-4 treatment sharply increased heart rate and reduced the powers of all spectral components (especially LF and VLF components). In maprotiline-treated rats, stress increased the powers of LF and VLF components. Thus, the central noradrenergic system participates in the formation of LF and VLF spectral components of heart rate variability at rest and especially during stressful stimulation, which can determine the phasic character of changes in the heart rate variability observed in stressed organism.

We studied heart rate variability and β-adrenergic responsiveness of erythrocytes and changes in these parameters in response to single administration of β-adrenoblocker propranolol (2 mg/kg) in outbred male rats against the background of activation of the noradrenergic, serotonergic, and dopaminergic neurotransmitter systems achieved by 4-fold injections maprotiline (10 mg/kg), 5-hydroxytryptophan (50 mg/kg) combined with fluoxetine (3 mg/kg), and L-DOPA (20 mg/kg) with amantadine (20 mg/kg), respectively. Stimulation of the noradrenergic system moderately enhanced the heart rhythm rigidity and β-adrenergic responsiveness of erythrocytes. In addition, it markedly augmented the moderating effect of subsequently administered propranolol on LF and VLF components in the heart rate variability and reversed the effect of propranolol on β-adrenergic responsiveness of erythrocytes. Stimulation of the serotonergic system dramatically decreased all components in the heart rate variability and pronouncedly enhanced β-adrenergic responsiveness of erythrocytes. Subsequent injection of propranolol slightly restored all components in the heart rate variability and decreased β-adrenergic responsiveness of erythrocytes to the control level. Stimulation of the dopaminergic system made the heart rate more rigid due to decrease of all components in the heart rate variability; in addition, it slightly but significantly enhanced β-adrenergic responsiveness of erythrocytes. Subsequent injection of propranolol produced no significant effects on all components in the heart rate variability and on β-adrenergic responsiveness of erythrocytes. Stimulation of noradrenergic, serotonergic, and dopaminergic neurotransmitter systems produced unidirectional and consorted effects on heart rate variability and β-adrenergic responsiveness of erythrocytes, although the magnitudes of these effects were different. Probably, the changes in the heart rate variability in rats with stimulated neurotransmitter systems results from modification of the cellular sensitivity in peripheral organs to adrenergic influences. However, the differences in the reactions to β-adrenoblocker attest to specificity of the mechanisms underlying the changes in membrane reception and adrenergic pathways in every experimental model employed in this study.

Around 20 % of people with intellectual disability (ID) develop epileptic seizures. ID is a risk factor for the development of epileptic seizures also in patients with autism (21.5 % vs 8 % in the general population). In both these conditions generalized seizures are more common than partial seizures. The incidence of epilepsy is four to seven times higher in patients with depression than in the general population. Epilepsy and depression share an unusually high co-occurrence leading to a common etiology. A lifetime history of depression is also associated with a worse seizure outcome even after anterior temporal lobectomy. Patients treated with an antidepressant have a 50 % reduction in the occurrence of seizures. Epilepsy and bipolar disorder also could share a number of biochemical and pathophysiological underpinnings, even though the current literature is scarce. Patients with schizophrenia have an 11-fold increase in the prevalence of comorbid epilepsy. At therapeutic doses, drugs with high epileptogenic potential include clozapine and phenothiazines; drugs with intermediate epileptogenic potential include maprotiline and tricyclic antidepressants, while drugs with low epileptogenic potential include bupropion. The antidepressants with higher seizure potential after overdose are imipramine, desipramine, nortriptyline, maprotiline, and bupropion.

Alterations in cardiac function were observed in antidepressants treated patients and published in several clinical reports. These detected changes could be either a consequence of the treatment or of depression itself, which has already been proved to be a risk factor in heart diseases. In order to determine a possible influence of chronic treatment with norepinephrinergic reuptake inhibitor, maprotiline, on the heart, we investigated gene expression of cardiac β-adrenoceptors both in controls and in animals with signs of depression. The rats were divided into two groups, unstressed controls and those exposed to chronic unpredictable mild stress (CUMS). The groups were further divided into two subgroups, one receiving daily intraperitoneal injections of vehicle (sterile water) and another one maprotiline (10 mg/kg) for four weeks. Tissue samples were collected after the last application. Gene expression of cardiac β1- and β2-adrenoceptor was determined using Real-time RT-PCR analysis. Our results show that in control animals expression of both adrenoreceptors was decreased in the right atria after 4 weeks of maprotiline application. Contrary, the same treatment led to a significant increase in expression of cardiac β1-adrenoceptor in the stressed rats, with no change in the characteristics of β2-adrenoceptor. Our findings might reflect the that molecular mechanisms are underlying factors involved in the development of cardiovascular diseases linked with antidepressant treatment. Vários relatórios clínicos observaram alterações de funcionamento cardíaco de pacientes depressivos que foram tratados com os antidepressivos. As alterações detectadas podem ser consequência do tratamento ou, por outro lado, da depressão que, como se tem provado, é um fator de risco no caso de doenças cardíacas. De modo a determinar a possível influência de tratamento crônico com o inibidor da recaptação de norepinefrina, maprotilina, no coração, foi investigada a expressão do gene aos receptores β-adrenérgicos cardíacos dos animais em grupos de controle e em grupos com sinais de depressão. Os ratos foram divididos em grupos de controle não estressados e os grupos de ratos submetidos ao estresse crônico moderado imprevisível (CUMS). Os grupos foram, ainda, divididos em dois subgrupos, que, durante quatro semanas, diariamente receberam injeções intraperitoneais de placebo (água estéril) ou de maprotilina (10 mg/kg). As amostras de tecido foram coletadas após a última aplicação. A expressão do gene aos receptores adrenérgicos β1 e β2 foi determinada utilizando a análise PCR quantitativa em tempo real (RT-PCR). Os nossos resultados demonstram a diminuição de expressão dos ambos os receptores adrenérgicos no átrio direito dos animais do grupo de controle depois de quatro semanas de aplicação de maprotilina. Em contraste, o mesmo tratamento conduziu ao aumento significativo na expressão do receptor β1-adrenérgico no coração dos ratos estressados, sem qualquer alteração nas características do receptor β2-adrenérgico. Estes resultados podem refletir os mecanismos moleculares envolvidos no desenvolvimento de doenças cardiovasculares associadas ao tratamento com os antidepressivos.

Background/Aim. Antidepressants are a widely used class of drugs. The aim of this study was to investigate different aspects of antidepressant prescribing practice at University Psychiatric Clinic in Belgrade. Methods. This cross-sectional study was carried out by retrospective analysis of the patient's medical charts. The study included all patients with antidepressant prescribed at discharge during 2009 (n = 296). The evaluation was focused on patient- related factors (socio-demographic and illness related), psychiatrist-related factors (sex and duration of working experience) and drug related factors (type of antidepressant, dose, polypharmacy and reimbursement by national health insurance). Results. Antidepressants were prescribed for unipolar depression (F32-34, ICD X) either without comorbidity (46.2%) or with comorbidity (24.7%), mostly as a monotherapy (91% had one antidepressant), to the patients who were 65% female, aged 50.1 ± 8.9, most of them with 12 years of education (52.6%), married (69.3%) and employed (55.9%). The majority of patients had a history of two hospitalizations (Med 2; 25th-75th perc. 1-4) during nine years (Med 9; 25th-75th perc. 2-15) after the first episode of depression. Among them, 19% were found to be suicidal in a lifetime. The single most prescribed antidepressant was sertraline (20.4%), followed by fluoxetine (13.3%) and maprotiline (11.7%). Utilization of antidepressants was positively correlated with the rate of reimbursement (p < 0.01). The most prescribed antidepressant group was selective serotonin reuptake inhibitors (SSRI) (47.8%), followed by tricyclic antidepresants (TCA) (25.3%) and new antidepressants - venlafaxine, tianeptine, mirtazapine, bupropion, trazodone (15.1%). Most of the drugs were prescribed in doses which are at the lower end of the recommended dose-range. Regarding severity of the actual depressive episode, TCA were prescribed for severe depression with psychotic features, while SSRI were choice for episodes with moderate symptom severity (p = 0.01). Psychiatrists with longer working age (20-30 years) hesitated to prescribe new antidepressants in comparison to younger colleagues (p = 0.01). Conclusion. Economic issues in Serbia as developing country influence the choice of antidepressants, as well as a psychiatrist’s working age and severity of depression. However, SSRI are the drugs of the first choice, as it was shown in most of the developed countries nowadays.

Background Cholinergic urticaria is uncommon and accounts for 10% of all young adults. To date, there is no effective therapy for cholinergic urticaria.Objective To determine the therapeutic efficacy of different drug combinations in the treatment of cholinergic urticaria.Patients and Methods The participants included in the study are in the age range of 16 to 29 years, with cholinergic urticaria of any duration as diagnosed by physicians. Patients were recruited from Asthma and Allergy Centers in Baghdad and Tikrit. The selected patients were divided randomly into 3 groups according to the treatment protocol. All patients completed screening before treatment.Results The study indicated that cholinergic urticaria was completely controlled in 30.4% of patients (group A) receiving 4 mg of chlorpheniramine maleate, half hour before the exercise, plus chlordiazopoxide (5 mg) and clindium bromide (2.5 mg) tablets, 3 times daily. However, cure rate was higher (83.1%) in patients (group B) receiving 4 mg of chlorpheniramine maleate (histadine), 3 times daily, plus 25 mg of maprotiline HCl (ludiomil), once daily at night. Furthermore, the complete cure rate was 85.4% in patients (group C) receiving 4 mg of chlorpheniramine maleate (histadine)3 times daily, plus 200 mg of cimetidine (tagadine), 3 times daily. The frequency of relapse was higher in group A (89%) as compared with group B (68.4%) and group C (23.5%) (P

There is increasing interest in the pathophysiology and neurochemistry of the prefrontal cortex (PFC) in depression. Blood flow and metabolism are decreased in the PFC of patients with depression compared to controls. Changes in long-chain polyunsaturated fatty acids (PUFAs) are also associated with depression. This study was conducted to elucidate a possible role of PFC activity of an enzyme involved in the release of docosahexaenoic acid (DHA), i.e. calcium-independent phospholipase A2 (iPLA₂), in the effects of the norepinephrine reuptake inhibitor (NRI) antidepressant, maprotiline, in mice. Treatment of Balb/C mice with maprotiline for 4 wk resulted in reduction in the level of behavioural despair, as determined by decreased immobility and increased climbing during the forced swim test. In contrast, mice treated with maprotiline plus bilateral prefrontal cortical injections of antisense oligonucleotide to iPLA₂, showed significantly increased immobility and decreased climbing, to levels comparable to saline-treated controls, indicating abolishment of the antidepressant-like effect of maprotiline. Lipidomic analyses showed significant decreases in phosphatidylcholine species containing long-chain PUFAs and increases in lysophosphatidylcholine after maprotiline treatment, indicating increased PLA₂ activity and endogenous release of eicosapentaenoic acid (EPA) or DHA after maprotiline treatment. These changes in lipid profiles were absent in mice that received maprotiline and PFC injections of antisense oligonucleotide to iPLA₂. Together, the results indicate that PFC iPLA₂ activity plays an important role in the antidepressant-like effect of maprotiline, possibly through endogenous release of long-chain PUFAs.

Recent clinical studies have suggested a risk of adverse gastric reactions from the concomitant use of selective serotonin (5-HT) reuptake inhibitors (SSRIs) with nonsteroidal anti-inflammatory drugs (NSAIDs). We examined the adverse effects of SSRIs on antral lesions produced by indomethacin in rats. Rats fasted for 24 h were refed for 1 h, then administered indomethacin (30 mg/kg s.c.) 1 h after the refeeding and killed 6 h later. Paroxetine (1-10 mg/kg) was given orally 30 min before indomethacin. Indomethacin caused antral lesions in refed rats. Paroxetine dose-dependently aggravated these lesions, despite provoking no damage by itself. Similar results were obtained when other NSAIDs such as diclofenac, flurbiprofen, and loxoprofen were coadministered with paroxetine or when indomethacin was coadministered with other antidepressants such as fluvoxamine and milnacipran, but not imipramine or maprotiline. Exogenous 5-HT also worsened the indomethacin-induced antral damage, whereas the aggravating effect of paroxetine was attenuated by ondansetron, a selective 5-HT(3) antagonist, but not antagonists for other 5-HT receptor subtypes. Indomethacin plus paroxetine had no effect on gastric secretion but significantly decreased mucosal superoxide dismutase (SOD) activity as well as GSH content. The antral damage induced by indomethacin plus paroxetine was significantly prevented by antisecretory (acid or pepsin) agents and mucosal protective agents as well as SOD and allopurinol. These results suggest that SSRIs aggravate NSAID-induced antral lesions, probably via the activation of 5HT(3) receptors, and the mechanism of aggravation may involve the corrosive action of acid/pepsin as well as an impaired antioxidative system.

Aim of the review Although there are several case reports in literature linking use of antidepressants and disturbances in glucose control, it is difficult to identify risk factors for serious adverse drug events from individual case reports. The aim of this review is to provide a descriptive analysis of the demographic and clinical characteristics of published glucose dysregulation case reports following initiation of antidepressant agents. Methods Published case reports of glucose dysregulation associated with antidepressants were accessed through PubMed (Medline), PsycINFO, and Web of Science (WOS) between January 1, 1970 and April 30, 2010. The following key words were used: antidepressant agents, glucose dysregulation, hypoglycemia, hyperglycemia, diabetes mellitus, and diabetic ketoacidosis. Case reports were excluded if glucose dysregulation occurred after a drug overdose/improper dosing or after the patient was prescribed drugs known to cause glucose disturbances in addition to antidepressant agents. Results Out of the 17 cases reports reviewed, nine (53%) were of hyperglycemia while eight (47%) were of hypoglycemia. Hyperglycemia was reported following treatment with clomipramine, fluvoxamine, imipramine, mianserin, mirtazapine, paroxetine, and sertraline. Hypoglycemia was reported following treatment with doxepine, fluoxetine, imipramine, nefazodone, nortriptyline, maprotiline, and sertraline. Fourteen out of the seventeen patients were female (82%) while ten had a history of diabetes mellitus (59%). The average age of the patients was 53.9 (SD = 17.5) years (range: 24–84 years). The time to onset of glucose dysregulation ranged from 4 days to 5 months after initiation of antidepressant therapy. More than two-thirds (68%) of the cases (n = 11) reported glucose control disturbances within 1 month of therapy. Conclusions It is not clear from published case reports whether changes in glucose regulation, following antidepressant therapy initiation are due to antidepressants or changes in mood and lifestyle. Nonetheless, healthcare providers should be aware of the potential changes in glucose regulation especially in the first month of antidepressant therapy, and use appropriate clinical and laboratory monitoring to prevent serious adverse events in patients at risk.

Noradrenaline exerts inhibitory effects on seizure susceptibility. Subtype selective agonists and antagonists were used to identify the anticonvulsant hippocampal adrenoreceptors. Intrahippocampal dialysis was used for administration of all compounds, including pilocarpine for limbic seizure induction, and as the neurotransmitter sampling tool. The noradrenaline reuptake inhibitor maprotiline mediated anticonvulsant effects, associated with dose-dependent increases in extracellular hippocampal noradrenaline, dopamine and GABA levels. At high concentrations, maprotiline produced proconvulsant effects associated with high levels of noradrenaline, dopamine and glutamate. Maprotiline's anticonvulsant effect was blocked by administration of either a selective α(2) - and β(2) -antagonist. α(2) -Antagonist administration with maprotiline was associated with a further increase in noradrenaline and dopamine from maprotiline alone; whereas β(2) -antagonist administered with maprotiline inhibited the dopamine increases produced by maprotiline. α(1A) -Antagonism blocked the GABA-ergic but not the anticonvulsive effect of maprotiline. These results were confirmed as combined but not separate α(2) - and β(2) -adrenoreceptor stimulation, using selective agonists, inhibited limbic seizures. Interestingly, α(1A) -receptor stimulation and α(1D) -antagonism alone also inhibited seizures associated with respectively significant hippocampal GABA increases and glutamate decreases. The main findings of this study are that (i) increased hippocampal noradrenergic neurotransmission inhibits limbic seizures via combined α(2) - and β(2) -receptor activation and (ii) α(1A) - and α(1D) -adrenoreceptors mediate opposite effects on hippocampal excitability.

1 Repeated maprotiline (a noradrenaline reuptake inhibitor) and fluoxetine (a serotonin reuptake inhibitor) treatment on gene expression of catecholamine biosynthetic enzymes were examined in adrenal medulla of unstressed control and chronic unpredictable mild stressed rats. 2 Maprotiline did not change gene expression of catecholamine biosynthetic enzymes in control and stressed rats. 3 Fluoxetine increased gene expression of tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DBH), but did not phenylethanolamine N-methyltransferase in both unstressed and chronic unpredictable mild stressed animals. 4 In conclusion, we have demonstrated that repeated administration of fluoxetine enhanced gene transcription of TH and DBH and subsequently stimulates noradrenaline synthesis in adrenal medulla of control and stressed rats.

The acute effects of single oral doses of antidepressants, maprotiline and amoxapine on serum levels of prolactin (PRL), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were studied in six normally cycling women. After oral administration of 25 mg maprotiline, no significant increase was observed in serum PRL levels, but PRL levels increased significantly (p

BackgroundMany patients discontinue antidepressant therapy long before the six-month minimum duration recommended for the treatment of major depression and many other diagnoses.PurposeTo estimate the duration of antidepressant treatment and to analyse the following factors in relation to treatment adherence: age, sex, polypharmacy and type of drug.MethodsRetrospective cohort followed up for five years (2003–2007) based on prescription database. Selection criteria: Users who had received at least one antidepressant prescription in 2003 and who had not received antidepressants during the previous 12 months.Variables studiedAge, sex, drug, polypharmacy, period of treatment, packs dispensed. Adequate adherence was defined as dispensation of medication during at least 80% of the treatment period, and compliance was defined as good when, in addition, the treatment lasted more than four months.ResultsOf the 7525 patients selected, 56% abandoned medication during the first four months. Men were more likely to give up medication before time than women. Good compliance was recorded in 22% of patients and was twice as frequent in patients with high levels of polypharmacy than in those with low levels (31% vs. 15.3%). Patients receiving maprotiline, venlafaxine, mirtazapine, citalopram, clomipramine and fluoxetine presented the highest percentages of good compliance.ConclusionsOnly one out of five patients complied with treatment for over four months. Treatment periods were shorter in men. In chronic processes, patients receiving polypharmacy presented the best compliance.

Influence of previous stress exposure on the effects of serotonergic and noradrenergic antidepressants on subsequent newly induced stress is still far from being completely understood. The aim of the present study was to investigate changes in the activity of the sympatho-adrenomedullary system in unstressed and chronic unpredictable mild stressed (CUMS) rats treated with either maprotiline or fluxilan, both under basal conditions and subsequent immobilization stress. Maprotiline and fluxilan elevated plasma norepinephrine in unstressed control and CUMS rats. Immobilization increased norepinephrine less in unstressed maprotiline- or fluxilan controls than in vehicle group. Subsequent immobilization elevated norepinephrine in CUMS rats the differences between the groups being insignificant. Maprotiline didnt affect epinephrine in unstressed and CUMS rats and fluxilan increased it. Subsequent immobilization elevated epinephrine in unstressed maprotiline controls less than in vehicle animals. Epinephrine increase was similar in maprotiline CUMS and vehicle CUMS rats. Immobilization of fluxilan unstressed and CUMS rats significantly increased epinephrine but without differences compared to vehicle group. Novel stressor activated sympatho-adrenomedullary system of CUMS rats upon antidepressants. (c) 2008 Elsevier B.V. All rights reserved.

Serotonin and noradrenaline are involved in the mechanisms of action of most antidepressant drugs. We examined the effects of chronic treatment with maprotiline, a selective inhibitor of noradrenaline reuptake, and fluxilan, a selective inhibitor of serotonin reuptake, on the behavior of unstressed controls and chronic unpredictable mild stress (CUMS) model rats in the forced swim test (FST) and elevated plus maze test. Both selective reuptake inhibitors resulted in a significant reduction of time spent in immobility. Climbing was significantly increased in maprotiline- and swimming was exclusively elicited in the fluxilan-treated unstressed control and CUMS rats. Maprotiline-treated ani?mals displayed decreased anxiety and fluxilan-treated rats enhanced anxiety. The obtained results suggest that central noradrenergic and serotonergic systems might be affected differently during FST. The results also demonstrate that the anxiogenic effects of chronic fluxilan treatment are similar to those reported by many other studies. These differences observed for the effects of fluxilan in relation to those reported for maprotiline and probably due to the different phar?macological profiles of these drugs.

To investigate the effects of antidepressants on glucose-insulin homeostasis, we provided homogenous situation and performed standard procedures to assess the interactions of antidepressants and glucose regulation during hospitalization.Twenty-three non-diabetic depressed males were recruited and assigned to two groups based on the antidepressants received (maprotiline n=11, fluoxetine n=12). The severity of depression was evaluated using a 21-item Hamilton depression rating scale (HAM-D). Before and after the 4-week treatment, participants underwent 75-g oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIGT). Insulin sensitivity (SI), glucose effectiveness (SG), acute insulin response (AIR), and disposition index (DI) were estimated using minimal model method.The HAM-D scores were reduced significantly (P0.005) after antidepressant treatment. Following maprotiline treatment, the body weight and BMI were significantly increased (P=0.02). Individuals treated with maprotiline displayed a significantly increased AIR (3239+/-682 vs. 4698+/-597 pmol; P=0.04) during the FSIGT.The sample size was limited. Furthermore, the study was conducted in the early phase of depression-treated course.The results suggest that the beta-cell function is hyperbolic in order to offset the insulin resistance following maprotiline treatment. Our findings imply that norepinephrine reuptake inhibitor (NRI) antidepressants might attenuate insulin sensitivity.

Substance P (SP) is possibly involved in the pathophysiology of depression and anxiety. We investigated interactions between antidepressants on SP-induced effects and their potential calcium-blocking activity in the isolated guinea pig ileum. All the antidepressants tested, except pargyline, moclobemide, mianserin, and reboxetine, were able to inhibit in a concentration-dependent manner the contraction induced by 100 nmol/L SP. Clomipramine, fluoxetine, maprotiline, and amitriptyline (all at 3 μmol/L) flattened the concentration–response curves to SP, resulting in a reduction of up to 59%, 63%, 32%, and 23%, respectively, of the maximum contractile effect. All the antidepressants tested (3 μmol/L), except pargyline, moclobemide, and mianserin, produced a rightward parallel shift of the concentration–response curve to CaCl2. The L-type selective calcium blocker nifedipine and the T-type selective mibefradil showed similar behaviour against both agonists used, SP and CaCl2. The relative order of potency was nifedipine (pA2, 7.6 ± 0.1) > clomipramine (pA2, 7.0 ± 0.1) > fluoxetine (pKB, 6.5 ± 0.1) = mibefradil (pKB, 6.6 ± 0.1) > amitriptyline (pKB, 6.3 ± 0.1) = maprotiline (pKB, 6.2 ± 0.1) > fluvoxamine (pKB, 5.9 ± 0.1). The data reported in the present study suggest that the antidepressants tested did not behave as competitive antagonists versus NK1-receptor subtypes, but their inhibitory action seems to be related to their calcium-blocking properties.

The present study was undertaken to investigate the spontaneous epileptiformic activity induced by antidepressants using amygdala-kindled rats. The intraperitoneal injection of imipramine and amitriptyline resulted in potent behavioral and electroencephalogram (EEG)-detected seizures in amygdala-kindled rats compared with those seen in sham rats (non-kindled rats). Almost the same findings were observed with clomipramine and maprotiline. On the other hand, paroxetine caused no or little behavioral or EEG seizures in either amygdala-kindled or sham rats, even at a dose of 50 mg/kg. In conclusion, our results indicate that epileptiformic activity induced by kindling increases the susceptibility to cyclic antidepressant-induced seizures.

Objective: To describe and compare general practitioners’ (GPs) opinions on antidepressant drugs and their prescriptions to depressed patients. Method: Between November 2000 and July 2001 a representative sample of French GPs was asked their opinion of the 15 most prescribed antidepressants, and then to describe the treatments of the current depressive episode of four depressive patients each, their changes and the reasons thereof. Results: One hundred and eighty-one GPs and 778 patients participated. The best-ranked antidepressants by the GPs were paroxetine, fluoxetine, sertraline and clomipramine for efficacy, and paroxetine, tianeptine, sertraline and fluoxetine for tolerability. In patients, the drugs most often prescribed were fluoxetine, paroxetine, and sertraline. Those least often stopped for intolerance were moclobemide (0%), dosulepine (0%), venlafaxine (4.5%) and citalopram (5.0%), and maprotiline (0%), citalopram (1.7%) and venlafaxine (2.3%) for lack of efficacy. The best predictor for prescription of antidepressants was the GPs’ overall ranking, itself depending on opinions of the tolerability and efficacy of the drug. However, opinions of tolerability and efficacy were not related to the rates of treatment discontinuation for intolerability or inefficacy. Conclusion: Prescriber opinion does not seem related to actual product performance.

The importance of signal transduction processes beyond receptors involving receptor-G protein coupling, in both the pathophysiology and the treatment of mood disorders, is well documented. Thus, regulatory elements of G protein function may play a role in the molecular mechanisms underlying these alterations. Phosducin-like proteins, a family of regulators of G protein function expressed throughout brain and body, modulate G protein function by high affinity sequestration of G protein-betagamma subunits, thus impeding G protein-mediated signal transmission by both Galpha and Gbetagamma subunits. An important consequence of Gbetagamma neutralization is the prevention of G protein-coupled receptor kinase phosphorylation resulting in a temporary protection to agonist-bound receptor desensitization. Phosducin-like protein levels were measured in brain cortices of rats chronically treated with one of five classes of antidepressants: imipramine, venlafaxine, maprotiline, citalopram, and moclobemide. None of the antidepressant treatments had any significant effect on phosducin-like protein levels. Phosducin-like protein levels were evaluated in mononuclear leukocytes from a group of 15 patients diagnosed with major depressive episode, both before the initiation of antidepressant treatment and after 4 weeks of antidepressant medication. No protein changes were found in leukocytes of either untreated patients with major depressive disorder or after 4 weeks of the treatment in comparison with healthy volunteers.

The autoinhibitory control of electrically evoked release of [ 3 H]-dopamine and the properties of that induced by nicotinic receptor (nAChR) stimulation were studied in slices of the human neocortex. In both models [ 3 H]-dopamine release was action potential-induced and exocytotic. The selective dopamine D 2 receptor agonist (−)-quinpirole reduced electrically evoked release of [ 3 H]-dopamine, yielding IC 50 and I max values of 23 nM and 76%, respectively. Also, the effects of several other subtype-selective dopamine receptor ligands confirmed that the terminal dopamine autoreceptor belongs to the D 2 subtype. The autoinhibitory feedback control was slightly operative under stimulation conditions of 90 pulses and 3 Hz, with a biophase concentration of endogenous dopamine of 3.6 nM, and was enhanced under blockade of dopamine reuptake. [ 3 H]-dopamine release evoked in an identical manner in mouse neocortical slices was not inhibited by (−)-quinpirole, suggesting the absence of dopamine autoreceptors in this tissue and underlining an important species difference. Also, nAChR stimulation-induced release of [ 3 H]-dopamine revealed a species difference: [ 3 H]-dopamine release was evoked in human, but not in rat neocortical slices. The nAChRs inducing [ 3 H]-dopamine release most probably belong to the α 3 /β 2 -subtype, according to the potencies and efficacies of subtype-selective nAChR ligands. Part of these receptors may be located on glutamatergic neurons.

State-dependent learning (SDL) is a phenomenon in which the retrieval of newly acquired information is possible if the subject is in the same physiological state as during the encoding phase. SDL makes it possible to separate the effects of drugs per se on learning from the effects due to changes in drug state during the task. The present work was designed to investigate whether the antidepressants amitriptyline (30 mg/kg), maprotiline (25 mg/kg), and fluoxetine (15 mg/kg) produce SDL of the inhibitory avoidance conditioning in male and female CD1 mice. In three separate experiments, independent groups were used for each pharmacological treatment and for each sex using a 2 × 2 experimental design. The results do not show SDL in any of the drugs. In the case of amitriptilyline, the data can be attributed to a memorization deficit, while the maprotiline results are interpreted as simultaneously influenced by memorization deficit and performance facilitation due to motor impairment. Fluoxetine treatment did not produce any deteriorating effect on the conditioning. Drugs had some different effects on the performance of males and females, males showing a slightly higher deterioration than females with administration of amitriptyline and maprotiline. This study shows that these antidepressants affect the acquisition/consolidation but not the retrieval process in the inhibitory avoidance learning.

Potentiation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function has been proposed as being useful in the treatment of depression, but thus far, little is known about the possible changes in AMPA receptor expression in the brain, after antidepressant treatment. The present study was carried out to study the expression of AMPA receptor subunits in different brain regions of mice that had been chronically injected with maprotiline. The latter is a modified tricyclic antidepressant that functions as a noradrenaline uptake inhibitor. Daily intraperitoneal injection with 10 mg/kg maprotiline for 30 days resulted in significantly increased GluR1 and GluR2/3 subunit expression in the nucleus accumbens and dorsal striatum as detected by immunohistochemistry; and significantly increased GluR1 and GluR2/3 expression in the hippocampus, as demonstrated by Western blot analysis. No change, or a decrease in GluR2 expression was detected in all the brain regions by both immunohistochemistry and Western blots. The increase in GluR1 and GluR2/3, but no increase in GluR2 subunits suggests that there could be an increase in calcium permeability of AMPA receptors in limbic/striatal brain regions after maprotiline treatment. This could lead to increased synaptic activity or plasticity in the hippocampus and striatum, and may underlie the therapeutic effect of maprotline, and possibly, other antidepressant drugs.

We have synthesized and evaluated several new ligands for imaging the norepinephrine transporter (NET) system in baboons with positron emission tomography (PET). Ligands possessing high brain penetration, high affinity and selectivity, appropriate lipophilicity (log P = 1.0–3.5), high plasma free fraction and reasonable stability in plasma were selected for further studies. Based on our characterization studies in baboons, including 11C-labeled (R)-nisoxetine (Nis), oxaprotiline (Oxap), lortalamine (Lort) and new analogs of methylreboxetine (MRB), in conjunction with our earlier evaluation of 11C and 18F derivatives of reboxetine, MRB and their individual (R,R) and (S,S) enantiomers, we have identified the superiority of (S,S)-[11C]MRB and the suitability of MRB analogs [(S,S)-[11C]MRB > (S,S)-[11C]3-Cl-MRB > (S,S)-[18F]fluororeboxetine] as potential NET ligands for PET. In contrast, Nis, Oxap and Lort displayed high uptake in striatum (higher than in thalamus). The use of these ligands is further limited by high non-specific binding and relatively low specific signal, as is characteristic of many earlier NET ligands. Thus, to our knowledge (S,S)-[11C]MRB remains by far the most promising NET ligand for PET studies.

Clinical research has indicated that antidepressants are efficacious in the treatment of anxiety disorders, especially when repeatedly administered. However, few animal models of anxiety are sensitive to antidepressants, a finding that may be due to procedures limited to acute administrations.The purpose of the present research was to further validate the chick separation-stress paradigm as an animal model of anxiety by examining its sensitivity to the monoamine oxidase inhibitor (MAOI) phenelzine (6.25, 12.5, 25.0 mg/kg), the tricyclic antidepressant (TCA) imipramine (5.0, 10.0, 20.0 mg/kg), the selective serotonin reuptake inhibitor (SSRI) citalopram (1.0, 2.5, 5.0 mg/kg), and the norepinephrine reuptake inhibitor (NRI) maprotiline (5.0, 10.0, 20.0 mg/kg) under acute (no pretreatment) or repeated (3 or 6 days pretreatment) administration procedures.Following any pretreatment, 8-day-old chicks received their respective vehicle or drug probe injection 15 min before tests in either a "mirror" (low stress) or "no mirror" (high stress) condition for a 180-s isolation period. The dependent measures were distress vocalizations to index separation stress and sleep onset latency to index sedation.The model was sensitive to acutely administered phenelzine (MAOI), imipramine (TCA), and maprotiline (NRI), but not citalopram (SSRI) and retained its sensitivity to these drug probes across both repeated administration procedures. None of the drug probes possessed any sedative properties.These results help extend the validity and utility of the chick separation-stress paradigm as an animal model of anxiety by demonstrating its sensitivity to antidepressants under both acute and repeated administration procedures.

In studies on superfused slices obtained from the rat hippocampus, we extracellularly recorded field EPSP (fEPSPs), pharmacologically isolated components of these fEPSP, which were related to activation of synaptic NMDA-glutamate receptors, and neuronal responses of the dentate gyrus, which were mediated by activation of extrasynaptic NMDA-glutamate receptors. Recordings were performed in junctions formed by fibers of the medial perforant pathway and dendrites of granular cells of the gyrus dentatus. In the course of the development of behavioral depression in rats, which was caused by zoosocial isolation or chronic injection of dexamethasone, the amplitude of fEPSPs decreased, on average, by 19.8 and 26.0%, respectively, while the NMDA components of fEPSP increased by 28.6 and 33.4%; the rise in the amplitude of neuronal responses recorded in the gyrus dentatus, which were mediated by the activation of extrasynaptic NMDA receptors (by 75.4 and 92.3%), was clearly expressed. In intact rats, chronic (over 14 days) injections of tricyclic antidepressants, imipramine and amitriptyline, as well as of an atypical antidepressant, maprotiline, resulted in an increase in the fEPSP amplitude by 22.1 to 25.9%. At the same time, the amplitude of NMDA components of fEPSP dropped by 27.0 to 29.1%, while the amplitude of responses mediated by the activation of extrasynaptic NMDA-glutamate receptors decreased by 46.1 to 49.8%. Changes in the neuronal responses in the gyrus dentatus, which were mediated by the activation of NMDA-glutamate receptors, are related to an increase or decrease in the number of such receptors. It is supposed that an increase in the total number of NMDA-glutamate receptors under conditions of behavioral depression results in a deterioration of the energy supply of cerebral neurons, while an increase in the extrasynaptic pool of NMDA-glutamate receptors leads to suppression of biosynthesis of neurotrophins and to injury of neurons. As a general result, informational processes in the brain are subjected to significant negative influences. Chronic injections of antidepressants promote a permanent rise in the concentration of noradrenaline and serotonin in extracellular environments and the activation of monoamine receptors positively conjugated with adenylate cyclase; suppression of expression of informational RNAs, which encode subunits of NMDA-glutamate receptors, and a decrease in the number of these receptors. These events improve the functional state of neurons.

In human neuroblastoma IMR32 cells, the effect of the anti-depressant maprotiline on baseline intracellular Ca 2+ concentrations ([Ca 2+ ] i ) was explored by using the Ca 2+ -sensitive probe fura-2. Maprotiline at concentrations greater than 100 μM caused a rapid rise in [Ca 2+ ] i in a concentration-dependent manner (EC 50 = 200 μM). Maprotiline-induced [Ca 2+ ] i rise was reduced by 50% by removal of extracellular Ca 2+ . Maprotiline-induced [Ca 2+ ] i rises were inhibited by half by nifedipine, but was unaffected by verapamil or diiltiazem. In Ca 2+ -free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca 2+ -ATPase, caused a monophasic [Ca 2+ ] i rise, after which the increasing effect of maprotiline on [Ca 2+ ] i was abolished. U73122, an inhibitor of phospholipase C, did not affect maprotiline-induced [Ca 2+ ] i rises. These findings suggest that in human neuroblastoma cells, maprotiline increases [Ca 2+ ] i by stimulating extracellular Ca 2+ influx and also by causing intracellular Ca 2+ release from the endoplasmic reticulum via a phospholiase C-independent manner.

G protein-activated inwardly rectifying K+ channels (GIRK, also known as Kir3) are activated by various G protein-coupled receptors. GIRK channels play an important role in the inhibitory regulation of neuronal excitability in most brain regions and the heart rate. Modulation of GIRK channel activity may affect many brain functions. Here, we report the inhibitory effects of various antidepressants: imipramine, desipramine, amitriptyline, nortriptyline, clomipramine, maprotiline, and citalopram, on GIRK channels. In Xenopus oocytes injected with mRNAs for GIRK1/GIRK2, GIRK2 or GIRK1/GIRK4 subunits, the various antidepressants tested, except fluvoxamine, zimelidine, and bupropion, reversibly reduced inward currents through the basal GIRK activity at micromolar concentrations. The inhibitions were concentration-dependent with various degrees of potency and effectiveness, but voltage- and time-independent. In contrast, Kir1.1 and Kir2.1 channels in other Kir channel subfamilies were insensitive to all of the drugs. Furthermore, GIRK current responses activated by the cloned A1 adenosine receptor were similarly inhibited by the tricyclic antidepressant desipramine. The inhibitory effects of desipramine were not observed when desipramine was applied intracellularly, and were not affected by extracellular pH, which changed the proportion of the uncharged to protonated desipramine, suggesting its action from the extracellular side. The GIRK currents induced by ethanol were also attenuated in the presence of desipramine. Our results suggest that inhibition of GIRK channels by the tricyclic antidepressants and maprotiline may contribute to some of the therapeutic effects and adverse side effects, especially seizures and atrial arrhythmias in overdose, observed in clinical practice.

The involvement of chronic inhibition of monoamine transporters (MAT) in the brain with respect to sensitization to cocaine- and local anesthetic-induced seizures was studied in mice. Repeated administration of subconvulsive doses of meprylcaine as well as cocaine, both of which inhibit MAT, but not lidocaine, which does not inhibit MAT, increased seizure activity and produced sensitization to other local anesthetics. The effects of five daily treatments of monoamine transporter inhibitors on lidocaine-induced convulsions were examined 2 or 3 days after the last dose of the inhibitors. Daily treatments of GBR 12935, a specific inhibitor of dopamine uptake, significantly increased the incidence and the intensity of lidocaine-induced convulsions at 20 mg/kg and decreased the threshold of the convulsions. Daily treatments of desipramine and maprotiline, selective norepinephrine uptake inhibitors, markedly increased the incidence and intensity of lidocaine-induced convulsions, and decreased the threshold in a dose-dependent manner at between 5 and 20 mg/kg. Daily treatments of citalopram, a selective serotonin uptake inhibitor, at 10 and 20 mg/kg, produced no significant increase in the incidence or intensity of lidocaine-induced convulsions, but decreased the threshold of the convulsions. These results suggest that the chronic intermittent inhibition of monoamine uptake increases susceptibility to cocaine- and local anesthetic-induced seizures, and the norepinephrine transporter is an integral component of this sensitization.

To test whether prolonged uptake blockade can lead to changes in the function of ATP-dependent potassium (K(ATP)) channels we investigated in rat neocortex slices the effects of K(ATP) channel blockers on electrically evoked [(3)H]-noradrenaline ([(3)H]-NA) overflow after short- (45 min) and long-term (210 min) exposure to the NA uptake blockers (+)-oxaprotiline or desipramine (1 microM each). The K(ATP) channel blocker glibenclamide (1 micro M) increased the evoked [(3)H]-NA overflow by 42% after short-term uptake inhibition. This effect was confirmed by tolbutamide and glipizide, two other K(ATP) channel antagonists. The evoked [(3)H]-NA overflow was enhanced by 73% following short-term uptake blockade (15 min) and by 110% following long-term blockade (180 min). After long-term blockade (210 min), however, glibenclamide failed to further enhance the overflow of [(3)H]-NA. The alpha(2)-autoreceptor-mediated feedback control was not involved in the glibenclamide-induced increase in [(3)H]-NA overflow after short-term uptake blockade or in the increase in [(3)H]-NA overflow due to long-term uptake blockade per se. The Na(+)/K(+)-ATPase inhibitor ouabain diminished the glibenclamide-induced enhancement of [(3)H]-NA overflow after short-term uptake blockade, suggesting that an operative Na(+)/K(+)-ATPase is the prerequisite of activation of K(ATP) channels. These results suggest that short-term uptake blockade activates the Na(+)/K(+)-ATPase, thereby reducing intracellular ATP which allows transient opening of K(ATP) channels. Activation of the Na(+)/K(+)-ATPase may increase the Na(+) gradient, probably over the membrane of noradrenergic nerve terminals. The resulting hyperpolarisation leads to inhibition of the evoked overflow which can be reversed, i.e. enhanced, by K(ATP) channel blockers. In contrast, longer lasting uptake blockade seems to reduce the activity of the Na(+)/K(+)-ATPase and hence the consumption of ATP. As a consequence, reduced Na(+) and K(+) gradients may facilitate transmitter release. Closure of K(ATP) channels by accumulating ATP may further promote membrane depolarisation and transmitter release. The unexpected effect of longer exposure to uptake blockers could be somehow related to the clinical time latency of the antidepressant efficacy of monoamine uptake blockers.

The effects of the 5-HT2 receptor antagonist, LY 53857 on the effects of noradrenaline and serotonin reuptake inhibitors were investigated using the forced swimming test. LY 53857 enhanced anti-immobility effects of clomipramine and maprotiline, which can inhibit reuptake of noradrenaline. However, LY 53857 did not affect the immobility time of mice treated with the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine. These results suggest that antagonism of the 5-HT2 receptor leads to potentiation of the antidepressant effects of noradrenaline reuptake inhibitors but not SSRIs and that LY 53857 may modify the activity of noradrenergic neurons.

In the present study, we examined whether chronic exposure of C6BU-1 cells to 100 nM of several different types of antidepressants directly influences serotonin, (5-HT 2A ) receptor-stimulated intracellular Ca 2+ mobilization. Imipramine, desipramine, clomipramine, and maprotiline amplified the 5-HT response at 48, but not at 2, h. Imipramine increased the maximum response to 5-HT without altering the EC 50 of the dose-response curve. This effect was time dependent and cycloheximide blocked the maximal induction, suggesting an essential role for protein synthesis in this process. Previous exposure of the cells to thrombin or isoproterenol did not influence 5-HT 2A receptor function and pretreatment with imipramine did not alter the thrombin- or bradykinin-induced Ca 2+ mobilization, which indicates that the effects of imipramine appear to be specific to the 5-HT 2A receptor. The effect of imipramine was potently suppressed by a calmodulin antagonist, W-13, in a dose-dependent manner. Furthermore, this amplified 5-HT response was blocked by KN-93, but not by H-7. Taken together, these results suggest that imipramine has a modulatory effect on the 5-HT 2A receptor-coupled intracellular Ca 2+ in C6 cells through a calmodulin-dependent pathway, possibly involving Ca 2+ /calmodulin kinase activation.

A number of data support the assumption that antidepressants (ADs) normalize the altered function of the hypothalamic-pituitary-adrenocortical (HPA) system involved in the pathophysiology of depressive disorder via direct effects on glucocorticoid receptors (GRs). In the present study, we examined the tricyclic ADs desipramine (DESI) and imipramine (IMI), the noradrenaline reuptake inhibitor maprotiline (MAPRO), and the noradrenergic and specific serotonergic AD (NaSSA) mirtazapine (MIR) for their effects on GR expression in primary human leukocytes and in monocytic U-937 cells. Semiquantitative RT-PCR indicated that the ADs exert differential effects on GR-mRNA levels in both primary human leukocytes and U-937 cells: whereas MAPRO and IMI did not induce pronounced changes in GR-mRNA levels, DESI and MIR significantly decreased the amounts of GR-mRNA in both cell systems. Further characterization of the effects of MIR revealed a time dependency of the regulation with an initial increase of GR-mRNA levels above control levels after 2.5 h of treatment and a decrease after 4, 24, and 48 h of incubation. A dose-response analysis demonstrated maximal effects of MIR at a concentration of 10(-7) M. Immunohistochemical studies showed that MIR increased the GR protein levels in a time-dependent manner and that this upregulation appeared earlier by additional treatment with dexamethasone (DEX). A translocation of the GR protein from the cytoplasm to the nucleus was induced between 24 and 48 h of treatment with MIR and MIR/DEX, respectively. Taken together, our data further support the assumption that ADs influence the neuroendocrine and immune system via effects on cellular GRs.

Imipramine, mianserine and maprotiline are three widely used antidepressant drugs with different chemical structure. In the present work we have studied the effects of these drugs on the delayed rectifier potassium current (I(K)) in myocytes isolated from rat ventricle. The delayed rectifier potassium current, responsible for action potential termination, is blocked by all of the three drugs I(K)studied in a state-independent manner. Imipramine and mianserine block I(K)in a 1 : 1 drug-receptor interaction, whereas maprotiline shows a negative cooperativity in the interaction between the channel complex and drug molecules.

Background. Anti-inflammatory and immunomodulatory activities have been reported for maprotiline, a strong norepinephrine reuptake inhibitor. In addition, some other antidepressant drugs have shown beneficial effects in experimental colitis. Methods. All the animals were divided into normal and depressed groups. In normal rats colitis was induced by instillation of 2 mL of 4% acetic acid and after 2 hours, maprotiline (10, 20, and 40 mg/kg, i.p.) was administered. In reserpinised depressed rats, depression was induced by injection of reserpine (6 mg/kg, i.p.), 1 h prior to colitis induction, and then treated with maprotiline (10, 20, and 40 mg/kg). Treatment continued daily for four days. Dexamethasone (1 mg/kg, i.p.) was given as a reference drug. On day five following colitis induction, animals were euthanized and distal colons were assessed macroscopically, histologically, and biochemically (assessment of myeloperoxidase activity). Results. Maprotiline significantly improved macroscopic and histologic scores and diminished myeloperoxidase activity in both normal and depressed rats while reserpine exacerbated the colonic damage. Conclusion. Our data suggests that the salutary effects of maprotiline on acetic acid colitis are probably mediated first through depressive behavioral changes that could be mediated through the brain-gut axis and second for the anti-inflammatory effect of the drug.

History and admission findings A 69-year-old somnolent woman developed severe heart failure, aggravated by recurrent episodes of ventricular tachycardia. The patient showed central and peripheral edema. 24 hours earlier, she had suffered cerebral seizures that were successfully terminated by phenytoin. For 13 years, persistent atrial fibrillation had been frequency-controlled with antiarrhythmic drugs (verapamil and glycosides) and treated by oral anticoagulation. In addition, there had been long-term anti-depressant therapy with the tetracyclic agent maprotiline. Investigations Torsade de pointes tachycardia was documented in the electrocardiograms. In addition, the QT interval was extensively prolonged (QTc = 0.70 sec). Neither electrolyte disturbances nor acute cardiac ischemia were seen. Echocardiography revealed a highly reduced ejection fraction of 25 % and a moderately dilated left ventricle. Angiography showed a collateralized occlusion of the right and plaques of the left coronary artery. Treatment and course Repeated torsade de pointes tachycardia resulted in hemodynamic compromise and were terminated by defibrillations. After intravenous magnesium and xylocaine administration as well as with termination of maprotiline and antiarrhythmic co-medication, QT prolongation decreased. In addition, the recurrent torsade de pointes tachycardia stopped. Subsequently, however, there were several bradycardia episodes, QT duration remained long. Accordingly, a VVI pacemaker was implanted. Up to now, the patient is doing well. Conclusions With antidepressant therapy, a risky constellation including comorbidity and interactions with potentially arrhythmogenic drugs may lead to QT prolongation. Medication that delays conduction or causes bradycardia may generally favour torsade de pointes tachycardia. In case of indispensable multi-drug therapy, regular clinical as well as electrocardiographic monitoring with special emphasis on QT interval is mandatory.

We have previously reported that MCI-225, a selective noradrenaline (NA) reuptake inhibitor with serotonin (5-HT) 3 receptor antagonism, shows antidepressant-like properties in experiments using rodents. In this study, we investigated the effect of MCI-225 in anxiety models in comparison with diazepam, ondansetron, maprotiline, imipramine, and trazodone. In social interaction (SI) test in rats, MCI-225 (10 and 30 mg/kg, po), diazepam (1–10 mg/kg, po), and a selective 5-HT 3 receptor antagonist ondansetron (1 mg/kg, po) significantly increased SI to an unfamiliar partner under high light conditions without changes in ambulation. The increase in SI induced by MCI-225 and ondansetron was blocked by a 5-HT 3 agonist, 1-( m -Chlorophenyl)-biguanide (mCPBG, 1 mg/kg, ip), which did not change SI when administered alone. MCI-225 (10 mg/kg, po) showed comparable anxiolytic-like effect between single and 5-day repeated administration. On the other hand, maprotiline, trazodone, and imipramine did not affect SI at doses of 3–30 mg/kg, po. In the elevated plus-maze test in rats, MCI-225 (10–100 mg/kg, po) increased the number of entries into the open arms only, while diazepam increased not only the number of open-arms entries (30 mg/kg, po), but also the total number of entries (10 mg/kg, po). Ondansetron (0.001–1 mg/kg, po) was less effective. Maprotiline, imipramine, and trazodone did not affect the number of open-arm entries, while trazodone and imipramine (100 mg/kg, po) decreased the total number of entries. These results show that MCI-225 has an anxiolytic-like effect without causing sedation and suggest that the 5-HT 3 receptor antagonism of MCI-225 probably contributes to its anxiolytic-like property.

Rationale: A recent study suggested that selective serotonin reuptake inhibitors were inactive in 40-week-old male mice in the mouse forced swimming test, possibly because of alteration of 5-HT1 receptors. Objectives: The present study was aimed at investigating the action of various antidepressant drugs in 4- and 40-week-old male mice using the mouse forced swimming test and determining the involvement of 5-HT1A and 5-HT1B receptors mediating the effects. Methods: Different classes of antidepressants [imipramine (tricyclic), maprotiline (noradrenline reuptake inhibitor), venlafaxine (mixed serotonin and noradrenaline reuptake inhibitors), fluvoxamine and sertraline (selective serotonin reuptake inhibitor)] were tested in the same randomised experimental session, alone and in combination with 5-HT1A and 5-HT1B receptor agonists [buspirone (partial 5-HT1A agonist), anpirtoline (5-HT1B agonist)] in the mouse forced swimming test. Results: All antidepressants were found to be active in the mouse forced swimming test in 4-week-old mice and 40-week-old mice, with the exception of fluvoxamine in the 40-week-old mice. The anti-immobility effect after antidepressant administration was higher in 4-week-old male mice than in 40-week-old male mice. Venlafaxine is the most active antidepressant drug in 40-week-old mice. Prior administration of buspirone (0.06 mg/kg, IP) or anpirtoline (1 mg/kg, IP) enhanced the antidepressant-like effects in 4-week-old mice (except in the case of sertraline, 8 mg/kg). In elderly mice, only prior administration of buspirone enhanced the antidepressant-like effects of fluvoxamine. A neurochemical study showed that significantly higher serotonin and dopamine concentrations were found in 40-week-old control mice brains than 4-week-old control mice brains but that the noradrenaline concentration is higher in 4-week-old mice. Conclusion: Tricyclic, noradrenaline reuptake inhibitors and serotonin reuptake inhibitors are more active in 4-week-old mice than 40-week-old mice. Our results suggested that 5-HT1B receptors may be more altered than 5-HT1A receptors in 40-week-old mice.